Journal Cover Journal of Neuroscience
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   ISSN (Print) 0270-6474 - ISSN (Online) 1529-2401
   Published by Society for Neuroscience Homepage  [2 journals]
  • This Week in The Journal
    • PubDate: 2018-02-28T08:29:57-08:00
      Issue No: Vol. 38, No. 9 (2018)
  • The Axon Initial Segment: An Updated Viewpoint
    • Authors: Leterrier C.
      Pages: 2135 - 2145
      Abstract: At the base of axons sits a unique compartment called the axon initial segment (AIS). The AIS generates and shapes the action potential before it is propagated along the axon. Neuronal excitability thus depends crucially on the AIS composition and position, and these adapt to developmental and physiological conditions. The AIS also demarcates the boundary between the somatodendritic and axonal compartments. Recent studies have brought insights into the molecular architecture of the AIS and how it regulates protein trafficking. This Viewpoints article summarizes current knowledge about the AIS and highlights future challenges in understanding this key actor of neuronal physiology.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.1922-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • A Role for Cellular Prion Protein in Late-Onset Alzheimer's Disease:
           Evidence from Preclinical Studies
    • Authors: Lima-Filho, R. A. S; Oliveira, M. M.
      Pages: 2146 - 2148
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.3307-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • An Interaction between Serotonin Receptor Signaling and Dopamine Enhances
           Goal-Directed Vigor and Persistence in Mice
    • Authors: Bailey, M. R; Goldman, O, Bello, E. P, Chohan, M. O, Jeong, N, Winiger, V, Chun, E, Schipani, E, Kalmbach, A, Cheer, J. F, Balsam, P. D, Simpson, E. H.
      Pages: 2149 - 2162
      Abstract: The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti–depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2088-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Antagonistic Interactions Between Microsaccades and Evidence Accumulation
           Processes During Decision Formation
    • Authors: Loughnane, G. M; Newman, D. P, Tamang, S, Kelly, S. P, O'Connell, R. G.
      Pages: 2163 - 2176
      Abstract: Despite their small size, microsaccades can impede stimulus detections if executed at inopportune times. Although it has been shown that microsaccades evoke both inhibitory and excitatory responses across different visual regions, their impact on the higher-level neural decision processes that bridge sensory responses to action selection has yet to be examined. Here, we show that when human observers monitor stimuli for subtle feature changes, the occurrence of microsaccades long after (up to 800 ms) change onset predicts slower reaction times and this is accounted for by momentary suppression of neural signals at each key stage of decision formation: visual evidence encoding, evidence accumulation, and motor preparation. Our data further reveal that, independent of the timing of the change events, the onset of neural decision formation coincides with a systematic inhibition of microsaccade production, persisting until the perceptual report is executed. Our combined behavioral and neural measures highlight antagonistic interactions between microsaccade occurrence and evidence accumulation during visual decision-making tasks.SIGNIFICANCE STATEMENT When fixating on a location in space, we frequently make tiny eye movements called microsaccades. In the present study, we show that these microsaccades impede our ability to make perceptual decisions about visual stimuli and this impediment specifically occurs via the disruption of several processing levels of the sensorimotor network: the encoding of visual evidence itself, the accumulation of visual evidence toward a response, and effector-selective motor preparation. Furthermore, we show that the production of microsaccades is inhibited during the perceptual decision, possibly as a counteractive measure to mitigate their negative effect on behavior in this context. The combined behavioral and neural measures used in this study provide strong and novel evidence for the interaction of fixational eye movements and the perceptual decision-making process.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2340-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Altered Baseline and Nicotine-Mediated Behavioral and Cholinergic Profiles
           in ChAT-Cre Mouse Lines
    • Authors: Chen, E; Lallai, V, Sherafat, Y, Grimes, N. P, Pushkin, A. N, Fowler, J, Fowler, C. D.
