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Journal of Neuroscience
Journal Prestige (SJR): 4.466
Citation Impact (citeScore): 6
Number of Followers: 253  
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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: 2018-07-11T09:19:43-07:00
      Issue No: Vol. 38, No. 28 (2018)
  • Is Spatial Context Privileged in the Neural Representation of Events'
    • Authors: Dimsdale-Zucker, H. R; Nicholas, J.
      Pages: 6241 - 6243
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0949-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • BMP/SMAD Pathway and the Development of Dopamine Substantia Nigra Neurons
    • Authors: Kouwenhoven, W. M; van Heesbeen, H. J.
      Pages: 6244 - 6246
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0821-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • NOS3 Inhibition Confers Post-Ischemic Protection to Young and Aging White
           Matter Integrity by Conserving Mitochondrial Dynamics and Miro-2 Levels
    • Authors: Bastian, C; Zaleski, J, Stahon, K, Parr, B, McCray, A, Day, J, Brunet, S, Baltan, S.
      Pages: 6247 - 6266
      Abstract: White matter (WM) damage following a stroke underlies a majority of the neurological disability that is subsequently observed. Although ischemic injury mechanisms are age-dependent, conserving axonal mitochondria provides consistent post-ischemic protection to young and aging WM. Nitric oxide synthase (NOS) activation is a major cause of oxidative and mitochondrial injury in gray matter during ischemia; therefore, we used a pure WM tract, isolated male mouse optic nerve, to investigate whether NOS inhibition provides post-ischemic functional recovery by preserving mitochondria. We show that pan-NOS inhibition applied before oxygen-glucose deprivation (OGD) promotes functional recovery of young and aging axons and preserves WM cellular architecture. This protection correlates with reduced nitric oxide (NO) generation, restored glutathione production, preserved axonal mitochondria and oligodendrocytes, and preserved ATP levels. Pan-NOS inhibition provided post-ischemic protection to only young axons, whereas selective inhibition of NOS3 conferred post-ischemic protection to both young and aging axons. Concurrently, genetic deletion of NOS3 conferred long-lasting protection to young axons against ischemia. OGD upregulated NOS3 levels in astrocytes, and we show for the first time that inhibition of NOS3 generation in glial cells prevents axonal mitochondrial fission and restores mitochondrial motility to confer protection to axons by preserving Miro-2 levels. Interestingly, NOS1 inhibition exerted post-ischemic protection selectively to aging axons, which feature age-dependent mechanisms of oxidative injury in WM. Our study provides the first evidence that inhibition of glial NOS activity confers long-lasting benefits to WM function and structure and suggests caution in defining the role of NO in cerebral ischemia at vascular and cellular levels.SIGNIFICANCE STATEMENT White matter (WM) injury during stroke is manifested as the subsequent neurological disability in surviving patients. Aging primarily impacts CNS WM and mechanisms of ischemic WM injury change with age. Nitric oxide is involved in various mitochondrial functions and we propose that inhibition of glia-specific nitric oxide synthase (NOS) isoforms promotes axon function recovery by preserving mitochondrial structure, function, integrity, and motility. Using electrophysiology and three-dimensional electron microscopy, we show that NOS3 inhibition provides a common target to improve young and aging axon function, whereas NOS1 inhibition selectively protects aging axons when applied after injury. This study provides the first evidence that inhibition of glial cell NOS activity confers long-lasting benefits to WM structure and function.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.3017-17.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Reorganization of Destabilized Nodes of Ranvier in {beta}IV Spectrin
           Mutants Uncovers Critical Timelines for Nodal Restoration and Prevention
           of Motor Paresis
    • Authors: Saifetiarova, J; Shi, Q, Paukert, M, Komada, M, Bhat, M. A.
