Publisher: Elsevier   (Total: 3200 journals)

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Showing 1 - 200 of 3200 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 42, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 27, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Hybrid Journal   (Followers: 107, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 30, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 47, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 10)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6)
Acta Astronautica     Hybrid Journal   (Followers: 476, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 31, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 5, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 355, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 3, SJR: 1.793, CiteScore: 6)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access   (Followers: 1)
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 9)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 20, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 17, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 208, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 14, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 20, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 31, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 12, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 25, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 35, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 6, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 7)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 15)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 11, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 11, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 27, SJR: 1.562, CiteScore: 3)
Advances in Clinical Radiology     Full-text available via subscription   (Followers: 2)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 21, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 15, SJR: 0.205, CiteScore: 1)
Advances in Cosmetic Surgery     Full-text available via subscription   (Followers: 2)
Advances in Dermatology     Full-text available via subscription   (Followers: 16)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 15)
Advances in Digestive Medicine     Open Access   (Followers: 15)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 8)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 46, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 31, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 10)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 55, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 2)
Advances in Family Practice Nursing     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 70, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 19)
Advances in Genetics     Full-text available via subscription   (Followers: 20, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 12, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 9, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 4, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 41, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 12, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 22, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 17, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 27)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Pathology     Hybrid Journal   (Followers: 1)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Ophthalmology and Optometry     Full-text available via subscription   (Followers: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 19, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 21)
Advances in Pharmacology     Full-text available via subscription   (Followers: 18, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription   (Followers: 1)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 74)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 3, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 7)
Advances in Space Research     Full-text available via subscription   (Followers: 448, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 6)
Advances in Surgery     Full-text available via subscription   (Followers: 12, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 21)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 59, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 418, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 492, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 47, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 60, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 7, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 8, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 12)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 2)
Alexandria Engineering J.     Open Access   (Followers: 3, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 10, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 11, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 60, SJR: 4.66, CiteScore: 10)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 62, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 71, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 53, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 18, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 45, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 36, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 42, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics & Gynecology MFM     Hybrid Journal   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 287, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 71, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 33, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 30, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 41, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 8)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 72, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 28, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 7, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 237, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 14, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)

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Similar Journals
Journal Cover
Neurobiology of Stress
Journal Prestige (SJR): 2.404
Citation Impact (citeScore): 6
Number of Followers: 4  

  This is an Open Access Journal Open Access journal
ISSN (Print) 2352-2895 - ISSN (Online) 2352-2895
Published by Elsevier Homepage  [3200 journals]
  • Cell signaling dependence of rapid glucocorticoid-induced endocannabinoid
           synthesis in hypothalamic neuroendocrine cells

    • Abstract: Publication date: Available online 21 March 2019Source: Neurobiology of StressAuthor(s): Christina Harris, Grant L. Weiss, Shi Di, Jeffrey G. TaskerAbstractGlucocorticoids induce a rapid synthesis of endocannabinoid in hypothalamic neuroendocrine cells by activation of a putative membrane receptor. Somato-dendritically released endocannabinoid acts as a retrograde messenger to suppress excitatory synaptic inputs to corticotropin-releasing hormone-, oxytocin-, and vasopressin-secreting cells. The non-genomic signaling mechanism responsible for rapid endocannabinoid synthesis by glucocorticoids has yet to be fully characterized. Here we manipulated cell signaling molecules pharmacologically using an intracellular approach to elucidate the signaling pathway activated by the membrane glucocorticoid receptor in hypothalamic neuroendocrine cells. We found that rapid glucocorticoid-induced endocannabinoid synthesis in magnocellular neuroendocrine cells requires the sequential activation of multiple kinases, phospholipase C, and intracellular calcium mobilization. While there remain gaps in our understanding, our findings reveal many of the critical players in the rapid glucocorticoid signaling that culminates in the retrograde endocannabinoid modulation of excitatory synaptic transmission.
  • Stress exposures, neurodevelopment and health measures in the ABCD study

    • Abstract: Publication date: Available online 19 March 2019Source: Neurobiology of StressAuthor(s): Elizabeth A. Hoffman, Duncan B. Clark, Natalia Orendain, James Hudziak, Lindsay M. Squeglia, Gayathri J. DowlingAbstractThe Adolescent Brain Cognitive Development (ABCD) Study, a large, longitudinal study of brain development and child health, is uniquely positioned to explore relationships among stress, neurodevelopment, and psychiatric symptomatology, including substance use and addiction. There is much we do not know about how adverse experiences affect the developing brain and cognitive, social, emotional, and academic outcomes. The data collected by the ABCD Study will allow the examination of the relationships among these variables in adolescence, including the effects of stressors (e.g., abuse, neglect, household challenges, parental substance use) on psychological adjustment and other stress responses. A comprehensive protocol that includes physical and mental health, substance use, culture and environment, neurocognitive assessments, biospecimen analyses, and structural and functional neuroimaging will provide opportunities for learning about the impacts of stressors on health and other outcomes in the context of adolescent development. This knowledge could lead to the development of interventions that reduce or even reverse the impacts of stressors.
  • Early life opioid exposure and potential long-term effects

    • Abstract: Publication date: Available online 13 March 2019Source: Neurobiology of StressAuthor(s): Hannah Harder, Anne Z. MurphyAbstractThe long-term consequences of perinatal opioid exposure and subsequent development of neonatal opioid withdrawal syndrome is largely unknown and likely dependent on a multitude of factors, including co-morbid drug use, pre- and post-natal care, and individual factors including the maternal-infant relationship and home environment. This review summarizes the current literature from clinical and preclinical studies on perinatal opioid exposure, focusing on the consequences in the offspring. Although a large number of preclinical studies have been conducted examining the impact of prenatal opioid exposure, the models employed are not necessarily representative of clinical use patterns, making it challenging to translate these results to the impacted population. Use of more clinically-relevant models of perinatal opioid exposure are requisite for the development of improved pharmacological and behavioral treatment strategies to improve quality of life for this vulnerable population.
  • Disaggregating physiological components of cortisol output: A novel
           approach to cortisol analysis in a clinical sample – A
           proof-of-principle study

    • Abstract: Publication date: Available online 7 March 2019Source: Neurobiology of StressAuthor(s): Veronika B. Dobler, Sharon AS. Neufeld, Paul F. Fletcher, Jesus Perez, Naresh Subramaniam, Christoph Teufel, Ian M. GoodyerAbstractAlthough childhood adversity (CA) increases risk for subsequent mental illnesses, developmental mechanisms underpinning this association remain unclear. The hypothalamic-pituitary-adrenal axis (HPAA) is one candidate system potentially linking CA with psychopathology. However, determining developmental effects of CA on HPAA output and differentiating these from effects of current illness has proven difficult. Different aspects of HPAA output are governed by differentiable physiological mechanisms. Disaggregating HPAA output according to its biological components (baseline tonic cortisol, background diurnal variation, phasic stress response) may improve precision of associations with CA and/or psychopathology. In a novel proof-of-principle investigation we test whether different predictors, CA (distal risk factor) and current depressive symptoms, show distinct associations with dissociable HPAA components. A clinical group (aged 16–25) at high-risk for developing severe psychopathology (n = 20) were compared to age and sex matched healthy controls (n = 21). Cortisol was measured at waking (x4), following stress induction (x8), and during a time-environment-matched non-stress condition. Using piecewise multilevel modeling, stress responses were disaggregated into increase and decrease, while controlling for waking cortisol, background diurnal output and confounding variables. Elevated waking cortisol was specifically associated with higher CA scores. Higher non-stress cortisol was specifically associated with higher depressive scores. Following stress induction, depressive symptoms attenuated cortisol increase, whilst CA attenuated cortisol decrease. The results support a differential HPAA dysregulation hypothesis where physiologically dissociable components of HPAA output are differentially associated with distal (CA) or proximal (depressive symptoms) predictors. This proof-of-principle study demonstrates that future cortisol analyses need to disaggregate biologically independent mechanisms of HPAA output.
  • Chronic unpredictable stress promotes cell-specific plasticity in
           prefrontal cortex D1 and D2 pyramidal neurons