      Pages: 2177 - 2188
      Abstract: The recent development of transgenic rodent lines expressing cre recombinase in a cell-specific manner, along with advances in engineered viral vectors, has permitted in-depth investigations into circuit function. However, emerging evidence has begun to suggest that genetic modifications may introduce unexpected caveats. In the current studies, we sought to extensively characterize male and female mice from both the ChAT(BAC)-Cre mouse line, created with the bacterial artificial chromosome (BAC) method, and ChAT(IRES)-Cre mouse line, generated with the internal ribosome entry site (IRES) method. ChAT(BAC)-Cre transgenic and wild-type mice did not differ in general locomotor behavior, anxiety measures, drug-induced cataplexy, nicotine-mediated hypolocomotion, or operant food training. However, ChAT(BAC)-Cre transgenic mice did exhibit significant deficits in intravenous nicotine self-administration, which paralleled an increase in vesicular acetylcholine transporter and choline acetyltransferase (ChAT) hippocampal expression. For the ChAT(IRES)-Cre line, transgenic mice exhibited deficits in baseline locomotor, nicotine-mediated hypolocomotion, and operant food training compared with wild-type and hemizygous littermates. No differences among ChAT(IRES)-Cre wild-type, hemizygous, and transgenic littermates were found in anxiety measures, drug-induced cataplexy, and nicotine self-administration. Given that increased cre expression was present in the ChAT(IRES)-Cre transgenic mice, as well as a decrease in ChAT expression in the hippocampus, altered neuronal function may underlie behavioral phenotypes. In contrast, ChAT(IRES)-Cre hemizygous mice were more similar to wild-type mice in both protein expression and the majority of behavioral assessments. As such, interpretation of data derived from ChAT-Cre rodents must consider potential limitations dependent on the line and/or genotype used in research investigations.SIGNIFICANCE STATEMENT Altered baseline and/or nicotine-mediated behavioral profiles were discovered in transgenic mice from the ChAT(BAC)-Cre and ChAT(IRES)-Cre lines. Given that these cre-expressing mice have become increasingly used by the scientific community, either independently with chemicogenetic and optogenetic viral vectors or crossed with other transgenic lines, the current studies highlight important considerations for the interpretation of data from previous and future experimental investigations. Moreover, the current findings detail the behavioral effects of either increased or decreased baseline cholinergic signaling mechanisms on locomotor, anxiety, learning/memory, and intravenous nicotine self-administration behaviors.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.1433-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Inhalation Frequency Controls Reformatting of Mitral/Tufted Cell Odor
           Representations in the Olfactory Bulb
    • Authors: Diaz-Quesada, M; Youngstrom, I. A, Tsuno, Y, Hansen, K. R, Economo, M. N, Wachowiak, M.
      Pages: 2189 - 2206
      Abstract: In mammals, olfactory sensation depends on inhalation, which controls activation of sensory neurons and temporal patterning of central activity. Odor representations by mitral and tufted (MT) cells, the main output from the olfactory bulb (OB), reflect sensory input as well as excitation and inhibition from OB circuits, which may change as sniff frequency increases. To test the impact of sampling frequency on MT cell odor responses, we obtained whole-cell recordings from MT cells in anesthetized male and female mice while varying inhalation frequency via tracheotomy, allowing comparison of inhalation-linked responses across cells. We characterized frequency effects on MT cell responses during inhalation of air and odorants using inhalation pulses and also "playback" of sniffing recorded from awake mice. Inhalation-linked changes in membrane potential were well predicted across frequency from linear convolution of 1 Hz responses; and, as frequency increased, near-identical temporal responses could emerge from depolarizing, hyperpolarizing, or multiphasic MT responses. However, net excitation was not well predicted from 1 Hz responses and varied substantially across MT cells, with some cells increasing and others decreasing in spike rate. As a result, sustained odorant sampling at higher frequencies led to increasing decorrelation of the MT cell population response pattern over time. Bulk activation of sensory inputs by optogenetic stimulation affected MT cells more uniformly across frequency, suggesting that frequency-dependent decorrelation emerges from odor-specific patterns of activity in the OB network. These results suggest that sampling behavior alone can reformat early sensory representations, possibly to optimize sensory perception during repeated sampling.SIGNIFICANCE STATEMENT Olfactory sensation in mammals depends on inhalation, which increases in frequency during active sampling of olfactory stimuli. We asked how inhalation frequency can shape the neural coding of odor information by recording from projection neurons of the olfactory bulb while artificially varying odor sampling frequency in the anesthetized mouse. We found that sampling an odor at higher frequencies led to diverse changes in net responsiveness, as measured by action potential output, that were not predicted from low-frequency responses. These changes led to a reorganization of the pattern of neural activity evoked by a given odorant that occurred preferentially during sustained, high-frequency inhalation. These results point to a novel mechanism for modulating early sensory representations solely as a function of sampling behavior.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.0714-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • A Unique Homeostatic Signaling Pathway Links Synaptic Inactivity to
           Postsynaptic mTORC1
    • Authors: Henry, F. E; Wang, X, Serrano, D, Perez, A. S, Carruthers, C. J. L, Stuenkel, E. L, Sutton, M. A.