      Pages: 6267 - 6282
      Abstract: Disorganization of nodes of Ranvier is associated with motor and sensory dysfunctions. Mechanisms that allow nodal recovery during pathological processes remain poorly understood. A highly enriched nodal cytoskeletal protein βIV spectrin anchors and stabilizes the nodal complex to actin cytoskeleton. Loss of murine βIV spectrin allows the initial nodal organization, but causes gradual nodal destabilization. Mutations in human βIV spectrin cause auditory neuropathy and impairment in motor coordination. Similar phenotypes are caused by nodal disruption due to demyelination. Here we report on the precise timelines of nodal disorganization and reorganization by following disassembly and reassembly of key nodal proteins in βIV spectrin mice of both sexes before and after βIV spectrin re-expression at specifically chosen developmental time points. We show that the timeline of nodal restoration has different outcomes in the PNS and CNS with respect to nodal reassembly and functional restoration. In the PNS, restoration of nodes occurs within 1 month regardless of the time of βIV spectrin re-expression. In contrast, the CNS nodal reorganization and functional restoration occurs within a critical time window; after that, nodal reorganization diminishes, leading to less efficient motor recovery. We demonstrate that timely restoration of nodes can improve both the functional properties and the ultrastructure of myelinated fibers affected by long-term nodal disorganization. Our studies, which indicate a critical timeline for nodal restoration together with overall motor performance and prolonged life span, further support the idea that nodal restoration is more beneficial if initiated before any axonal damage, which is critically relevant to demyelinating disorders.SIGNIFICANCE STATEMENT Nodes of Ranvier are integral to efficient and rapid signal transmission along myelinated fibers. Various demyelinating disorders are characterized by destabilization of the nodal molecular complex, accompanied by severe reduction in nerve conduction and the onset of motor and sensory dysfunctions. This study is the first to report in vivo reassembly of destabilized nodes with sequential improvement in overall motor performance. Our study reveals that nodal restoration is achievable before any axonal damage, and that long-term nodal destabilization causes irreversible axonal structural changes that prevent functional restoration. Our studies provide significant insights into timely restoration of nodal domains as a potential therapeutic approach in treatment of demyelinating disorders.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0515-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Homeostatic Feedback Modulates the Development of Two-State Patterned
           Activity in a Model Serotonin Motor Circuit in Caenorhabditis elegans
    • Authors: Ravi, B; Garcia, J, Collins, K. M.
      Pages: 6283 - 6298
      Abstract: Neuron activity accompanies synapse formation and maintenance, but how early circuit activity contributes to behavior development is not well understood. Here, we use the Caenorhabditis elegans egg-laying motor circuit as a model to understand how coordinated cell and circuit activity develops and drives a robust two-state behavior in adults. Using calcium imaging in behaving animals, we find the serotonergic hermaphrodite-specific neurons (HSNs) and vulval muscles show rhythmic calcium transients in L4 larvae before eggs are produced. HSN activity in L4 is tonic and lacks the alternating burst-firing/quiescent pattern seen in egg-laying adults. Vulval muscle activity in L4 is initially uncoordinated but becomes synchronous as the anterior and posterior muscle arms meet at HSN synaptic release sites. However, coordinated muscle activity does not require presynaptic HSN input. Using reversible silencing experiments, we show that neuronal and vulval muscle activity in L4 is not required for the onset of adult behavior. Instead, the accumulation of eggs in the adult uterus renders the muscles sensitive to HSN input. Sterilization or acute electrical silencing of the vulval muscles inhibits presynaptic HSN activity and reversal of muscle silencing triggers a homeostatic increase in HSN activity and egg release that maintains ~12–15 eggs in the uterus. Feedback of egg accumulation depends upon the vulval muscle postsynaptic terminus, suggesting that a retrograde signal sustains HSN synaptic activity and egg release. Our results show that egg-laying behavior in C. elegans is driven by a homeostat that scales serotonin motor neuron activity in response to postsynaptic muscle feedback.SIGNIFICANCE STATEMENT The functional importance of early, spontaneous neuron activity in synapse and circuit development is not well understood. Here, we show in the nematode Caenorhabditis elegans that the serotonergic hermaphrodite-specific neurons (HSNs) and postsynaptic vulval muscles show activity during circuit development, well before the onset of adult behavior. Surprisingly, early activity is not required for circuit development or the onset of adult behavior and the circuit remains unable to drive egg laying until fertilized embryos are deposited into the uterus. Egg accumulation potentiates vulval muscle excitability, but ultimately acts to promote burst firing in the presynaptic HSNs which results in egg laying. Our results suggest that mechanosensory feedback acts at three distinct steps to initiate, sustain, and terminate C. elegans egg-laying circuit activity and behavior.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.3658-17.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Single-Trial Phase Entrainment of Theta Oscillations in Sensory Regions
           Predicts Human Associative Memory Performance
    • Authors: Wang, D; Clouter, A, Chen, Q, Shapiro, K. L, Hanslmayr, S.