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): E.M. Anderson, D. Gomez, A. Caccamise, D. McPhail, M. HearingAbstractExposure to unpredictable environmental stress is widely recognized as a major determinant for risk and severity in neuropsychiatric disorders such as major depressive disorder, anxiety, schizophrenia, and PTSD. The ability of ostensibly unrelated disorders to give rise to seemingly similar psychiatric phenotypes highlights a need to identify circuit-level concepts that could unify diverse factors under a common pathophysiology. Although difficult to disentangle a causative effect of stress from other factors on medial prefrontal cortex (PFC) dysfunction, a wealth of data from humans and rodents demonstrates that the PFC is a key target of stress. The present study sought to identify a model of chronic unpredictable stress (CUS) which induces affective behaviors in C57BL6J mice and once established, measure stress-related alterations in intrinsic excitability and synaptic regulation of mPFC layer 5/6 pyramidal neurons. Adult male mice received 2 weeks of ‘less intense’ stress or 2 or 4 weeks of ‘more intense’ CUS followed by sucrose preference for assessment of anhedonia, elevated plus maze for assessment of anxiety and forced swim test for assessment of depressive-like behaviors. Our findings indicate that more intense CUS exposure results in increased anhedonia, anxiety, and depressive behaviors, while the less intense stress results in no measured behavioral phenotypes. Once a behavioral model was established, mice were euthanized approximately 21 days post-stress for whole-cell patch clamp recordings from layer 5/6 pyramidal neurons in the prelimbic (PrL) and infralimbic (IL) cortices. No significant differences were initially observed in intrinsic cell excitability in either region. However, post-hoc analysis and subsequent confirmation using transgenic mice expressing tdtomato or eGFP under control of dopamine D1-or D2-type receptor showed that D1-expressing pyramidal neurons (D1-PYR) in the PrL exhibit reduced thresholds to fire an action potential (increased excitability) but impaired firing capacity at more depolarized potentials, whereas D2-expressing pyramidal neurons (D2-PYR) showed an overall reduction in excitability and spike firing frequency. Examination of synaptic transmission showed that D1-and D2-PYR exhibit differences in basal excitatory and inhibitory signaling under naïve conditions. In CUS mice, D1-PYR showed increased frequency of both miniature excitatory and inhibitory postsynaptic currents, whereas D2-PYR only showed a reduction in excitatory currents. These findings demonstrate that D1-and D2-PYR subpopulations differentially undergo stress-induced intrinsic and synaptic plasticity that may have functional implications for stress-related pathology, and that these adaptations may reflect unique differences in basal properties regulating output of these cells.
  • Sex differences in stress-related alcohol use

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): MacKenzie R. Peltier, Terril L. Verplaetse, Yann S. Mineur, Ismene L. Petrakis, Kelly P. Cosgrove, Marina R. Picciotto, Sherry A. McKeeAbstractRates of alcohol use disorder (AUD) have increased in women by 84% over the past ten years relative to a 35% increase in men. This substantive increase in female drinking is alarming given that women experience greater alcohol-related health consequences compared to men. Stress is strongly associated with all phases of alcohol addiction, including drinking initiation, maintenance, and relapse for both women and men, but plays an especially critical role for women. The purpose of the present narrative review is to highlight what is known about sex differences in the relationship between stress and drinking. The critical role stress reactivity and negative affect play in initiating and maintaining alcohol use in women is addressed, and the available evidence for sex differences in drinking for negative reinforcement as it relates to brain stress systems is presented. This review discusses the critical structures and neurotransmitters that may underlie sex differences in stress-related alcohol use (e.g., prefrontal cortex, amygdala, norepinephrine, corticotropin releasing factor, and dynorphin), the involvement of sex and stress in alcohol-induced neurodegeneration, and the role of ovarian hormones in stress-related drinking. Finally, the potential avenues for the development of sex-appropriate pharmacological and behavioral treatments for AUD are identified. Overall, women are generally more likely to drink to regulate negative affect and stress reactivity. Sex differences in the onset and maintenance of alcohol use begin to develop during adolescence, coinciding with exposure to early life stress. These factors continue to affect alcohol use into adulthood, when reduced responsivity to stress, increased affect-related psychiatric comorbidities and alcohol-induced neurodegeneration contribute to chronic and problematic alcohol use, particularly for women. However, current research is limited regarding the examination of sex in the initiation and maintenance of alcohol use. Probing brain stress systems and associated brain regions is an important future direction for developing sex-appropriate treatments to address the role of stress in AUD.
  • Drug-induced stress responses and addiction risk and relapse

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Stephanie E. Wemm, Rajita SinhaAbstractA number of studies have assessed the effects of psychoactive drugs on stress biology, the neuroadaptations resulting from chronic drug use on stress biology, and their effects on addiction risk and relapse. This review mainly covers human research on the acute effects of different drugs of abuse (i.e., nicotine, cannabis, psychostimulants, alcohol, and opioids) on the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) responses. We review the literature on acute peripheral stress responses in naïve or light recreational users and binge/heavy or chronic drug users. We also discuss evidence of alterations in tonic levels, or tolerance, in the latter relative to the former and associated changes in the phasic stress responses. We discuss the impact of the stress system tolerance in heavy users on their response to drug- and stress-related cue responses and craving as compared to control subjects. A summary is provided of the effects of glucocorticoid responses and their adaptations on brain striatal and prefrontal cortices involved in the regulation of drug seeking and relapse risk. Finally, we summarize important considerations, including individual difference factors such as gender, co-occurring drug use, early trauma and adversity and drug use history and variation in methodologies, that may further influence the effects of these drugs on stress biology.
  • Child maltreatment and the development of substance use and disorder

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Dante Cicchetti, Elizabeth D. HandleyAbstractChildren who experience maltreatment are at well-documented risk for the development of problematic substance use and disorder in adolescence and beyond. This review applies a developmental psychopathology framework to discuss the complex multilevel probabilistic pathways from child maltreatment to substance use and substance use disorder (SUD). We begin with an overview of the myriad vulnerabilities associated with child maltreatment, including the development of substance use and SUD. Prominent pathways that may potentiate liability for SUD are discussed. Specifically, we highlight the robust empirical support for the prominent externalizing pathway of risk, and also discuss the state of the research regarding the internalizing pathway. Consistent with the developmental psychopathology perspective, we then review biological processes such as neuroendrocrine mechanisms, allostatic load, and neurobiological pathways that may underlie child maltreatment risk, as well as discuss broader contextual issues. Elucidating the processes underlying the development of substance use and disorder among children exposed to this form of early adversity is paramount for not only informing developmental theories, but also designing effective prevention and intervention programs. Thus, implications for preventive interventions are provided. Finally, critical next steps for research within the area of child maltreatment and the developmental psychopathology of substance use and SUD are proffered.
  • Stress and substance use among sexual and gender minority individuals
           across the lifespan

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Mike C. Parent, Andrew S. Arriaga, Teresa Gobble, Lexie WilleAbstractSexual and gender minority (SGM) individuals face marked disparities in substance use. The present narrative review explores research on substance use in SGM communities using a minority stress theory lens. We define the SGM population and minority stress, and explore stresses and substance use disparities in adolescence, adulthood, and older age. Though research on this topic is beginning to highlight the relationship between stress and substance use for SGM individuals, more work is needed on older SGM populations and in translating research findings to effective interventions.
  • The cellular basis of fetal endoplasmic reticulum stress and oxidative
           stress in drug-induced neurodevelopmental deficits

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): S-Y.A. Tsai, Raphael M. Bendriem, Chun-Ting D. LeeAbstractPrenatal substance exposure is a growing public health concern worldwide. Although the opioid crisis remains one of the most prevalent addiction problems in our society, abuse of cocaine, methamphetamines, and other illicit drugs, particularly amongst pregnant women, are nonetheless significant and widespread. Evidence demonstrates prenatal drug exposure can affect fetal brain development and thus can have long-lasting impact on neurobehavioral and cognitive performance later in life. In this review, we highlight research examining the most prevalent drugs of abuse and their effects on brain development with a focus on endoplasmic reticulum stress and oxidative stress signaling pathways. A thorough exploration of drug-induced cellular stress mechanisms during prenatal brain development may provide insight into therapeutic interventions to combat effects of prenatal drug exposure.
  • Effects of hormonal contraceptive phase and progestin generation on
           stress-induced cortisol and progesterone release

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Alexandra Ycaza Herrera, Sophia Faude, Shawn E. Nielsen, Mallory Locke, Mara MatherAbstractThe stress response differs between women using hormonal contraception and naturally cycling women. Yet, despite ample evidence showing that the stress response differs across the menstrual cycle in naturally cycling women, limited work has investigated whether the stress response differs across the hormonal contraceptive cycle, during which synthetic hormones are taken most of the month but not all of it. To induce a stress response, women using hormonal contraception completed the cold pressor test during either the active phase, when hormones are present, or during the inactive phase, when hormones are not present. Saliva was collected and assayed for free cortisol and progesterone levels prior to stress onset, immediately after stress termination, and 15-min post stress onset. Free cortisol and progesterone increased to a similar degree across both hormonal contraceptive phases in response to the cold pressor test. Post-hoc investigation indicates that the progestin “generation” (classification of synthetic progestins based on the compounds they are derived from) can differentially affect the free steroid response to cold pressor test stress, with the largest effects observed in women using formulations containing second-generation progestins. These findings indicate that progestin generation, particularly second-generation progestins, may have a more impactful influence on the stress response than hormonal contraceptive cycle phase. Potential mechanisms driving this effect and need for additional research are discussed.
  • FAAH genotype, CRFR1 genotype, and cortisol interact to predict anxiety in
           an aging, rural Hispanic population: A Project FRONTIER study