      Pages: 2207 - 2225
      Abstract: mTORC1-dependent translational control plays a key role in several enduring forms of synaptic plasticity such as long term potentiation (LTP) and mGluR-dependent long term depression. Recent evidence demonstrates an additional role in regulating synaptic homeostasis in response to inactivity, where dendritic mTORC1 serves to modulate presynaptic function via retrograde signaling. Presently, it is unclear whether LTP and homeostatic plasticity use a common route to mTORC1-dependent signaling or whether each engage mTORC1 through distinct pathways. Here, we report a unique signaling pathway that specifically couples homeostatic signaling to postsynaptic mTORC1 after loss of excitatory synaptic input. We find that AMPAR blockade, but not LTP-inducing stimulation, induces phospholipase D (PLD)-dependent synthesis of the lipid second messenger phosphatidic acid (PA) in rat cultured hippocampal neurons of either sex. Pharmacological blockade of PLD1/2 or pharmacogenetic disruption of PA interactions with mTOR eliminates mTORC1 signaling and presynaptic compensation driven by AMPAR blockade, but does not alter mTORC1 activation or functional changes during chemical LTP (cLTP). Overexpression of PLD1, but not PLD2, recapitulates both functional synaptic changes as well as signature cellular adaptations associated with homeostatic plasticity. Finally, transient application of exogenous PA is sufficient to drive rapid presynaptic compensation requiring mTORC1-dependent translation of BDNF in the postsynaptic compartment. These results thus define a unique homeostatic signaling pathway coupling mTORC1 activation to changes in excitatory synaptic drive. Our results further imply that more than one canonical mTORC1 activation pathway may be relevant for the design of novel therapeutic approaches against neurodevelopmental disorders associated with mTORC1 dysregulation.SIGNIFICANCE STATEMENT Homeostatic and Hebbian forms of synaptic plasticity are thought to play complementary roles in regulating neural circuit function, but we know little about how these forms of plasticity are distinguished at the single neuron level. Here, we define a signaling pathway that uniquely links mTORC1 with homeostatic signaling in neurons.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.1843-17.2017
      Issue No: Vol. 38, No. 9 (2018)
  • Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral
           and Type II at Central Nociceptor Terminals
    • Authors: Araldi, D; Khomula, E. V, Ferrari, L. F, Levine, J. D.
      Pages: 2226 - 2245
      Abstract: Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague Dawley rats, the effect of local administration of agents that reverse type I (protein translation) or type II [combination of Src and mitogen-activated protein kinase (MAPK)] priming. At the central terminal, priming induced by systemic, intradermal, or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, but at the peripheral terminal, it was reversed by the protein translation inhibitor. Mu-opioid receptor (MOR) antisense prevented fentanyl hyperalgesia and priming. To determine whether type I and II priming occur in the same population of neurons, we used isolectin B4–saporin or [Sar9, Met(O2)11]-substance P–saporin to deplete nonpeptidergic or peptidergic nociceptors, respectively. Following intrathecal fentanyl, central terminal priming was prevented by both saporins, whereas that in peripheral terminal was not attenuated even by their combination. However, after intradermal fentanyl, priming in the peripheral terminal requires both peptidergic and nonpeptidergic nociceptors, whereas that in the central terminal is dependent only on peptidergic nociceptors. Pretreatment with dantrolene at either terminal prevented fentanyl-induced priming in both terminals, suggesting communication between central and peripheral terminals mediated by intracellular Ca2+ signaling. In vitro application of fentanyl increased cytoplasmic Ca2+ concentration in dorsal root ganglion neurons, which was prevented by pretreatment with dantrolene and naloxone. Therefore, acting at MOR in the nociceptor, fentanyl induces hyperalgesia and priming rapidly at both the central (type II) and peripheral (type I) terminal and this is mediated by Ca2+ signaling.SIGNIFICANCE STATEMENT Fentanyl, acting at the μ-opioid receptor (MOR), induces hyperalgesia and hyperalgesic priming at both the central and peripheral terminal of nociceptors and this is mediated by endoplasmic reticulum Ca2+ signaling. Priming in the central terminal is type II, whereas that in the peripheral terminal is type I. Our findings may provide useful information for the design of drugs with improved therapeutic profiles, selectively disrupting individual MOR signaling pathways, to maintain an adequate long-lasting control of pain.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.3476-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Notch Suppression Collaborates with Ascl1 and Lin28 to Unleash a
           Regenerative Response in Fish Retina, But Not in Mice
    • Authors: Elsaeidi, F; Macpherson, P, Mills, E. A, Jui, J, Flannery, J. G, Goldman, D.