      Pages: 6299 - 6309
      Abstract: Episodic memories are rich in sensory information and often contain integrated information from different sensory modalities. For instance, we can store memories of a recent concert with visual and auditory impressions being integrated in one episode. Theta oscillations have recently been implicated in playing a causal role synchronizing and effectively binding the different modalities together in memory. However, an open question is whether momentary fluctuations in theta synchronization predict the likelihood of associative memory formation for multisensory events. To address this question we entrained the visual and auditory cortex at theta frequency (4 Hz) and in a synchronous or asynchronous manner by modulating the luminance and volume of movies and sounds at 4 Hz, with a phase offset at 0° or 180°. EEG activity from human subjects (both sexes) was recorded while they memorized the association between a movie and a sound. Associative memory performance was significantly enhanced in the 0° compared with the 180° condition. Source-level analysis demonstrated that the physical stimuli effectively entrained their respective cortical areas with a corresponding phase offset. The findings suggested a successful replication of a previous study (Clouter et al., 2017). Importantly, the strength of entrainment during encoding correlated with the efficacy of associative memory such that small phase differences between visual and auditory cortex predicted a high likelihood of correct retrieval in a later recall test. These findings suggest that theta oscillations serve a specific function in the episodic memory system: binding the contents of different modalities into coherent memory episodes.SIGNIFICANCE STATEMENT How multisensory experiences are bound to form a coherent episodic memory representation is one of the fundamental questions in human episodic memory research. Evidence from animal literature suggests that the relative timing between an input and theta oscillations in the hippocampus is crucial for memory formation. We precisely controlled the timing between visual and auditory stimuli and the neural oscillations at 4 Hz using a multisensory entrainment paradigm. Human associative memory formation depends on coincident timing between sensory streams processed by the corresponding brain regions. We provide evidence for a significant role of relative timing of neural theta activity in human episodic memory on a single-trial level, which reveals a crucial mechanism underlying human episodic memory.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0349-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Dominant Neuropeptide Cotransmission in Kisspeptin-GABA Regulation of GnRH
           Neuron Firing Driving Ovulation
    • Authors: Piet, R; Kalil, B, McLennan, T, Porteous, R, Czieselsky, K, Herbison, A. E.