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Breanna N. Harris, Zachary P. Hohman, Callie M. Campbell, Kaleb S. King, Cody A. Tucker, the Garrison Institute on AgingAbstractThe neurophysiological underpinnings involved in susceptibility to and maintenance of anxiety are not entirely known. However, two stress-responsive systems, the hypothalamic-pituitary-adrenal axis and the endocannabinoid system, may interact in anxiety. Here, we examine the relationship between FAAH genotype, CRFR1 genotype, baseline cortisol, and state anxiety in a rural adult population using data from Project FRONTIER. We predicted that FAAH A (AA and AC vs CC; rs324420) and three CRFR1 SNP minor alleles (rs7209436 C→ T [minor allele]; rs110402, G → A [minor]; and rs242924 G→ T [minor]), would interact to predict low baseline cortisol and low state anxiety scores. We found partial support for our prediction. In CRFR1 minor carriers, the FAAH AA or AC (vs. CC) genotype was associated with higher cortisol and with lower anxiety. In CRFR1 non-minors, those with FAAH AA or AC (vs. CC) showed decreased cortisol and higher anxiety. These results suggest that FAAH CC genotype only conveys risk for anxiety in individuals who are also carriers of the CRFR1 minor combination. FAAH genotype was significantly associated with baseline cortisol but was not independently associated with anxiety. Contrary to our predictions, baseline cortisol was negatively associated with anxiety. Lastly, we did not find any independent relationships between any of our SNPs and baseline cortisol or anxiety. These data suggest FAAH and cortisol interact to predict state anxiety, but that the relationship depends on CRFR1 genotype. The Project FRONTIER dataset is supported by Texas Tech University Health Sciences Center Garrison Institute on Aging.
  • Sex differences in corticotropin releasing factor regulation of medial
           septum-mediated memory formation

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Kimberly R. Wiersielis, Attilio Ceretti, Arron Hall, Sydney T. Famularo, Madeleine Salvatore, Alexandra S. Ellis, Harah Jang, Mathieu E. Wimmer, Debra A. BangasserAbstractStress can disrupt memory and contribute to cognitive impairments in psychiatric disorders, including schizophrenia and attention deficit hyperactivity disorder. These diseases are more common in men than in women, with men showing greater cognitive impairments. Mnemonic deficits induced by stress are mediated, in part, by corticotropin releasing factor (CRF). However, where CRF is acting to regulate memory, and sex differences therein, is understudied. Here we assessed whether CRF in the medial septum (MS), which projects to the hippocampus, affected memory formation in male and female rats. CRF in the MS did not alter hippocampal-independent object recognition memory, but impaired hippocampal-dependent object location memory in both sexes. Interestingly, males were more sensitive than females to the disruptive effect of a low dose of CRF in the MS. Female resistance was not due to circulating ovarian hormones. However, compared to males, females had higher MS expression of CRF binding protein, which reduces CRF bioavailability and thus may mitigate the effect of the low dose of CRF in females. In contrast, there was no sex difference in CRF1 expression in the MS. Consistent with this finding, CRF1 antagonism blocked the memory impairment caused by the high dose of CRF in the MS in both sexes. Collectively, these results suggest that males are more vulnerable than females to the memory impairments caused by CRF in the MS. In both sexes, CRF1 antagonists prevented MS-mediated memory deficits caused by high levels of CRF, and such levels can result from very stressful events. Thus, CRF1 antagonists may be a viable option for treating cognitive deficits in stressed individuals with psychiatric disorders.
  • Chronic stress produces enduring sex- and region-specific alterations in
           novel stress-induced c-Fos expression

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Kelly M. Moench, Michaela R. Breach, Cara L. WellmanAbstractProlonged or repeated exposure to stress increases risk for a variety of psychological disorders, many of which are marked by dysfunction of corticolimbic brain regions. Notably, women are more likely than men to be diagnosed with these disorders, especially when onset of symptoms follows stressful life events. Using rodent models, investigators have recently begun to elucidate sex-specific changes in the brain and behavior that occur immediately following chronic stress. However, little is known regarding the lasting sequelae of chronic stress, as well as how potential changes may impact responsivity to future stressors. We recently demonstrated that male and female rats show different patterns of dendritic reorganization in medial prefrontal cortex in the days following chronic stress. Here, we examined the immediate and lasting effects of chronic restraint stress (CRS; 3 h/day, 10 days) on neuronal activation, across several corticolimbic brain regions, induced by novel acute stress exposure. Chronically stressed male and female rats were exposed to acute elevated platform stress (EPS) either 1 (CRS-EPS) or 7 (CRS-Rest-EPS) days after CRS. Compared to rats exposed to EPS only, significant reductions in acute stress-induced c-Fos expression were observed in the medial prefrontal cortex, hippocampus, and paraventricular nucleus of the hypothalamus (PVN) in CRS-EPS male rats, some of which persisted to 7 days post-stress. In contrast, we found little modulation of novel stress-induced c-Fos expression in CRS-EPS female rats. However, CRS-Rest-EPS female rats exhibited a significant enhancement of acute stress-induced neuronal activity in the PVN. Together, these data show that prior chronic stress produces sex- and region-specific alterations in novel stress-induced neuronal activation, which are dependent on the presence or absence of a rest period following chronic stress. These findings suggest that the post-stress rest period may give rise to sex-specific neuroadaptations to stress, which may underlie sex differences in stress susceptibility versus resilience.
  • Brain activity associated with social exclusion overlaps with drug-related
           frontal-striatal circuitry in cocaine users: A pilot study

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Colleen A. Hanlon, Erin E. Shannon, Linda J. PorrinoAbstractBackgroundExposure to various types of stress can elevate craving for cocaine and hasten relapse among substance dependent individuals. This investigation evaluated the effects of social exclusion on brain activity in cocaine dependent individuals.MethodForty three individuals (18 crack-cocaine users, 25 controls) were recruited from the community to participate in functional neuroimaging study in which they performed a simulated 3 person ball-tossing game (Cyberball). Each participant was told that the other 2 players were in nearby MRI scanners. Task blocks included: Inclusion (likelihood of our participant receiving the ball = 50%), Exclusion (likelihood gradually decreases to 0%), and Rest. Self-worth variables (e.g self-esteem, locus of control) were measured before and after the ball-tossing game. General linear model-based statistics were used to measure the brain response to inclusion and exclusion within and between the groups with respect to rest.ResultsRelative to controls, cocaine users had significantly more activity during Exclusion versus Inclusion in 3 areas: the right medial frontal gyrus (Brodmann Area 9,10), left ventral lateral frontal gyrus (Brodmann Area 10,47) and right caudate. This was driven by a higher response to social exclusion in the cocaine users. There was no difference between groups in the brain reactivity to social inclusion.ConclusionCocaine dependent individuals have an amplified brain response to social exclusion stress in cortical regions associated with emotional regulation, arousal, craving and perception of physical pain. These data suggest that there may be a neurological basis for the well-established relationship between social stress and addiction.
  • Examining the effect of Early Life Stress on autonomic and endocrine
           indicators of individual stress reactivity

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Luisa Bönke, Sabine Aust, Yan Fan, Katharina Wirth, Elissa Khawli, Amie Stevense, Ana Herrera, Andrea Loayza, Malek Bajbouj, Simone GrimmAbstractEarly life stress (ELS) is associated with altered stress reactivity and an increased risk for the development of psychopathological conditions in later life. However, depending on whether autonomic or endocrine measures were used as indicators of stress reactivity, previous studies reported conflicting findings of either increased or decreased stress reactivity after ELS experience. In the present study we therefore aimed to investigate the effect of ELS on both autonomic and endocrine indicators (heart rate and salivary cortisol) of individual stress reactivity and applied a psychosocial stress task in a sample of healthy participants with and without exposure to mild to moderate ELS. Results showed no significant effects of ELS on autonomic and endocrine indicators of individual stress reactivity. Importantly though, heart rate proved as more sensitive than salivary cortisol with regard to differentiating between stress and control conditions and thereby as a more feasible indicator of an individual's stress reactivity. Accordingly, our data suggest that sole reliance on salivary cortisol as an indicator of stress reactivity might lead to an oversight of more subtle effects of psychosocial stress.
  • Stress matters: Randomized controlled trial on the effect of probiotics on

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): S. Papalini, F. Michels, N. Kohn, J. Wegman, S. van Hemert, K. Roelofs, A. Arias-Vasquez, E. AartsAbstractProbiotics are microorganisms that provide health benefits when consumed. In animals, probiotics reverse gut microbiome-related alterations in depression-like symptoms, in cognition, and in hormonal stress response. However, in humans, a causal understanding of the gut-brain link in emotion and cognition is lacking. Additionally, whether the effects of probiotics on neurocognition are visible only in presence of stress, remains unclear. We investigated the effects of a multispecies probiotic (Ecologic®Barrier) on specific neurocognitive measures of emotion reactivity, emotion regulation, and cognitive control using fMRI. Critically, we also tested whether probiotics can buffer against the detrimental effects of acute stress on working memory. In a double blind, randomized, placebo-controlled, between-subjects intervention study, 58 healthy participants were tested once before and once after a 28-day intervention.Without stress induction, probiotics did not affect brain, behavioral, or related self-report measures. However, relative to placebo, the probiotics group did show a significant stress-related increase in working memory performance after supplementation. This change was associated with intervention-related neural changes in frontal cortex during cognitive control exclusively in the probiotics group. Overall, our results show neurocognitive effects of a multispecies probiotic in healthy women only under challenging situations, buffering against the detrimental effects of stress on cognition.
  • Sex-associated differences in excitability within the bed nucleus of the
           stria terminalis are reflective of cell-type