      Pages: 2246 - 2261
      Abstract: Müller glial (MG) cells in the zebrafish retina respond to injury by acquiring retinal stem-cell characteristics. Thousands of gene expression changes are associated with this event. Key among these changes is the induction of Ascl1a and Lin28a, two reprogramming factors whose expression is necessary for retina regeneration. Whether these factors are sufficient to drive MG proliferation and subsequent neuronal-fate specification remains unknown. To test this, we conditionally expressed Ascl1a and Lin28a in the uninjured retina of male and female fish. We found that together, their forced expression only stimulates sparse MG proliferation. However, in combination with Notch signaling inhibition, widespread MG proliferation and neuron regeneration ensued. Remarkably, Ascl1 and Lin28a expression in the retina of male and female mice also stimulated sparse MG proliferation, although this was not enhanced when combined with inhibitors of Notch signaling. Lineage tracing in both fish and mice suggested that the proliferating MG generated multipotent progenitors; however, this process was much more efficient in fish than mice. Overall, our studies suggest that the overexpression of Ascl1a and Lin28a in zebrafish, in combination with inhibition of Notch signaling, can phenocopy the effects of retinal injury in Müller glia. Interestingly, Ascl1 and Lin28a seem to have similar effects in fish and mice, whereas Notch signaling may differ. Understanding the different consequences of Notch signaling inhibition in fish and mice, may suggest additional strategies for enhancing retina regeneration in mammals.SIGNIFICANCE STATEMENT Mechanisms underlying retina regeneration in fish may suggest strategies for stimulating this process in mammals. Here we report that forced expression of Ascl1 and Lin28a can stimulate sparse MG proliferation in fish and mice; however, only in fish does Notch signaling inhibition collaborate with Ascl1a and Lin28a to stimulate widespread MG proliferation in the uninjured retina. Discerning differences in Notch signaling between fish and mice MG may reveal strategies for stimulating retina regeneration in mammals.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2126-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • A Collaborator's Reputation Can Bias Decisions and Anxiety under
    • Authors: Qi, S; Footer, O, Camerer, C. F, Mobbs, D.
      Pages: 2262 - 2269
      Abstract: Informational social influence theory posits that under conditions of uncertainty, we are inclined to look to others for advice. This leaves us remarkably vulnerable to being influenced by others' opinions or advice. Rational agents, however, do not blindly seek and act on arbitrary information, but often consider the quality of its source before committing to a course of action. Here, we ask the question of whether a collaborator's reputation can increase their social influence and, in turn, bias perception and anxiety under changing levels of uncertainty. Human male and female participants were asked to provide estimations of dot direction using the random dot motion (RDM) perceptual discrimination task and were paired with transient collaborators of high or low reputation whom provided their own estimations. The RDM varied in degrees of uncertainty and joint performance accuracy was linked to risk of an electric shock. Despite providing identical information, we show that collaborating with a high reputation compared with a low reputation partner, led to significantly more conformity during the RDM task for uncertain perceptual decisions. Consequently, high reputation partners decreased the subjects' anxiety during the anticipatory shock periods. fMRI data showed that parametric changes in conformity resulted in increased activity in the ventromedial PFC, whereas dissent was associated with increased in activity in the dorsal anterior cingulate cortex (dACC). Furthermore, the dACC and insula, regions involved in anticipatory pain, were significantly more active when collaborating with a low reputation partner. These results suggest that information about reputation can influence both cognitive and affective processes and in turn alter the neural circuits that underlie decision-making and emotion.SIGNIFICANCE STATEMENT Humans look to others for advice when making decisions under uncertainty. Rational agents, however, do not blindly seek information, but often consider the quality of its source before committing to a course of action. Here, we ask the question of whether a collaborators' reputation can increase social influence and in turn bias perception and anxiety in the context of perceptual uncertainty. We show that when subjects are partnered with collaborators with a high reputation, this leads to increased conformity during uncertain perceptual decision-making and reduces anxiety when joint performance accuracy leads to an electric shock. Furthermore, our results show that information about reputation alters the neural circuits that underlie decision-making and emotion.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2337-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Role of Anterior Intralaminar Nuclei of Thalamus Projections to
           Dorsomedial Striatum in Incubation of Methamphetamine Craving
    • Authors: Li, X; Witonsky, K. R, Lofaro, O. M, Surjono, F, Zhang, J, Bossert, J. M, Shaham, Y.