      Pages: 6310 - 6322
      Abstract: A population of kisspeptin-GABA coexpressing neurons located in the rostral periventricular area of the third ventricle (RP3V) is believed to activate gonadotropin-releasing hormone (GnRH) neurons to generate the luteinizing hormone (LH) surge triggering ovulation. Selective optogenetic activation of RP3V kisspeptin (RP3VKISS) neurons in female mice for >30 s and ≥10 Hz in either a continuous or bursting mode was found to reliably generate a delayed and long-lasting activation of GnRH neuron firing in brain slices. Optogenetic activation of RP3VKISS neurons in vivo at 10 Hz generated substantial increments in LH secretion of similar amplitude to the endogenous LH surge. Studies using GABAA receptor antagonists and optogenetic activation of RP3V GABA (RP3VGABA) neurons in vitro revealed that low-frequency (2 Hz) stimulation generated immediate and transient GABAA receptor-mediated increases in GnRH neuron firing, whereas higher frequencies (10 Hz) recruited the long-lasting activation observed following RP3VKISS neuron stimulation. In vivo, 2 Hz activation of RP3VGABA neurons did not alter LH secretion, whereas 10 Hz stimulation evoked a sustained large increase in LH identical to RP3VKISS neuron activation. Optogenetic activation of RP3VKISS neurons in which kisspeptin had been deleted did not alter LH secretion. These studies demonstrate the presence of parallel transmission streams from RP3V neurons to GnRH neurons that are frequency dependent and temporally distinct. This comprises a rapid and transient GABAA receptor-mediated activation and a slower onset kisspeptin-mediated stimulation of long duration. At the time of the LH surge, GABA release appears to be functionally redundant with the neuropeptide kisspeptin being the dominant cotransmitter influencing GnRH neuron output.SIGNIFICANCE STATEMENT Miscommunication between the brain and ovaries is thought to represent a major cause of infertility in humans. Studies in rodents suggest that a population of neurons located in the rostral periventricular area of the third ventricle (RP3V) are critical for activating the gonadotropin-releasing hormone (GnRH) neurons that trigger ovulation. The present study provides evidence that an RP3V neuron population coexpressing kisspeptin and GABA provides a functionally important excitatory input to GnRH neurons at the time of ovulation. This neural input releases GABA and/or kisspeptin in the classical frequency dependent and temporally distinct nature of amino acid-neuropeptide cotransmission. Unusually, however, the neuropeptide stream is found to be functionally dominant in activating GnRH neurons at the time of ovulation.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0658-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Hand Motor Recovery Following Extensive Frontoparietal Cortical Injury Is
           Accompanied by Upregulated Corticoreticular Projections in Monkey
    • Authors: Darling, W. G; Ge, J, Stilwell-Morecraft, K. S, Rotella, D. L, Pizzimenti, M. A, Morecraft, R. J.
      Pages: 6323 - 6339
      Abstract: We tested the hypothesis that arm/hand motor recovery after injury of the lateral sensorimotor cortex is associated with upregulation of the corticoreticular projection (CRP) from the supplementary motor cortex (M2) to the gigantocellular reticular nucleus of the medulla (Gi). Three groups of rhesus monkeys of both genders were studied: five controls, four cases with lesions of the arm/hand area of the primary motor cortex (M1) and the lateral premotor cortex (LPMC; F2 lesion group), and five cases with lesions of the arm/hand area of M1, LPMC, S1, and anterior parietal cortex (F2P2 lesion group). CRP strength was assessed using high-resolution anterograde tracers injected into the arm/hand area of M2 and stereology to estimate of the number of synaptic boutons in the Gi. M2 projected bilaterally to the Gi, primarily targeting the medial Gi subsector and, to a lesser extent, lateral, dorsal, and ventral subsectors. Total CRP bouton numbers were similar in controls and F2 lesion cases but F2P2 lesion cases had twice as many boutons as the other two groups (p = 0.0002). Recovery of reaching and fine hand/digit function was strongly correlated with estimated numbers of CRP boutons in the F2P2 lesion cases. Because we previously showed that F2P2 lesion cases experience decreased strength of the M2 corticospinal projection (CSP), whereas F2 lesion monkeys experienced increased strength of the M2 CSP, these results suggest one mechanism underlying arm/hand motor recovery after F2P2 injury is upregulation of the M2 CRP. This M2-CRP response may influence an important reticulospinal tract contribution to upper-limb motor recovery following frontoparietal injury.SIGNIFICANCE STATEMENT We previously showed that after brain injury affecting the lateral motor cortex controlling arm/hand motor function, recovery is variable and closely associated with increased strength of corticospinal projection (CSP) from an uninjured medial cortical motor area. Hand motor recovery also varies after brain injury affecting the lateral sensorimotor cortex, but medial motor cortex CSP strength decreases and cannot account for recovery. Here we observed that motor recovery following sensorimotor cortex injury is closely associated with increased strength of the descending projection from an uninjured medial cortical motor area to a brainstem reticular nucleus involved in control of arm/hand function, suggesting an enhanced corticoreticular projection may compensate for injury to the sensorimotor cortex to enable recovery of arm/hand motor function.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0403-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Brain Circuits Mediating Opposing Effects on Emotion and Pain
    • Authors: Cai, Y.-Q; Wang, W, Paulucci-Holthauzen, A, Pan, Z. Z.