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Hannah E. Smithers, John R. Terry, Jonathan T. Brown, Andrew D. RandallAbstractThe bed nucleus of the stria terminalis (BNST) is a sexually dimorphic brain region which plays a key role in stress, anxiety, and anxiety-related disorders. Human females have an increased susceptibility to anxiety-related disorders, however the physiological basis of this is not fully understood. Here we examined the effect of the oestrous cycle and sex on the electrophysiological properties of Type I and Type II cells in the anterolateral area of the BNST (BNSTALG) in unstressed animals. There was no significant effect of oestrous cycle on any of the parameters examined in either cell type. Compared to males, the female cohort had lower capacitance in Type I cells while having a higher capacitance in Type II cells. Type II cells also displayed decreased excitability in the female cohort. In order to confirm the effect of these populations on stress and anxiety, a correlation with behaviour on the elevated zero maze was carried out. We observed that increased excitability in Type II neurons correlated with a decrease in anxiety-like behaviour. These sex-specific differences in excitability may contribute to altered susceptibility to anxiety-related disorders.
  • Effect of a multistrain probiotic (Lactoflorene® Plus) on inflammatory
           parameters and microbiota composition in subjects with stress-related

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Sara Soldi, Sara Carlotta Tagliacarne, Chiara Valsecchi, Simone Perna, Mariangela Rondanelli, Luigi Ziviani, Stefano Milleri, Ariella Annoni, Annamaria CastellazziAbstractStress affects the immune system and intestinal microbiota composition and can lead to imbalance between pro- and anti-inflammatory cytokines or to uncontrolled production of cytokines. The effect of emotional stress on secretory IgA levels also indicates that stress decreases mucosal integrity. Our aim was to evaluate whether a probiotic product (Lactoflorene® Plus) can prevent alterations in the immune response associated with self-reported stress and microbiota composition. Healthy adult volunteers who self-reported psychological stress were enrolled and randomised into a placebo and a probiotic group. Salivary stress markers (α-amylase, cortisol, chromogranin A) and immunological parameters (sIgA, NK cell activity, IL-8, IL-10, TNF-α) in feces and the composition of intestinal microbiota were evaluated. Administration of the product did not exert a direct effect on the salivary stress markers or NK cell activity but did reduce abdominal pain and increase faecal IgA and IL-10 levels. The probiotic product induced a moderate increase in Bifidobacterium and Lactobacillus spp., as expected, and in Faecalibacterium spp., and decreased the size of the Dialister spp. and Escherichia and Shigella populations. Administration of the product helped protect the mucosal barrier by supporting the number of short-chain fatty acid producers and decreasing the load of potentially harmful bacteria, thus reducing intestinal inflammation and abdominal discomfort.ClinicalTrials.govNCT03234452.
  • Contextual fear memory modulates PSD95 phosphorylation, AMPAr subunits,
           PKMζ and PI3K differentially between adult and juvenile rats

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Roseanna M. Zanca, Shirley Sanay, Jorge A. Avila, Edgar Rodriguez, Harry N. Shair, Peter A. SerranoAbstractIt is well known that young organisms do not maintain memories as long as adults, but the mechanisms for this ontogenetic difference are undetermined. Previous work has revealed that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr) subunits are trafficked into the synaptic membrane following memory retrieval in adults. Additionally, phosphorylated PSD-95-pS295 promotes AMPAr stabilization at the synapse. We investigated these plasticity related proteins as potential mediators in the differential contextual stress memory retrieval capabilities observed between adult and juvenile rats. Rats were assigned to either pedestal stress (1 h) or no stress control (home cage). Each animal was placed alone in an open field for 5 min at the base of a 6 × 6 sq inch pedestal (4ft high). Stress subjects were then placed on this pedestal for 1hr and control subjects were placed in their home cage following initial exploration. Each animal was returned to the open field for 5 min either 1d or 7d following initial exposure. Freezing postures were quantified during the memory retrieval test. The 1d test shows adult (P90) and juvenile (P26) stressed rats increase their freezing time compared to controls. However, the 7d memory retrieval test shows P90 stress rats but not P26 stress rats freeze while in the fear context. Twenty minutes after the memory retrieval test, hippocampi and amygdala were micro-dissected and prepared for western blot analysis. Our results show that 1d fear memory retrieval induced an upregulation of PSD-95 and pS295 in the adult amygdala but not in the juvenile. However, the juvenile animals upregulated PKMζ, PI3K and GluA2/3, GluA1-S845 in the dorsal hippocampus (DH), but the adults did not. Following the 7d memory retrieval test, adults upregulated GluA2 in the amygdala but not the juveniles. In the DH, adults increased PSD-95 and pS295 but not the juveniles. The adults appear to preferentially increase amygdala-driven processing at 1d and increase DH-driven context specific processing at 7d. These data identify molecular processes that may underlie the reduced fear-memory retrieval capability of juveniles. Together these data provide a potential molecular target that could be beneficial in treatment of anxiety disorders and PTSD.
  • Shared gray matter reductions across alcohol use disorder and
           posttraumatic stress disorder in the anterior cingulate cortex: A dual

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Ruth Klaming, Katia M. Harlé, M. Alejandra Infante, Jessica Bomyea, Charles Kim, Andrea D. SpadoniAbstractThe considerable comorbidity of posttraumatic stress disorder (PTSD) and alcohol use disorders (AUD) poses a greater public health burden than either condition alone. Although there is a substantial body of evidence linking the direct neurotoxic effect of heavy drinking to gray matter (GM) deficits, as well as a growing body of literature supporting a strong association between PTSD and GM alterations, there is scant research interrogating the direct interaction of the two disorders. In order to generate data-driven, specific hypotheses regarding the overlapping neural substrates of PTSD and AUD, we conducted a meta-analysis of GM volumes in each disorder relative to healthy control subjects. We found shared GM deficits in the anterior cingulate cortex (ACC) across both disorders relative to healthy control participants. These findings suggest that reduced volumes of the ACC across PTSD and AUD may have implications for the development, expression, or treatment of symptoms linked to these frequently co-existing disorders. Recommendations are made for future work aimed at delineating the specific and shared effects of traumatic stress and alcoholism on neural integrity.
  • Sleep and circadian rhythm disruption and stress intersect in Alzheimer's

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Trongha X. Phan, Roneil G. MalkaniAbstractAlzheimer's disease (AD) was discovered and the pathological hallmarks were revealed more than a century ago. Subsequently, many remarkable discoveries and breakthroughs provided us with mechanistic insights into the pathogenesis of AD. The identification of the molecular underpinning of the disease not only provided the framework of AD pathogenesis but also targets for therapeutic inventions. Despite all the initial successes, no effective treatment for AD has emerged yet as all the late stages of clinical trials have failed. Many factors ranging from genetic to environmental factors have been critically appraised as the potential causes of AD. In particular, the role of stress on AD has been intensively studied while the relationship between sleep and circadian rhythm disruption (SCRD) and AD have recently emerged. SCRD has always been thought to be a corollary of AD pathologies until recently, multiple lines of evidence converge on the notion that SCRD might be a contributing factor in AD pathogenesis. More importantly, how stress and SCRD intersect and make their concerted contributions to AD phenotypes has not been reviewed. The goal of this literature review is to examine at multiple levels – molecular, cellular (e.g. microglia, gut microbiota) and holistic – how the interaction between stress and SCRD bi-directionally and synergistically exacerbate AD pathologies and cognitive impairment. AD, in turn, worsens stress and SCRD and forms the vicious cycle that perpetuates and amplifies AD.
  • Stress: Influence of sex, reproductive status and gender

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Millie Rincón-Cortés, James P. Herman, Sonia Lupien, Jamie Maguire, Rebecca M. ShanskyAbstractEmerging evidence from the preclinical and human research suggests sex differences in response to different types of stress exposure, and that developmental timing, reproductive status, and biological sex are important factors influencing the degree of HPA activation/function. Here we review data regarding: i) sex differences in behavioral and neural responses to uncontrollable and controllable stressors; ii) distinct trajectories of behavioral development and HPA-axis function in male and female rats following adolescent stress exposure; iii) normative changes in behavior and dopamine function in early postpartum rats; iv) aberrant HPA-axis function and its link to abnormal behaviors in two independent, preclinical mouse models of postpartum depression; and, v) data indicating that gender, in addition to sex, is an important determinant of stress reactivity in humans. Based on these findings, we conclude it will be important for future studies to investigate the short and long-term effects of a wide variety of stressors, how these effects may differ according to developmental timing and in relation to gonadal function, the relationship between aberrant HPA-axis activity during the postpartum and mood disorders, and influences of both sex and gender on stress reactivity in humans.
  • Stress, sensitive periods, and substance abuse

    • Abstract: Publication date: February 2019Source: Neurobiology of Stress, Volume 10Author(s): Susan L. AndersenAbstractResearch on the inter-relationship between drug abuse and social stress has primarily focused on the role of stress exposure during adulthood and more recently, adolescence. Adolescence is a time of heightened reward sensitivity, but it is also a time when earlier life experiences are expressed. Exposure to stress early in postnatal life is associated with an accelerated age of onset for drug use. Lifelong addiction is significantly greater if drug use is initiated during early adolescence. Understanding how developmental changes following stress exposure interact with sensitive periods to unfold over the course of maturation is integral to reducing their later impact on substance use. Arousal levels, gender/sex, inflammation, and the timing of stress exposure play a role in the vulnerability of these circuits. The current review focuses on how early postnatal stress impacts brain development during a sensitive period to increase externalizing and internalizing behaviors in adolescence that include social interactions (aggression; sexual activity), working memory impairment, and depression. How stress effects the developmental trajectories of brain circuits that are associated with addiction are discussed for both clinical and preclinical studies.
  • Elimination of vesicular zinc alters the behavioural and neuroanatomical
           effects of social defeat stress in mice