      Pages: 2270 - 2282
      Abstract: Relapse to methamphetamine (Meth) seeking progressively increases after withdrawal from drug self-administration (incubation of Meth craving). We previously demonstrated a role of dorsomedial striatum (DMS) dopamine D1 receptors (D1Rs) in this incubation. Here, we studied the role of afferent glutamatergic projections into the DMS and local D1R–glutamate interaction in this incubation in male rats. We first measured projection-specific activation on day 30 relapse test by using cholera toxin b (retrograde tracer) + Fos (activity marker) double-labeling in projection areas. Next, we determined the effect of pharmacological reversible inactivation of lateral or medial anterior intralaminar nuclei of thalamus (AIT-L or AIT-M) on incubated Meth seeking on withdrawal day 30. We then used an anatomical asymmetrical disconnection procedure to determine whether an interaction between AIT-L->DMS glutamatergic projections and postsynaptic DMS D1Rs contributes to incubated Meth seeking. We also determined the effect of unilateral inactivation of AIT-L and D1R blockade of DMS on incubated Meth seeking, and the effect of contralateral disconnection of AIT-L->DMS projections on nonincubated Meth seeking on withdrawal day 1. Incubated Meth seeking was associated with selective activation of AIT->DMS projections; other glutamatergic projections to DMS were not activated. AIT-L (but not AIT-M) inactivation or anatomical disconnection of AIT-L->DMS projections decreased incubated Meth seeking. Unilateral inactivation of AIT-L or D1R blockade of the DMS had no effect on incubated Meth craving, and contralateral disconnection of AIT-L->DMS projections had no effect on nonincubated Meth seeking. Our results identify a novel role of AIT-L and AIT-L->DMS glutamatergic projections in incubation of drug craving and drug seeking.SIGNIFICANCE STATEMENT Methamphetamine seeking progressively increases after withdrawal from drug self-administration, a phenomenon termed incubation of methamphetamine craving. We previously found that D1R-mediated dopamine transmission in the dorsomedial striatum plays a critical role in this incubation phenomenon. Here, we used neuroanatomical and neuropharmacological methods in rats to demonstrate that an interaction between the glutamatergic projection from the lateral anterior intralaminar nuclei of the thalamus to the dorsomedial striatum and local dopamine D1 receptors plays a critical role in relapse to methamphetamine seeking after prolonged withdrawal. Our study identified a novel motivation-related thalamostriatal projection critical to relapse to drug seeking.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2873-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Prepubertal Development of GABAergic Transmission to
           Gonadotropin-Releasing Hormone (GnRH) Neurons and Postsynaptic Response
           Are Altered by Prenatal Androgenization
    • Authors: Berg, T; Silveira, M. A, Moenter, S. M.
      Pages: 2283 - 2293
      Abstract: Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction through pulsatile GnRH release. Women with polycystic ovary syndrome (PCOS) have persistently elevated luteinizing hormone release frequency, reflecting GnRH release; this exacerbates hyperandrogenemia and disrupted reproductive cycles that are characteristic of this disorder. Clinical evidence suggests that neuroendocrine features of PCOS may manifest peripubertally. Adult mice prenatally exposed to androgens (PNA) mimic several reproductive features of PCOS. GnRH neurons from these mice have increased firing activity and receive increased GABAergic transmission, which is excitatory. When changes emerge during development is unknown. To study the typical postnatal development of GABAergic transmission and the effects of PNA treatment and sex, whole-cell voltage-clamp recordings were made of GABAergic postsynaptic currents (PSCs) in GnRH neurons in brain slices from prepubertal through adult control and PNA female and male mice. GABAergic transmission was present by 1 week of age in females and males and increased in frequency, reaching adult levels at 3 and 4 weeks, respectively. GABAergic PSC frequency was elevated in 3-week-old PNA versus control females. PSC frequency in both controls and PNA mice was activity independent, suggesting that PNA induces changes in synapse organization. PNA also alters the functional response of GnRH neurons to GABA. GABA induced firing in fewer neurons from 3-week-old PNA than control females; membrane potential depolarization induced by GABA was also reduced in cells from PNA mice at this age. PNA thus induces changes during development in the presynaptic organization of the GABAergic network afferent to GnRH neurons as well as the postsynaptic GnRH neuron response, both of which may contribute to adult reproductive dysfunction.SIGNIFICANCE STATEMENT The central neuronal network that regulates reproduction is overactive in polycystic ovary syndrome (PCOS), a leading cause of infertility. Recent evidence of neuroendocrine dysfunction in midpubertal girls suggests that the pathophysiological mechanisms underlying PCOS may arise before pubertal maturation. Prenatal exposure to androgens (PNA) in mice mimics several neuroendocrine features of PCOS. GABAergic transmission to gonadotropin-releasing hormone (GnRH) neurons is important for reproduction and is increased in adult PNA mice. The typical development of this network and when changes with PNA and sex arise relative to puberty are unknown. These studies provide evidence that PNA alters prepubertal development of the GABAergic network afferent to GnRH neurons, including both the presynaptic organization and postsynaptic response. These changes may contribute to reproductive dysfunction in adults.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2304-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Differential Sampling of Visual Space in Ventral and Dorsal Early Visual
    • Authors: Silson, E. H; Reynolds, R. C, Kravitz, D. J, Baker, C. I.