      Pages: 6340 - 6349
      Abstract: The amygdala is important for processing emotion, including negative emotion such as anxiety and depression induced by chronic pain. Although remarkable progress has been achieved in recent years on amygdala regulation of both negative (fear) and positive (reward) behavioral responses, our current understanding is still limited regarding how the amygdala processes and integrates these negative and positive emotion responses within the amygdala circuits. In this study with optogenetic stimulation of specific brain circuits, we investigated how amygdala circuits regulate negative and positive emotion behaviors, using pain as an emotional assay in male rats. We report here that activation of the excitatory pathway from the parabrachial nucleus (PBN) that relays peripheral pain signals to the central nucleus of amygdala (CeA) is sufficient to cause behaviors of negative emotion including anxiety, depression, and aversion in normal rats. In strong contrast, activation of the excitatory pathway from basolateral amygdala (BLA) that conveys processed corticolimbic signals to CeA dramatically opposes these behaviors of negative emotion, reducing anxiety and depression, and induces behavior of reward. Surprisingly, activating the PBN–CeA pathway to simulate pain signals does not change pain sensitivity itself, but activating the BLA–CeA pathway inhibits basal and sensitized pain. These findings demonstrate that the pain signal conveyed through the PBN–CeA pathway is sufficient to drive negative emotion and that the corticolimbic signal via the BLA–CeA pathway counteracts the negative emotion, suggesting a top-down brain mechanism for cognitive control of negative emotion under stressful environmental conditions such as pain.SIGNIFICANCE STATEMENT It remains unclear how the amygdala circuits integrate both negative and positive emotional responses and the brain circuits that link peripheral pain to negative emotion are largely unknown. Using optogenetic stimulation, this study shows that the excitatory projection from the parabrachial nucleus to the central nucleus of amygdala (CeA) is sufficient to drive behaviors of negative emotion including anxiety, depression, and aversion in rats. Conversely, activation of the excitatory projection from basolateral amygdala to CeA counteracts each of these behaviors of negative emotion. Thus, this study identifies a brain pathway that mediates pain-driven negative emotion and a brain pathway that counteracts these emotion behaviors in a top-down mechanism for brain control of negative emotion.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.2780-17.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Comparison of Decision-Related Signals in Sensory and Motor Preparatory
           Responses of Neurons in Area LIP
    • Authors: Shushruth, S; Mazurek, M, Shadlen, M. N.
      Pages: 6350 - 6365
      Abstract: Neurons in the lateral intraparietal (LIP) area of Macaques exhibit both sensory and oculomotor preparatory responses. During perceptual decision making, the preparatory responses have been shown to track the state of the evolving evidence leading to the decision. The sensory responses are known to reflect categorical properties of visual stimuli, but it is not known whether these responses also track evolving evidence. We recorded neural responses from lateral intraparietal area of 2 female rhesus monkeys during a direction discrimination task. We compared sensory and oculomotor-preparatory responses in the same neurons when either the discriminandum (random dot motion) or an eye movement choice-target was in the neuron's response field. The neural responses in both configurations reflected the strength and direction of motion and were correlated with the animal's choice, albeit more prominently when the choice-target was in the response field. However, the variance and autocorrelation pattern of only the motor preparatory responses reflected the process of evidence accumulation. Simulations suggest that the task related activity of sensory responses could be inherited through lateral interactions with neurons that are carrying evidence accumulation signals in their motor-preparatory responses. The results are consistent with the proposal that evolving decision processes are supported by persistent neural activity in the service of actions or intentions, as opposed to high-order representations of stimulus properties.SIGNIFICANCE STATEMENT Perceptual decision making is the process of choosing an appropriate motor action based on perceived sensory information. Association areas of the cortex play an important role in this sensory-motor transformation. The neurons in these areas show both sensory- and motor-related activity. We show here that, in the macaque parietal association area LIP, signatures of the process of evidence accumulation that underlies the decisions are predominantly reflected in the motor-related activity. This finding supports the proposal that perceptual decision making is implemented in the brain as a process of choosing between available motor actions rather than as a process of representing the properties of the sensory stimulus.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0668-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Monoamines Inhibit GABAergic Neurons in Ventrolateral Preoptic Area That
           Make Direct Synaptic Connections to Hypothalamic Arousal Neurons
    • Authors: Saito, Y. C; Maejima, T, Nishitani, M, Hasegawa, E, Yanagawa, Y, Mieda, M, Sakurai, T.