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Brendan B. McAllister, David K. Wright, Ryan C. Wortman, Sandy R. Shultz, Richard H. DyckAbstractChronic stress can have deleterious effects on mental health, increasing the risk of developing depression or anxiety. But not all individuals are equally affected by stress; some are susceptible while others are more resilient. Understanding the mechanisms that lead to these differing outcomes has been a focus of considerable research. One unexplored mechanism is vesicular zinc – zinc that is released by neurons as a neuromodulator. We examined how chronic stress, induced by repeated social defeat, affects mice that lack vesicular zinc due to genetic deletion of zinc transporter 3 (ZnT3). These mice, unlike wild type mice, did not become socially avoidant of a novel conspecific, suggesting resilience to stress. However, they showed enhanced sensitivity to the potentiating effect of stress on cued fear memory. Thus, the contribution of vesicular zinc to stress susceptibility is not straightforward. Stress also increased anxiety-like behaviour but produced no deficits in a spatial Y-maze test. We found no evidence that microglial activation or hippocampal neurogenesis accounted for the differences in behavioural outcome. Volumetric analysis revealed that ZnT3 KO mice have larger corpus callosum and parietal cortex volumes, and that corpus callosum volume was decreased by stress in ZnT3 KO, but not wild type, mice.
  • A review of nonhuman primate models of early life stress and adolescent
           drug abuse

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Alison G.P. Wakeford, Elyse L. Morin, Sara N. Bramlett, Leonard L. Howell, Mar M. SanchezAbstractAdolescence represents a developmental stage in which initiation of drug use typically occurs and is marked by dynamic neurobiological changes. These changes present a sensitive window during which perturbations to normative development lead to alterations in brain circuits critical for stress and emotional regulation as well as reward processing, potentially resulting in an increased susceptibility to psychopathologies. The occurrence of early life stress (ELS) is related to a greater risk for the development of substance use disorders (SUD) during adolescence. Studies using nonhuman primates (NHP) are ideally suited to examine how ELS may alter the development of neurobiological systems modulating the reinforcing effects of drugs, given their remarkable neurobiological, behavioral, and developmental homologies to humans. This review examines NHP models of ELS that have been used to characterize its effects on sensitivity to drug reinforcement, and proposes future directions using NHP models of ELS and drug abuse in an effort to develop more targeted intervention and prevention strategies for at risk clinical populations.
  • Social defeat stress and escalation of cocaine and alcohol consumption:
           Focus on CRF

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Emily L. Newman, Michael Z. Leonard, Danielle T. Arena, Rosa M.M. de Almeida, Klaus A. MiczekAbstractBoth the ostensibly aversive effects of unpredictable episodes of social stress and the intensely rewarding effects of drugs of abuse activate the mesocorticolimbic dopamine systems. Significant neuroadaptations in interacting stress and reward neurocircuitry may underlie the striking connection between stress and substance use disorders. In rodent models, recurring intermittent exposure to social defeat stress appears to produce a distinct profile of neuroadaptations that translates most readily to the repercussions of social stress in humans. In the present review, preclinical rodent models of social defeat stress and subsequent alcohol, cocaine or opioid consumption are discussed with regard to: (1) the temporal pattern of social defeat stress, (2) male and female protocols of social stress-escalated drug consumption, and (3) the neuroplastic effects of social stress, which may contribute to escalated drug-taking. Neuroadaptations in corticotropin-releasing factor (CRF) and CRF modulation of monoamines in the ventral tegmental area and the bed nucleus of the stria terminalis are highlighted as potential mechanisms underlying stress-escalated drug consumption. However, the specific mechanisms that drive CRF-mediated increases in dopamine require additional investigation as do the stress-induced neuroadaptations that may contribute to the development of compulsive patterns of drug-taking.
  • Neuroendocrine and immune pathways from pre- and perinatal stress to
           substance abuse

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Sarah R. Horn, Leslie E. Roos, Elliot T. Berkman, Philip A. FisherAbstractEarly life adversity is a documented risk factor for substance abuse and addiction. The pre- and perinatal period (i.e., from implantation, through pregnancy, to 6 months of age) is a critical period marked by high biological plasticity and vulnerability, making perinatal stress a particularly robust form of adversity. The neuroendocrine and immune systems are key mechanisms implicated in the transmission of addiction risk. We review animal and human studies that provide preliminary evidence for links between perinatal stress, neuroendocrine and immune dysregulation, and risk for substance abuse and addiction. A translational neuroscience perspective is employed to elucidate pre- and perinatally-induced biological mechanisms linked to addiction and discuss implications for prevention and intervention efforts. Significant evidence supports associations between pre- and perinatal stress and dysregulation of the hypothalamic-pituitary-adrenal axis and immune systems as well as links between neuroendocrine/immune functioning and addiction risk. More work is needed to explicitly examine the interplay between pre- and perinatal stress and neuroendocrine/immune disruptions that together heighten substance abuse risk. Future work is needed to fully understand how pre- and perinatal stress induces biological alterations to predispose individuals to higher risk for addiction. Such knowledge will strengthen theoretically-driven and empirically-supported prevention efforts for substance abuse and addiction.
  • Stress reactivity and the developmental psychopathology of adolescent
           substance use

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Tara M. Chaplin, Claire Niehaus, Stefanie F. GonçalvesAbstractAdolescence represents a period of risk for initiation of substance use and the development of substance use disorders (SUDs). In addition, during adolescence, there is rapid development of stress reactivity systems. This paper describes a conceptual model of the role of stress reactivity in the development of substance use in adolescence. It is proposed that some children develop maladaptive patterns of emotional, physiological, and neural reactivity to stressful situations that are either too high or too low and that their patterns of reactivity interact with increased stressful life events during adolescence to lead to potential for substance use and SUDs. In one pathway, youth develop a heightened reactivity to stress, which leads to high negative emotion and using substances to cope. In a second pathway, youth develop a blunted reactivity to stress, which leads to chronic under-arousal and using substances to increase sensation/arousal. We propose that girls may be more likely to take the high-reactivity pathway to substance use and boys may be more likely to take the low-reactivity pathway. We review existing studies of stress reactivity in adolescents, which support our theory that altered stress reactivity is correlated with and, in some cases, predictive of adolescent substance use, with some studies finding high stress reactivity and some finding low stress reactivity to be correlated with increased substance use and SUD risk. Some studies find that the blunted reactivity pathway to substance use occurs particularly for youth from high-risk contexts. Further, some evidence supports the proposed sex differences in stress reactivity pathways. We discuss future directions and implications of these findings for developing and refining developmentally-sensitive stress reactivity-focused SUD prevention programs.
  • What does the Fos say' Using Fos-based approaches to understand the
           contribution of stress to substance use disorders

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Jayme R. McReynolds, John P. Christianson, Jordan M. Blacktop, John R. MantschAbstractDespite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity that corresponds to stressor-induced drug seeking in rodent relapse models. Much of what we have learned about the mechanisms that mediate stressor-induced relapse has been informed by studies that have used the expression of the immediate early gene, cfos, or its protein product, Fos, as post-mortem activity markers. In this review we provide an overview of the rodent models used to study stressor-induced relapse and briefly summarize what is known about the underlying neurocircuitry before describing the use of cfos/Fos-based approaches. In addition to reviewing findings obtained using this approach, its advantages and limitations are considered. Moreover, new techniques that leverage the expression profile of cfos to tag and manipulate cells based on their activity patterns are discussed. The intent of the review is to guide the interpretation of old and design of new studies that utilize cfos/Fos-based strategies to study the neurocircuitry that contributes to stress-related drug use.
  • Alternations in functional connectivity of amygdalar subregions under
           acute social stress

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Jingjing Chang, Rongjun YuAbstractThe amygdala has long been considered a vital region involved in acute and chronic stress responses. Extensive evidences from animal and human studies suggest that the functional connectivity of amygdalar subnuclei (basolateral amygdala (BLA), centromedial amygdala (CMA) and superficial amygdala (SFA)) undergo specific alterations in stress-related psychopathology. However, whether and how intrinsic functional connectivity within the amygdalar subcomponents is differently altered in the aftermath of an acute stressor remains unknown. In the present study, using a within-subject design, we examined the impact of acute psychological social stress on the functional connectivity of amygdalar subregions at rest. Results showed that stress mainly affected the connectivity pattern of CMA. In particular, in the stress condition compared with the control, the connectivity of CMA to left posterior cingulate cortex and right thalamus was decreased under stress, while the connectivity of CMA to left caudate connectivity was increased at rest post-stressor. The findings suggest that healthy individuals may adapt to threatening surroundings by reducing threatening information input, and shifting to well-learned procedural behaviors.
  • Mapping stress networks using functional magnetic resonance imaging in
           awake animals