      Pages: 2294 - 2303
      Abstract: A fundamental feature of cortical visual processing is the separation of visual processing for the upper and lower visual fields. In early visual cortex (EVC), the upper visual field is processed ventrally, with the lower visual field processed dorsally. This distinction persists into several category-selective regions of occipitotemporal cortex, with ventral and lateral scene-, face-, and object-selective regions biased for the upper and lower visual fields, respectively. Here, using an elliptical population receptive field (pRF) model, we systematically tested the sampling of visual space within ventral and dorsal divisions of human EVC in both male and female participants. We found that (1) pRFs tend to be elliptical and oriented toward the fovea with distinct angular distributions for ventral and dorsal divisions of EVC, potentially reflecting a radial bias; and (2) pRFs in ventral areas were larger (~1.5x) and more elliptical (~1.2x) than those in dorsal areas. These differences potentially reflect a tendency for receptive fields in ventral temporal cortex to overlap the fovea with less emphasis on precise localization and isotropic representation of space compared with dorsal areas. Collectively, these findings suggest that ventral and dorsal divisions of EVC sample visual space differently, likely contributing to and/or stemming from the functional differentiation of visual processing observed in higher-level regions of the ventral and dorsal cortical visual pathways.SIGNIFICANCE STATEMENT The processing of visual information from the upper and lower visual fields is separated in visual cortex. Although ventral and dorsal divisions of early visual cortex (EVC) are commonly assumed to sample visual space equivalently, we demonstrate systematic differences using an elliptical population receptive field (pRF) model. Specifically, we demonstrate that (1) ventral and dorsal divisions of EVC exhibit diverging distributions of pRF angle, which are biased toward the fovea; and (2) ventral pRFs exhibit higher aspect ratios and cover larger areas than dorsal pRFs. These results suggest that ventral and dorsal divisions of EVC sample visual space differently and that such differential sampling likely contributes to different functional roles attributed to the ventral and dorsal pathways, such as object recognition and visually guided attention, respectively.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2717-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Timescales of Intrinsic BOLD Signal Dynamics and Functional Connectivity
           in Pharmacologic and Neuropathologic States of Unconsciousness
    • Authors: Huang, Z; Liu, X, Mashour, G. A, Hudetz, A. G.
      Pages: 2304 - 2317
      Abstract: Environmental events are processed on multiple timescales via hierarchical organization of temporal receptive windows (TRWs) in the brain. The dependence of neural timescales and TRWs on altered states of consciousness is unclear. States of reduced consciousness are marked by a shift toward slowing of neural dynamics (
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2545-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Dynamic Interactions between Top-Down Expectations and Conscious Awareness
    • Authors: Meijs, E. L; Slagter, H. A, de Lange, F. P, van Gaal, S.
      Pages: 2318 - 2327
      Abstract: It is well known that top–down expectations affect perceptual processes. Yet, remarkably little is known about the relationship between expectations and conscious awareness. We address three crucial outstanding questions: (1) how do expectations affect the likelihood of conscious stimulus perception'; (2) does the brain register violations of expectations nonconsciously'; and (3) do expectations need to be conscious to influence perceptual decisions' Using human participants, we performed three experiments in which we manipulated stimulus predictability within the attentional blink paradigm, while combining visual psychophysics with electrophysiological recordings. We found that valid stimulus expectations increase the likelihood of conscious access of stimuli. Furthermore, our findings suggest a clear dissociation in the interaction between expectations and consciousness: conscious awareness seems crucial for the implementation of top–down expectations, but not for the generation of bottom-up stimulus-evoked prediction errors. These results constrain and update influential theories about the role of consciousness in the predictive brain.SIGNIFICANCE STATEMENT While the relationship between expectations and conscious awareness plays a major role in many prediction-based theories of brain functioning, thus far few empirical studies have examined this relationship. Here, we address this gap in knowledge in a set of three experiments. Our results suggest that the effect of expectations on conscious awareness varies between different steps of the hierarchy of predictive processing. While the active use of top–down expectations for perceptual decisions requires conscious awareness, prediction errors can be triggered outside of conscious awareness. These results constrain and update influential theories about the role of consciousness in the predictive brain.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.1952-17.2017
      Issue No: Vol. 38, No. 9 (2018)
  • Corticosterone Production during Repeated Social Defeat Causes Monocyte
           Mobilization from the Bone Marrow, Glucocorticoid Resistance, and
           Neurovascular Adhesion Molecule Expression
    • Authors: Niraula, A; Wang, Y, Godbout, J. P, Sheridan, J. F.
      Pages: 2328 - 2340
      Abstract: Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged anxiety-like behavior. Physiological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57BL/6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress-induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule intercellular cell adhesion molecule-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression.SIGNIFICANCE STATEMENT Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune, and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2568-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial
           Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid
    • Authors: Arrant, A. E; Onyilo, V. C, Unger, D. E, Roberson, E. D.