      Pages: 6366 - 6378
      Abstract: The hypothalamus plays an important role in the regulation of sleep/wakefulness states. While the ventrolateral preoptic nucleus (VLPO) plays a critical role in the initiation and maintenance of sleep, the lateral posterior part of the hypothalamus contains neuronal populations implicated in maintenance of arousal, including orexin-producing neurons (orexin neurons) in the lateral hypothalamic area (LHA) and histaminergic neurons in the tuberomammillary nucleus (TMN). During a search for neurons that make direct synaptic contact with histidine decarboxylase-positive (HDC+), histaminergic neurons (HDC neurons) in the TMN and orexin neurons in the LHA of male mice, we found that these arousal-related neurons are heavily innervated by GABAergic neurons in the preoptic area including the VLPO. We further characterized GABAergic neurons electrophysiologically in the VLPO (GABAVLPO neurons) that make direct synaptic contact with these hypothalamic arousal-related neurons. These neurons (GABAVLPO->HDC or GABAVLPO->orexin neurons) were both potently inhibited by noradrenaline and serotonin, showing typical electrophysiological characteristics of sleep-promoting neurons in the VLPO. This work provides direct evidence of monosynaptic connectivity between GABAVLPO neurons and hypothalamic arousal neurons and identifies the effects of monoamines on these neuronal pathways.SIGNIFICANCE STATEMENT Rabies-virus-mediated tracing of input neurons of two hypothalamic arousal-related neuron populations, histaminergic and orexinergic neurons, showed that they receive similar distributions of input neurons in a variety of brain areas, with rich innervation by GABAergic neurons in the preoptic area, including the ventrolateral preoptic area (VLPO), a region known to play an important role in the initiation and maintenance of sleep. Electrophysiological experiments found that GABAergic neurons in the VLPO (GABAVLPO neurons) that make direct input to orexin or histaminergic neurons are potently inhibited by noradrenaline and serotonin, suggesting that these monoamines disinhibit histamine and orexin neurons. This work demonstrated functional and structural interactions between GABAVLPO neurons and hypothalamic arousal-related neurons.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.2835-17.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Causal Evidence for Mnemonic Metacognition in Human Precuneus
    • Authors: Ye, Q; Zou, F, Lau, H, Hu, Y, Kwok, S. C.