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): David Dopfel, Nanyin ZhangAbstractThe neurobiology of stress is studied through behavioral neuroscience, endocrinology, neuronal morphology and neurophysiology. There is a shift in focus toward progressive changes throughout stress paradigms and individual susceptibility to stress that requires methods that allow for longitudinal study design and study of individual differences in stress response. Functional magnetic resonance imaging (fMRI), with the advantages of noninvasiveness and a large field of view, can be used for functionally mapping brain-wide regions and circuits critical to the stress response, making it suitable for longitudinal studies and understanding individual variability of short-term and long-term consequences of stress exposure. In addition, fMRI can be applied to both animals and humans, which is highly valuable in translating findings across species and examining whether the physiology and neural circuits involved in the stress response are conserved in mammals. However, compared to human fMRI studies, there are a number of factors that are essential for the success of fMRI studies in animals. This review discussed the use of fMRI in animal studies of stress. It reviewed advantages, challenges and technical considerations of the animal fMRI methodology as well as recent literature of stress studies using fMRI in animals. It also highlighted the development of combining fMRI with other methods and the future potential of fMRI in animal studies of stress. We conclude that animal fMRI studies, with their flexibility, low cost and short time frame compared to human studies, are crucial to advancing our understanding of the neurobiology of stress.
  • Multimodal canonical correlation reveals converging neural circuitry
           across trauma-related disorders of affect and cognition

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Daniel M. Stout, Monte S. Buchsbaum, Andrea D. Spadoni, Victoria B. Risbrough, Irina A. Strigo, Scott C. Matthews, Alan N. SimmonsAbstractTrauma-related disorders of affect and cognition (TRACs) are associated with a high degree of diagnostic comorbidity, which may suggest that these disorders share a set of underlying neural mechanisms. TRACs are characterized by aberrations in functional and structural circuits subserving verbal memory and affective anticipation. Yet, it remains unknown how the neural circuitry underlying these multiple mechanisms contribute to TRACs. Here, in a sample of 47 combat Veterans, we measured affective anticipation using functional magnetic resonance imaging (fMRI), verbal memory with fluorodeoxyglucose positron emission tomography (FDG-PET), and grey matter volume with structural magnetic resonance imaging (sMRI). Using a voxel-based multimodal canonical correlation analysis (mCCA), the set of neural measures were statistically integrated, or fused, with a set of TRAC symptom measures including mild traumatic brain injury (mTBI), posttraumatic stress, and depression severity. The first canonical correlation pair revealed neural convergence in clusters encompassing the middle frontal gyrus and supplemental motor area, regions implicated in top-down cognitive control and affect regulation. These results highlight the potential of leveraging multivariate neuroimaging analysis for linking neurobiological mechanisms associated with TRACs, paving the way for transdiagnostic biomarkers and targets for treatment.
  • Diminished positive affect and traumatic stress: A biobehavioral review
           and commentary on trauma affective neuroscience

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Gregory A. FonzoAbstractPost-traumatic stress manifests in disturbed affect and emotion, including exaggerated severity and frequency of negative valence emotions, e.g., fear, anxiety, anger, shame, and guilt. However, another core feature of common post-trauma psychopathologies, i.e. post-traumatic stress disorder (PTSD) and major depression, is diminished positive affect, or reduced frequency and intensity of positive emotions and affective states such as happiness, joy, love, interest, and desire/capacity for interpersonal affiliation. There remains a stark imbalance in the degree to which the neuroscience of each affective domain has been probed and characterized in PTSD, with our knowledge of post-trauma diminished positive affect remaining comparatively underdeveloped. This remains a prominent barrier to realizing the clinical breakthroughs likely to be afforded by the increasing availability of neuroscience assessment and intervention tools. In this review and commentary, the author summarizes the modest extant neuroimaging literature that has probed diminished positive affect in PTSD using reward processing behavioral paradigms, first briefly reviewing and outlining the neurocircuitry implicated in reward and positive emotion and its interrelationship with negative emotion and negative valence circuitry. Specific research guidelines are then offered to best and most efficiently develop the knowledge base in this area in a way that is clinically translatable and will exert a positive impact on routine clinical care. The author concludes with the prediction that the development of an integrated, bivalent theoretical and predictive model of how trauma impacts affective neurocircuitry to promote post-trauma psychopathology will ultimately lead to breakthroughs in how trauma treatments are conceptualized mechanistically and developed pragmatically.
  • The potential of calibrated fMRI in the understanding of stress in eating

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Christina E. Wierenga, Jason M. Lavender, Chelsea C. HaysAbstractEating disorders (ED), including Anorexia Nervosa (AN), Bulimia Nervosa (BN), and Binge Eating Disorder (BED), are medically dangerous psychiatric disorders of unknown etiology. Accumulating evidence supports a biopsychosocial model that includes genetic heritability, neurobiological vulnerability, and psychosocial factors, such as stress, in the development and maintenance of ED. Notably, stress hormones influence appetite and eating, and dysfunction of the physiological stress response has been implicated in ED pathophysiology. Stress signals also appear associated with food reward neurocircuitry response in ED, providing a possible mechanism for the role of stress in appetite dysregulation. This paper provides a review of some of the interacting psychological, behavioral, physiological, and neurobiological mechanisms involved in the stress response among individuals with ED, and discusses novel neuroimaging techniques to address potential physiological confounds of studying neural correlates of stress in ED, such as calibrated fMRI.
  • Exercise, the diurnal cycle of cortisol and cognitive impairment in older

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): J. Tortosa-Martínez, C. Manchado, J.M. Cortell-Tormo, I. Chulvi-MedranoAbstractExercise has been shown to reduce the risk of developing Mild Cognitive Impairment and Alzheimer's disease as well as to improve cognition in healthy and cognitively impaired individuals. However, the mechanisms of these benefits are not well understood. The stress hypothesis suggests that the cognitive benefits attributed to exercise may partially be mediated by changes in the cortisol secretion pattern. Chronic stress may increase the risk of AD and exacerbate the cognitive deficits and brain pathology characteristic of the condition while physical activity has been shown to attenuate most of stress consequences and risk factors for AD. Initially, research on the effects of cortisol on cognition and physical activity focused on cortisol levels at one time point but the circadian pattern of cortisol secretion is complex and it is still unclear which aspects are most closely associated with cognitive function. Thus, the aim of this review was to analyze the exercise/stress/cognition hypothesis focusing on the effects of the diurnal cycle of cortisol on cognitive function and physical activity in older adults with and without cognitive impairment.
  • Chronic stress as a risk factor for Alzheimer's disease: Roles of
           microglia-mediated synaptic remodeling, inflammation, and oxidative stress

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Kanchan Bisht, Kaushik Sharma, Marie-Ève TremblayAbstractMicroglia are the predominant immune cells of the central nervous system (CNS) that exert key physiological roles required for maintaining CNS homeostasis, notably in response to chronic stress, as well as mediating synaptic plasticity, learning and memory. The repeated exposure to stress confers a higher risk of developing neurodegenerative diseases including sporadic Alzheimer's disease (AD). While microglia have been causally linked to amyloid beta (Aβ) accumulation, tau pathology, neurodegeneration, and synaptic loss in AD, they were also attributed beneficial roles, notably in the phagocytic elimination of Aβ. In this review, we discuss the interactions between chronic stress and AD pathology, overview the roles played by microglia in AD, especially focusing on chronic stress as an environmental risk factor modulating their function, and present recently-described microglial phenotypes associated with neuroprotection in AD. These microglial phenotypes observed under both chronic stress and AD pathology may provide novel opportunities for the development of better-targeted therapeutic interventions.
  • Leveraging translational neuroscience to inform early intervention and
           addiction prevention for children exposed to early life stress

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Leslie E. Roos, Sarah Horn, Elliot T. Berkman, Katherine Pears, Philip A. FisherAbstractSubstance use and addiction are disproportionately experienced by individuals with a history of exposure to early life stress (ELS), such as maltreatment, domestic violence and parent psychopathology. Unfortunately, extant interventions have mixed effectiveness at improving outcome trajectories for ELS-exposed children, who are often underserved by evidenced-based programs. Here, we employ a translational neuroscience framework to delineate how neuroscience can deepen our understanding of ELS-linked alterations in children's function to inform the development of more targeted, effective early intervention and addiction prevention programs. Candidate neural pathways altered by ELS and linked to addiction are described across sensory, affective, motivational, and executive function domains. Next, we provide an example of the application of translational neuroscience principles in a family of early interventions (i.e. Multidimensional Treatment Foster Care – Preschool, Kids in Transition to School) focused on improving self-regulation in ELS-exposed children. Future directions and areas of unmet need in intervention research detail the significant potential of translational neuroscience to advance interventionists' ability to support positive adjustment in ELS-exposed children and prevent harmful addiction outcomes.
  • The social defeat/overcrowding murine psychosocial stress model results in
           a pharmacologically reversible body weight gain but not depression -
           related behaviours