      Pages: 2341 - 2358
      Abstract: Loss-of-function mutations in progranulin, a lysosomal glycoprotein, cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency causes CLN11 neuronal ceroid lipofuscinosis (NCL). Progranulin replacement is a rational therapeutic strategy for these disorders, but there are critical unresolved mechanistic questions about a progranulin gene therapy approach, including its potential to reverse existing pathology. Here, we address these issues using an AAV vector (AAV-Grn) to deliver progranulin in Grn–/– mice (both male and female), which model aspects of NCL and FTD pathology, developing lysosomal dysfunction, lipofuscinosis, and microgliosis. We first tested whether AAV-Grn could improve preexisting pathology. Even with treatment after onset of pathology, AAV-Grn reduced lipofuscinosis in several brain regions of Grn–/– mice. AAV-Grn also reduced microgliosis in brain regions distant from the injection site. AAV-expressed progranulin was only detected in neurons, not in microglia, indicating that the microglial activation in progranulin deficiency can be improved by targeting neurons and thus may be driven at least in part by neuronal dysfunction. Even areas with sparse transduction and almost undetectable progranulin showed improvement, indicating that low-level replacement may be sufficiently effective. The beneficial effects of AAV-Grn did not require progranulin binding to sortilin. Finally, we tested whether AAV-Grn improved lysosomal function. AAV-derived progranulin was delivered to the lysosome, ameliorated the accumulation of LAMP-1 in Grn–/– mice, and corrected abnormal cathepsin D activity. These data shed light on progranulin biology and support progranulin-boosting therapies for NCL and FTD due to GRN mutations.SIGNIFICANCE STATEMENT Heterozygous loss-of-function progranulin (GRN) mutations cause frontotemporal dementia (FTD) and homozygous mutations cause neuronal ceroid lipofuscinosis (NCL). Here, we address several mechanistic questions about the potential of progranulin gene therapy for these disorders. GRN mutation carriers with NCL or FTD exhibit lipofuscinosis and Grn–/– mouse models develop a similar pathology. AAV-mediated progranulin delivery reduced lipofuscinosis in Grn–/– mice even after the onset of pathology. AAV delivered progranulin only to neurons, not microglia, but improved microgliosis in several brain regions, indicating cross talk between neuronal and microglial pathology. Its beneficial effects were sortilin independent. AAV-derived progranulin was delivered to lysosomes and corrected lysosomal abnormalities. These data provide in vivo support for the efficacy of progranulin-boosting therapies for FTD and NCL.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.3081-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Age-Dependent Decline in Fate Switch from NG2 Cells to Astrocytes After
           Olig2 Deletion
    • Authors: Zuo, H; Wood, W. M, Sherafat, A, Hill, R. A, Lu, Q. R, Nishiyama, A.
      Pages: 2359 - 2371
      Abstract: NG2 cells are a resident glial progenitor cell population that is uniformly distributed throughout the developing and mature mammalian CNS. Those in the postnatal CNS generate exclusively myelinating and non-myelinating oligodendrocytes and are thus equated with oligodendrocyte precursor cells. Prenatally, NG2 cells in the ventral gray matter of the forebrain generate protoplasmic astrocytes as well as oligodendrocytes. The fate conversion from NG2 cells into protoplasmic astrocytes is dependent on downregulation of the key oligodendrocyte transcription factor Olig2. We showed previously that constitutive deletion of Olig2 in NG2 cells converts NG2 cells in the neocortex into protoplasmic astrocytes at the expense of oligodendrocytes. In this study, we show that postnatal deletion of Olig2 caused NG2 cells in the neocortex but not in other gray matter regions to become protoplasmic astrocytes. However, NG2 cells in the neocortex became more resistant to astrocyte fate switch over the first 3 postnatal weeks. Fewer NG2 cells differentiated into astrocytes and did so with longer latency after Olig2 deletion at postnatal day 18 (P18) compared with deletion at P2. The high-mobility group transcription factor Sox10 was not downregulated for at least 1 month after Olig2 deletion at P18 despite an early transient upregulation of the astrocyte transcription factor NFIA. Furthermore, inhibiting cell proliferation in slice culture reduced astrocyte differentiation from Olig2-deleted perinatal NG2 cells, suggesting that cell division might facilitate nuclear reorganization needed for astrocyte transformation.SIGNIFICANCE STATEMENT NG2 cells are glial progenitor cells that retain a certain degree of lineage plasticity. In the normal postnatal neocortex, they generate mostly oligodendrocyte lineage cells. When the oligodendrocyte transcription factor Olig2 is deleted in NG2 cells in the neocortex, they switch their fate to protoplasmic astrocytes. However, the efficiency of the fate switch decreases with age over the first 3 postnatal weeks and is reduced when cell proliferation is inhibited. As the neocortex matures, sustained expression of the oligodendrocyte lineage-specific key transcription factor Sox10 becomes less dependent on Olig2. Together, our findings suggest a gradual stabilization of the oligodendrocyte lineage genes and loss of lineage plasticity during the first 3 weeks after birth, possibly due to nuclear reorganization.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.0712-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Endoplasmic Reticulum Stress Contributes to the Loss of Newborn
           Hippocampal Neurons after Traumatic Brain Injury
    • Authors: Hood, K. N; Zhao, J, Redell, J. B, Hylin, M. J, Harris, B, Perez, A, Moore, A. N, Dash, P. K.