      Pages: 6379 - 6387
      Abstract: Metacognition is the capacity to introspectively monitor and control one's own cognitive processes. Previous anatomical and functional neuroimaging findings implicated the important role of the precuneus in metacognition processing, especially during mnemonic tasks. However, the issue of whether this medial parietal cortex is a domain-specific region that supports mnemonic metacognition remains controversial. Here, we focally disrupted this parietal area with repetitive transcranial magnetic stimulation in healthy human participants of both sexes, seeking to ascertain its functional necessity for metacognition in memory versus perceptual decisions. Perturbing precuneal activity selectively impaired metacognitive efficiency of temporal-order memory judgment, but not perceptual discrimination. Moreover, the correlation in individuals' metacognitive efficiency between domains disappeared when the precuneus was perturbed. Together, these findings provide evidence reinforcing the notion that the precuneal region plays an important role in mediating metacognition of episodic memory retrieval.SIGNIFICANCE STATEMENT Theories on the neural basis of metacognition have thus far been largely centered on the role of the prefrontal cortex. Here we refined the theoretical framework through characterizing a unique precuneal involvement in mnemonic metacognition with a noninvasive but inferentially powerful method: transcranial magnetic stimulation. By quantifying metacognitive efficiency across two distinct domains (memory vs perception) that are matched for stimulus characteristics, we reveal an instrumental role of the precuneus in mnemonic metacognition. This causal evidence corroborates ample clinical reports that parietal lobe lesions often produce inaccurate self-reports of confidence in memory recollection and establish the precuneus as a nexus for the introspective ability to evaluate the success of memory judgment in humans.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0660-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • {alpha}2{delta}-1 Is Essential for Sympathetic Output and NMDA Receptor
           Activity Potentiated by Angiotensin II in the Hypothalamus
    • Authors: Ma, H; Chen, S.-R, Chen, H, Li, L, Li, D.-P, Zhou, J.-J, Pan, H.-L.
      Pages: 6388 - 6398
      Abstract: Both the sympathetic nervous system and the renin-angiotensin system are critically involved in hypertension development. Although angiotensin II (Ang II) stimulates hypothalamic paraventricular nucleus (PVN) neurons to increase sympathetic vasomotor tone, the molecular mechanism mediating this action remains unclear. The glutamate NMDAR in the PVN controls sympathetic outflow in hypertension. In this study, we determined the interaction between α2-1 (encoded by Cacna2d1), commonly known as a Ca2+ channel subunit, and NMDARs in the hypothalamus and its role in Ang II-induced synaptic NMDAR activity in PVN presympathetic neurons. Coimmunoprecipitation assays showed that α2-1 interacted with the NMDAR in the hypothalamus of male rats and humans (both sexes). Ang II increased the prevalence of synaptic α2-1–NMDAR complexes in the hypothalamus. Also, Ang II increased presynaptic and postsynaptic NMDAR activity via AT1 receptors, and such effects were abolished either by treatment with pregabalin, an inhibitory α2-1 ligand, or by interrupting the α2-1–NMDAR interaction with an α2-1 C terminus-interfering peptide. In Cacna2d1 knock-out mice (both sexes), Ang II failed to affect the presynaptic and postsynaptic NMDAR activity of PVN neurons. In addition, the α2-1 C terminus-interfering peptide blocked the sympathoexcitatory response to microinjection of Ang II into the PVN. Our findings indicate that Ang II augments sympathetic vasomotor tone and excitatory glutamatergic input to PVN presympathetic neurons by stimulating α2-1-bound NMDARs at synapses. This information extends our understanding of the molecular basis for the interaction between the sympathetic nervous and renin-angiotensin systems and suggests new strategies for treating neurogenic hypertension.SIGNIFICANCE STATEMENT Although both the sympathetic nervous system and renin-angiotensin system are closely involved in hypertension development, the molecular mechanisms mediating this involvement remain unclear. We showed that α2-1, previously known as a calcium channel subunit, interacts with NMDARs in the hypothalamus of rodents and humans. Angiotensin II (Ang II) increases the synaptic expression level of α2-1–NMDAR complexes. Furthermore, inhibiting α2-1, interrupting the α2-1–NMDAR interaction, or deleting α2-1 abolishes the potentiating effects of Ang II on presynaptic and postsynaptic NMDAR activity in the hypothalamus. In addition, the sympathoexcitatory response to Ang II depends on α2-1-bound NMDARs. Thus, α2-1–NMDAR complexes in the hypothalamus serve as an important molecular substrate for the interaction between the sympathetic nervous system and the renin-angiotensin system. This evidence suggests that α2-1 may be a useful target for the treatment neurogenic hypertension.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0447-18.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Network Controllability in the Inferior Frontal Gyrus Relates to
           Controlled Language Variability and Susceptibility to TMS
    • Authors: Medaglia, J. D; Harvey, D. Y, White, N, Kelkar, A, Zimmerman, J, Bassett, D. S, Hamilton, R. H.