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Ryan J. Keenan, Jacky Chan, Paul S. Donnelly, Kevin J. Barnham, Laura H. JacobsonAbstractDepression is a highly prevalent psychiatric disorder, yet its etiology is not well understood. The validation of animal models is therefore a critical step towards advancing knowledge about the neurobiology of depression. Psychosocial stress has been promoted as a prospective animal model of depression, however, different protocols exist with variable responses, and further investigations are therefore required. We aimed to characterise the behavioural and body weight responses to the social defeat/overcrowding (SD/OC) model and to explore the effects of the antidepressant fluoxetine and the peroxynitrite scavenger, CuII(atsm), therein. Male C57BL/6JArc mice were exposed to a 19 day SD/OC protocol at two levels of aggression, determined by terminating SD bouts after one, or approximately five social defeat postures. This was followed by a battery of behavioural tests including social interaction test (SIT), locomotor activity (LMA), light-dark box test (LDB), saccharin preference test (SPT) and the forced swim test (FST). Mice were dosed daily with vehicle, fluoxetine (20 mg/kg) or CuII(atsm) (30 mg/kg) throughout the protocol. SD/OC increased body weight compared to controls, which was abolished by fluoxetine and attenuated by CuII(atsm). Weight gain specifically peaked during OC sessions but was not affected by either drug treatment. Fluoxetine reduced the number of defeat postures during fight bouts on some days. SD/OC otherwise failed to elicit depression- or anxiety-like behaviour in the tests measured. These data raise questions over the SD/OC model as an etiological model of depression-related behaviours but highlight the potential of this model for investigations into mechanisms regulating binge eating and weight gain under conditions of chronic social stress.
  • Stress alters social behavior and sensitivity to pharmacological
           activation of kappa opioid receptors in an age-specific manner in Sprague
           Dawley rats

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Elena I. Varlinskaya, Linda Patia Spear, Marvin R. DiazAbstractThe dynorphin/kappa opioid receptor (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adult rodents, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny. Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U-62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U-62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U-62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U-62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development.
  • Contradictory effects of erythropoietin on inhibitory synaptic
           transmission in left and right prelimbic cortex of mice

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Andre Dik, Roja Saffari, Mingyue Zhang, Weiqi ZhangErythropoietin (EPO) has been shown to improve cognitive function in mammals as well as in patients of psychiatric diseases by directly acting on the brain. In addition, EPO attenuates the synaptic transmission and enhances short- and long-term synaptic plasticity in hippocampus of mice, although there are still many discrepancies between different studies. It has been suggested that the divergences of different studies take root in different in-vivo application schemata or in long-term trophic effects of EPO. In the current study, we investigated the direct effects of EPO in slices of prelimbic cortex (PrL) by acute ex-vivo application of EPO, so that the erythropoietic or other trophic effects could be entirely excluded. Our results showed that the EPO effects were contradictory between the left and the right PrL. It enhanced the inhibitory transmission in the left and depressed the inhibitory transmission in the right PrL. Strikingly, this lateralized effect of EPO could be consistently found in individual bi-lateral PrL of all tested mice. Thus, our data suggest that EPO differentially modulates the inhibitory synaptic transmission of neuronal networks in the left and the right PrL. We hypothesize that such lateralized effects of EPO contribute to the development of the lateralization of stress reaction in PFC and underlie the altered bilateral GAGAergic synaptic transmission and oscillation patterns under stress that impact the central emotional and cognitive control in physiology as well as in pathophysiology.Graphical abstractImage 1
  • Neuroendocrine and neuroimmune adaptation to Chronic Escalating Distress
           (CED): A novel model of chronic stress

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Dennis F. Lovelock, Terrence DeakAbstractAcute and chronic stress challenges have a profound influence on the development and expression of subsequent affective disorders, alcohol use disorders, and natural aging processes. These experiments examined adaptation in neuroimmune and neuroendocrine responses that occurred as a result of exposure to a novel model of chronic stress, termed chronic escalating distress (CED). This model involves exposure to highly predictable daily stress challenges involving a systematic escalation in both the intensity and length of daily stress challenges, and has recently been shown to profoundly alter alcohol sensitivity. Male Sprague-Dawley rats were exposed to an 11 day procedure where days 1–5 consisted of 60  min of restraint, days 6–10 consisted of 60  min of restraint immediately followed by 30  min of forced swim, and on day 11 subjects were exposed to a 2 h session of intermittent footshock. Experiment 1 examined adaptation in the corticosterone (CORT) response at key points in the 11 day procedure, and found that the escalation in stressors disrupted habituation to restraint, whereas the CORT response to daily forced swim exposure increased across days. Experiment 2 investigated the impact of this stress paradigm on the expression of several cytokine (IL-1β, IL-6, TNF-α) and cellular activation marker (c-Fos, CD14, CD200R) genes in key brain regions (PVN, HPC, & PFC) known to be influenced by stress. Interestingly, a history of CED had no effect on footshock-induced neuroimmune changes (increased IL-1 in the PVN; increased IL-6 in the HPC and PFC). In addition, acute footshock and CED produced similar c-fos induction within the PVN whereas CED led to enhanced c-fos induction in both the HPC and PFC. These findings support recent work indicating that neuroimmune responses to acute stress challenges persisted in rats with a recent history of repeated stress exposure, and that these effects occurred contemporaneously with ongoing changes in HPA axis reactivity. Overall, this CED model may serve as a highly tractable model for studying adaptation to chronic stress, and may have implications for understanding stress-induced alterations in alcohol sensitivity and natural aging processes.
  • Distinctive stress sensitivity and anxiety-like behavior in female mice:
           Strain differences matter

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Renata Cristina Nunes Marchette, Maíra Assunção Bicca, Evelyn Cristina da Silva Santos, Thereza Christina Monteiro de LimaAbstractEpidemiologic studies have shown that the prevalence of stress-related mood disorders is higher in women, which suggests a different response of neuroendocrine circuits involved in the response to stressful events, as well as a genetic background influence. The aim of this study was to investigate the baseline differences in anxiety-like behaviors of females of two commonly used mice strains. Secondly, we have also aimed to study their behavioral and biochemical alterations following stress. Naïve 3-4 months-old Swiss and C57BL/6 female mice were evaluated in the elevated plus maze (EPM) and in the acoustic startle response (ASR) for anxiety-like behaviors. Besides, an independent group of animals from each strain was exposed to cold-restraint stress (30 min/4 °C, daily) for 21 consecutive days and then evaluated in EPM and in the sucrose consumption tests. Twenty-four hours following behavioral experimentation mice were decapitated and their hippocampi (HP) and cortex (CT) dissected for further Western blotting analysis of glucocorticoid receptor (GR) and glial fibrillary acid protein (GFAP). Subsequent to each behavioral protocol, animal blood samples were collected for further plasma corticosterone analysis. C57BL/6 presented a lower anxiety profile than Swiss female mice in both behavioral tests, EPM and ASR. These phenomena could be correlated with the fact that both strains have distinct corticosterone levels and GR expression in the HP at the baseline level. Moreover, C57BL/6 female mice were more vulnerable to the stress protocol, which was able to induce an anhedonic state characterized by lower preference for a sucrose solution. Behavioral anhedonic-like alterations in these animals coincide with reduced plasma corticosterone accompanied with increased GR and GFAP levels, both in the HP. Our data suggest that in C57BL/6 female mice a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) occurs, in which corticosterone acting on GRs would possibly exert its pro-inflammatory role, ultimately leading to astrocyte activation in response to stress.
  • REM sleep and safety signal learning in posttraumatic stress disorder: A
           preliminary study in military veterans

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Laura D. Straus, Sonya B. Norman, Victoria B. Risbrough, Dean T. Acheson, Sean P.A. DrummondAbstractBackgroundPosttraumatic Stress Disorder (PTSD) is associated with a number of negative physical and mental health consequences. Fear conditioning plays an important mechanistic role in PTSD, and PTSD patients also show deficits in safety signal learning. Sleep, particularly REM sleep, is linked to improved safety learning and extinction processes in animal models and healthy humans. No studies have examined the link between REM sleep and safety signal learning or extinction memory in clinical populations.MethodsThis study examined the relationship between REM sleep, safety signal learning, and extinction processes in veterans with PTSD (n = 13). Patients' overnight sleep was characterized in the laboratory via polysomnography (PSG). The next day, participants underwent a fear conditioning paradigm during which they acquired fear toward a visual cue. This testing session also included a visual cue that became a safety signal (CS-). Following conditioning, the veterans' sleep was monitored overnight again, after which they underwent extinction training. Following a third night of sleep, extinction recall and safety recall were tested. Bivariate correlations examined the relationship between the slope of safety signal learning and subsequent REM sleep, as well as the relationship between REM sleep and subsequent extinction recall and safety recall on the last day of testing.ResultsVeterans learned to differentiate the CS+ and the CS- on the first day of testing. Veterans who underwent safety learning more quickly on the first day of testing showed more efficient REM sleep that night (r = .607, p = .028). On the second day of testing, the patients successfully underwent extinction learning. Patients with a higher percentage of REM sleep on the last night of the study showed more safety recall early on the last day of testing (r = .688, p = .009).ConclusionTo our knowledge, this was the first study to examine the relationship between objective sleep and fear-potentiated startle performance in veterans with PTSD. Study methods were well tolerated by participants, supporting feasibility of the experimental design. Results indicated REM sleep was associated with both initial safety learning and subsequent safety recall. Taken together with previous studies in healthy controls, these preliminary results provide additional evidence suggesting REM sleep could play a mechanistic role in the maintenance of PTSD and thus identify a modifiable biological process to target in treatment of PTSD. These findings should be replicated in larger samples.
  • Effects of high fat or high sucrose diet on behavioral-response to social
           defeat stress in mice