      Pages: 2372 - 2384
      Abstract: Adult hippocampal neurogenesis has been shown to be required for certain types of cognitive function. For example, studies have shown that these neurons are critical for pattern separation, the ability to store similar experiences as distinct memories. Although traumatic brain injury (TBI) has been shown to cause the loss of newborn hippocampal neurons, the signaling pathway(s) that triggers their death is unknown. Endoplasmic reticulum (ER) stress activates the PERK-eIF2α pathway that acts to restore ER function and improve cell survival. However, unresolved/intense ER stress activates C/EBP homologous protein (CHOP), leading to cell death. We show that TBI causes the death of hippocampal newborn neurons via CHOP. Using CHOP KO mice, we show that loss of CHOP markedly reduces newborn neuron loss after TBI. Injured CHOP mice performed significantly better in a context fear discrimination task compared with injured wild-type mice. In contrast, the PERK inhibitor GSK2606414 exacerbated doublecortin cell loss and worsened contextual discrimination. Administration of guanabenz (which reduces ER stress) to injured male rats reduced the loss of newborn neurons and improved one-trial contextual fear memory. Interestingly, we also found that the surviving newborn neurons in brain-injured animals had dendritic loss, which was not observed in injured CHOP KO mice or in animals treated with guanabenz. These results indicate that ER stress plays a key role in the death of newborn neurons after TBI. Further, these findings indicate that ER stress can alter dendritic arbors, suggesting a role for ER stress in neuroplasticity and dendritic pathologies.SIGNIFICANCE STATEMENT The hippocampus, a structure in the temporal lobe, is critical for learning and memory. The hippocampus is one of only two areas in which neurons are generated in the adult brain. These newborn neurons are required for certain types of memory, and are particularly vulnerable to traumatic brain injury (TBI). However, the mechanism(s) that causes the loss of these cells after TBI is poorly understood. We show that endoplasmic reticulum (ER) stress pathways are activated in newborn neurons after TBI, and that manipulation of the CHOP cascade improves newborn neuron survival and cognitive outcome. These results suggest that treatments that prevent/resolve ER stress may be beneficial in treating TBI-triggered memory dysfunction.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.1756-17.2018
      Issue No: Vol. 38, No. 9 (2018)
  • Saliency Detection as a Reactive Process: Unexpected Sensory Events Evoke
           Corticomuscular Coupling
    • Authors: Novembre, G; Pawar, V. M, Bufacchi, R. J, Kilintari, M, Srinivasan, M, Rothwell, J. C, Haggard, P, Iannetti, G. D.
      Pages: 2385 - 2397
      Abstract: Survival in a fast-changing environment requires animals not only to detect unexpected sensory events, but also to react. In humans, these salient sensory events generate large electrocortical responses, which have been traditionally interpreted within the sensory domain. Here we describe a basic physiological mechanism coupling saliency-related cortical responses with motor output. In four experiments conducted on 70 healthy participants, we show that salient substartle sensory stimuli modulate isometric force exertion by human participants, and that this modulation is tightly coupled with electrocortical activity elicited by the same stimuli. We obtained four main results. First, the force modulation follows a complex triphasic pattern consisting of alternating decreases and increases of force, time-locked to stimulus onset. Second, this modulation occurs regardless of the sensory modality of the eliciting stimulus. Third, the magnitude of the force modulation is predicted by the amplitude of the electrocortical activity elicited by the same stimuli. Fourth, both neural and motor effects are not reflexive but depend on contextual factors. Together, these results indicate that sudden environmental stimuli have an immediate effect on motor processing, through a tight corticomuscular coupling. These observations suggest that saliency detection is not merely perceptive but reactive, preparing the animal for subsequent appropriate actions.SIGNIFICANCE STATEMENT Salient events occurring in the environment, regardless of their modalities, elicit large electrical brain responses, dominated by a widespread "vertex" negative-positive potential. This response is the largest synchronization of neural activity that can be recorded from a healthy human being. Current interpretations assume that this vertex potential reflects sensory processes. Contrary to this general assumption, we show that the vertex potential is strongly coupled with a modulation of muscular activity that follows the same pattern. Both the vertex potential and its motor effects are not reflexive but strongly depend on contextual factors. These results reconceptualize the significance of these evoked electrocortical responses, suggesting that saliency detection is not merely perceptive but reactive, preparing the animal for subsequent appropriate actions.
      PubDate: 2018-02-28T08:29:57-08:00
      DOI: 10.1523/JNEUROSCI.2474-17.2017
      Issue No: Vol. 38, No. 9 (2018)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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