      Pages: 6399 - 6410
      Abstract: In language production, humans are confronted with considerable word selection demands. Often, we must select a word from among similar, acceptable, and competing alternative words to construct a sentence that conveys an intended meaning. In recent years, the left inferior frontal gyrus (LIFG) has been identified as being critical to this ability. Despite a recent emphasis on network approaches to understanding language, how the LIFG interacts with the brain's complex networks to facilitate controlled language performance remains unknown. Here, we take a novel approach to understanding word selection as a network control process in the brain. Using an anatomical brain network derived from high-resolution diffusion spectrum imaging, we computed network controllability underlying the site of transcranial magnetic stimulation (TMS) in the LIFG between administrations of language tasks that vary in response (cognitive control) demands: open-response tasks (word generation) versus closed response tasks (number naming). We found that a statistic that quantifies the LIFG's theoretically predicted control of communication across modules in the human connectome explains TMS-induced changes in open-response language task performance only. Moreover, we found that a statistic that quantifies the LIFG's theoretically predicted control of difficult-to-reach states explains vulnerability to TMS in the closed-ended (but not open-ended) response task. These findings establish a link among network controllability, cognitive function, and TMS effects.SIGNIFICANCE STATEMENT This work illustrates that network control statistics applied to anatomical connectivity data demonstrate relationships with cognitive variability during controlled language tasks and TMS effects.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0092-17.2018
      Issue No: Vol. 38, No. 28 (2018)
  • Anterior Thalamic Excitation and Feedforward Inhibition of Presubicular
           Neurons Projecting to Medial Entorhinal Cortex
    • Authors: Nassar, M; Simonnet, J, Huang, L.-W, Mathon, B, Cohen, I, Bendels, M. H. K, Beraneck, M, Miles, R, Fricker, D.
      Pages: 6411 - 6425
      Abstract: The presubiculum contains head direction cells that are crucial for spatial orientation. Here, we examined the connectivity and strengths of thalamic inputs to presubicular layer 3 neurons projecting to the medial entorhinal cortex in the mouse. We recorded pairs of projection neurons and interneurons while optogenetically stimulating afferent fibers from the anterior thalamic nuclei. Thalamic input differentially affects presubicular neurons: layer 3 pyramidal neurons and fast-spiking parvalbumin-expressing interneurons are directly and monosynaptically activated, with depressing dynamics, whereas somatostatin-expressing interneurons are indirectly excited, during repetitive anterior thalamic nuclei activity. This arrangement ensures that the thalamic excitation of layer 3 cells is often followed by disynaptic inhibition. Feedforward inhibition is largely mediated by parvalbumin interneurons, which have a high probability of connection to presubicular pyramidal cells, and it may enforce temporally precise head direction tuning during head turns. Our data point to the potential contribution of presubicular microcircuits for fine-tuning thalamic head direction signals transmitted to medial entorhinal cortex.SIGNIFICANCE STATEMENT How microcircuits participate in shaping neural inputs is crucial to understanding information processing in the brain. Here, we show how the presubiculum may process thalamic head directional information before transmitting it to the medial entorhinal cortex. Synaptic inputs from the anterior thalamic nuclei excite layer 3 pyramidal cells and parvalbumin interneurons, which mediate disynaptic feedforward inhibition. Somatostatin interneurons are excited indirectly. Presubicular circuits may switch between two regimens depending on the angular velocity of head movements. During immobility, somatostatin-pyramidal cell interactions could support maintained head directional firing with attractor-like dynamics. During rapid head turns, in contrast, parvalbumin-mediated feedforward inhibition may act to tune the head direction signal transmitted to medial entorhinal cortex.
      PubDate: 2018-07-11T09:19:43-07:00
      DOI: 10.1523/JNEUROSCI.0014-18.2018
      Issue No: Vol. 38, No. 28 (2018)
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