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Deseree M. Eudave, McKenna N. BeLow, Elizabeth I. FlandreauAbstractStress increases risk for psychopathology, and diet may moderate the impact of stress on mental health. A “Western” diet has been linked to psychopathology in humans; animal studies also show that diet can influence negative valence behavior in the presence or absence of stress, but findings are inconsistent. Contradictions in existing studies may result from differences in macronutrient content of diets and presence of metabolic syndrome. The present study exposed mice to 10 days of high fat or high sucrose diet concurrent with social defeat stress exposure and examined negative valence behavior at acute (30 days) time points after stress/diet exposure. Predictably, stress increased negative valence behavior in the social interaction, open field, elevated zero maze, and tail suspension tests at the acute time point. While most stress-induced behaviors normalized after the 30-day recovery period, social avoidance was still highly significant for stress-exposed mice, supporting the hypothesis that avoidance of a trauma-related cue persists beyond non-specific anxiety-like behaviors. Supporting the hypothesis that an unhealthy diet contributes to psychopathology, non-stressed mice fed high fat or high sucrose diets spent less time exploring the center of the open field. This effect was no longer present after a 30-day recovery. Intriguingly, mice previously fed either high fat or high sucrose diets exhibited increased rearing behavior in the elevated zero maze 30 days post stress and diet exposure. This finding could be evidence that short-term diet administration can initiate a long-term increase in risk-assessment behavior.
  • Tauopathy and neurodegeneration: A role for stress

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Jorge A. Sierra-Fonseca, Kristin L. GosselinkAbstractNeurodegenerative diseases are characterized by an irreversible and progressive loss of neuronal structure and function. While many alterations to normal cellular processes occur during neurodegeneration, a pathological accumulation of aggregated proteins constitutes a hallmark of several neurodegenerative disorders. Alzheimer's disease, specifically, is pathologically defined by the formation of amyloid plaques and tangles of hyperphosphorylated tau protein. Stress has emerged as an important factor in the development and progression of neurodegenerative diseases, including Alzheimer's. Very little is known, however, regarding the effects of stress on the mechanisms controlling abnormal protein aggregation and clearance. Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis, causing an excessive secretion of glucocorticoids that are capable of impacting diverse physiological and cellular processes. The present review focuses on the influence of stress on a key feature of Alzheimer's disease pathology, emphasizing the relationship between tau phosphorylation and accumulation and its connection to HPA axis dysfunction.
  • Negative consequences of early-life adversity on substance use as mediated
           by corticotropin-releasing factor modulation of serotonin activity

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Gina L. Forster, Eden M. Anderson, Jamie L. Scholl, Jodi L. Lukkes, Michael J. WattAbstractEarly-life adversity is associated with increased risk for substance abuse in later life, with women more likely to report past and current stress as a mediating factor in their substance use and relapse as compared to men. Preclinical models of neonatal and peri-adolescent (early through late adolescence) stress all support a direct relationship between experiences of early-life adversity and adult substance-related behaviors, and provide valuable information regarding the underlying neurobiology. This review will provide an overview of these animal models and how these paradigms alter drug and alcohol consumption and/or seeking in male and female adults. An introduction to the corticotropin-releasing factor (CRF) and serotonin systems, their development and their interactions at the level of the dorsal raphe will be provided, illustrating how this particular stress system is sexually dimorphic, and is well positioned to be affected by stressors early in development and throughout maturation. A model for CRF-serotonin interactions in the dorsal raphe and how these influence dopaminergic activity within the nucleus accumbens and subsequent reward-associated behaviors will be provided, and alterations to the activity of this system following early-life adversity will be identified. Overall, converging findings suggest that early-life adversity has long-term effects on the functioning of the CRF-serotonin system, highlighting a potentially important and targetable mediator linking stress to addiction. Future work should focus on identifying the exact mechanisms that promote long-term changes to the expression and activity of CRF receptors in the dorsal raphe. Moreover, it is important to clarify whether similar neurobiological mechanisms exist for males and females, given the sexual dimorphism both in CRF receptors and serotonin indices in the dorsal raphe and in the behavioral outcomes of early-life adversity.
  • Early life stress and environmental influences on the neurodevelopment of
           children with prenatal opioid exposure

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Elisabeth Conradt, Sheila E. Crowell, Barry M. LesterAbstractPrenatal opioid exposure has reached epidemic proportions. In the last 10 years, there has been a 242% increase in the number of babies born with the drug withdrawal syndrome known as Neonatal Opioid Withdrawal Syndrome (NOWS). Developmental outcome studies of infants with prenatal opioid exposure are limited by methodological issues including small sample sizes and lack of control for confounding variables such as exposure to poverty and maternal psychopathology. Thus, there is a critical gap in the literature that limits our ability to predict short-term effects of opioid exposure. Here we review direct neurotoxic, indirect, and stress-related pathophysiologies of prenatal opioid exposure. We describe the literature on short and long-term neurodevelopmental outcomes of children with prenatal opioid exposure, highlighting sex differences and the role of early life stress. We conclude by prioritizing avenues for future research for this group of underserved women and their children at risk for neurodevelopmental delays.
  • Anti-stress neuropharmacological mechanisms and targets for addiction
           treatment: A translational framework

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): Mark K. GreenwaldAbstractStress-related substance use is a major challenge for treating substance use disorders. This selective review focuses on emerging pharmacotherapies with potential for reducing stress-potentiated seeking and consumption of nicotine, alcohol, marijuana, cocaine, and opioids (i.e., key phenotypes for the most commonly abused substances). I evaluate neuropharmacological mechanisms in experimental models of drug-maintenance and relapse, which translate more readily to individuals presenting for treatment (who have initiated and progressed). An affective/motivational systems model (three dimensions: valence, arousal, control) is mapped onto a systems biology of addiction approach for addressing this problem. Based on quality of evidence to date, promising first-tier neurochemical receptor targets include: noradrenergic (α1 and β antagonist, α2 agonist), kappa-opioid antagonist, nociceptin antagonist, orexin-1 antagonist, and endocannabinoid modulation (e.g., cannabidiol, FAAH inhibition); second-tier candidates may include corticotropin releasing factor-1 antagonists, serotonergic agents (e.g., 5-HT reuptake inhibitors, 5-HT3 antagonists), glutamatergic agents (e.g., mGluR2/3 agonist/positive allosteric modulator, mGluR5 antagonist/negative allosteric modulator), GABA-promoters (e.g., pregabalin, tiagabine), vasopressin 1b antagonist, NK-1 antagonist, and PPAR-γ agonist (e.g., pioglitazone). To address affective/motivational mechanisms of stress-related substance use, it may be advisable to combine agents with actions at complementary targets for greater efficacy but systematic studies are lacking except for interactions with the noradrenergic system. I note clinically-relevant factors that could mediate/moderate the efficacy of anti-stress therapeutics and identify research gaps that should be pursued. Finally, progress in developing anti-stress medications will depend on use of reliable CNS biomarkers to validate exposure-response relationships.
  • On the safety of repeated ketamine infusions for the treatment of
           depression: Effects of sex and developmental periods

    • Abstract: Publication date: November 2018Source: Neurobiology of Stress, Volume 9Author(s): C.E. Strong, Mohamed KabbajAbstractIn this review, we will discuss the safety of repeated treatments with ketamine for patients with treatment-resistant depression (TRD), a condition in which patients with major depression do not show any clinical improvements following treatments with at least two antidepressant drugs. We will discuss the effects of these treatments in both sexes at different developmental periods. Numerous small clinical studies have shown that a single, low-dose ketamine infusion can rapidly alleviate depressive symptoms and thoughts of suicidality in patients with TRD, and these effects can last for about one week. Interestingly, the antidepressant effects of ketamine can be prolonged with intermittent, repeated infusion regimens and produce more robust therapeutic effects when compared to a single infusion. The safety of such repeated treatments with ketamine has not been thoroughly investigated. Although more studies are needed, some clinical and preclinical reports indicated that repeated infusions of low doses of ketamine may have addictive properties, and suggested that adolescent and adult female subjects may be more sensitive to ketamine's addictive effects. Additionally, during ketamine infusions, many TRD patients report hallucinations and feelings of dissociation and depersonalization, and therefore the effects of repeated treatments of ketamine on cognition must be further examined. Some clinical reports indicated that, compared to women, men are more sensitive to the psychomimetic effects of ketamine. Preclinical studies extended these findings to both adolescent and adult male rodents and showed that male rodents at both developmental periods are more sensitive to ketamine's cognitive-altering effects. Accordingly, in this review we shall focus our discussion on the potential addictive and cognitive-impairing effects of repeated ketamine infusions in both sexes at two important developmental periods: adolescence and adulthood. Although more work about the safety of ketamine is warranted, we hope this review will bring some answers about the safety of treating TRD with repeated ketamine infusions.
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762

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