Bed Nucleus Of The Stria Terminalis Research Articles

Convergence of monosynaptic inputs from neurons in the brainstem and forebrain on parabrachial neurons that project to the paraventricular nucleus of the thalamus

The paraventricular nucleus of the thalamus (PVT) projects to areas of the forebrain involved in regulating behavior. Homeostatic challenges and salient cues activate the PVT and evidence shows that the PVT regulates appetitive and aversive responses. The brainstem is a source of afferents to the PVT and the present study was done to determine if the lateral parabrachial nucleus (LPB) is a relay for inputs to the PVT. Retrograde tracing experiments with cholera toxin B (CTB) demonstrate that the LPB contains more PVT projecting neurons than other regions of the brainstem including the catecholamine cell groups. The hypothesis that the LPB is a relay for signals to the PVT was assessed using an intersectional monosynaptic rabies tracing approach. Sources of inputs to LPB included the reticular formation; periaqueductal gray (PAG); nucleus cuneiformis; and superior and inferior colliculi. Distinctive clusters of input cells to LPB-PVT projecting neurons were also found in the dorsolateral bed nucleus of the stria terminalis (BSTDL) and the lateral central nucleus of the amygdala (CeL). Anterograde viral tracing demonstrates that LPB-PVT neurons densely innervate all regions of the PVT in addition to providing collateral innervation to the preoptic area, lateral hypothalamus, zona incerta and PAG but not the BSTDL and CeL. The paper discusses the anatomical evidence that suggests that the PVT is part of a network of interconnected neurons involved in arousal, homeostasis, and the regulation of behavioral states with forebrain regions potentially providing descending modulation or gating of signals relayed from the LPB to the PVT.

Distinct Encoding of Reward and Aversion by Peptidergic BNST Inputs to the VTA.

Neuropeptides play an important role in modulating mesolimbic system function. However, while synaptic inputs to the ventral tegmental area (VTA) have been extensively mapped, the sources of many neuropeptides are not well resolved. Here, we mapped the anatomical locations of three neuropeptide inputs to the VTA: neurotensin (NTS), corticotrophin releasing factor (CRF), and neurokinin B (NkB). Among numerous labeled inputs we identified the bed nucleus of the stria terminalis (BNST) as a major source of all three peptides, containing similar numbers of NTS, CRF, and NkB VTA projection neurons. Approximately 50% of BNST to VTA inputs co-expressed two or more of the peptides examined. Consistent with this expression pattern, analysis of calcium dynamics in the terminals of these inputs in the VTA revealed both common and distinct patterns of activation during appetitive and aversive conditioning. These data demonstrate additional diversification of the mesolimbic dopamine system through partially overlapping neuropeptidergic inputs.

Organization of neural systems expressing melanocortin-3 receptors in the mouse brain: Evidence for sexual dimorphism.

The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well-characterized melanocortin-4 receptor (MC4R), little is known regarding the organization of MC3R-expressing neural circuits. To increase our understanding of the intrinsic organization of MC3R neural circuits, identify specific differences between males and females, and gain a neural systems level perspective of this circuitry, we conducted a brain-wide mapping of neurons labeled for MC3R and characterized the distribution of their projections. Analysis revealed MC3R neuronal and terminal labeling in multiple brain regions that control a diverse range of physiological functions and behavioral processes. Notably, dense labeling was observed in the hypothalamus, as well as areas that share considerable connections with the hypothalamus, including the cortex, amygdala, thalamus, and brainstem. Additionally, MC3R neuronal labeling was sexually dimorphic in several areas, including the anteroventral periventricular area, arcuate nucleus, principal nucleus of the bed nucleus of the stria terminalis, and ventral premammillary region. Altogether, anatomical evidence reported here suggests that MC3R has the potential to influence several different classes of motivated behavior that are essential for survival, including ingestive, reproductive, defensive, and arousal behaviors, and is likely to modulate these behaviors differently in males and females.

Divergent neural and endocrine responses in wild-caught and laboratory-bred Rattus norvegicus

Although rodents have represented the most intensely studied animals in neurobiological investigations for more than a century, few studies have systematically compared neural and endocrine differences between wild rodents in their natural habitats and laboratory strains raised in traditional laboratory environments. In the current study, male and female Rattus norvegicus rats were trapped in an urban setting and compared to weight-and sex-matched conspecifics living in standard laboratory housing conditions. Brains were extracted for neural assessments and fecal boli were collected for endocrine [corticosterone and dehydroepiandrosterone (DHEA)] assays. Additionally, given their role in immune and stress functions, spleen and adrenal weights were recorded. A separate set of wild rats was trapped at a dairy farm and held in captivity for one month prior to assessments; in these animals, brains were processed but no hormone data were available. The results indicated that wild-trapped rats exhibited 31% heavier brains, including higher densities of cerebellar neurons and glial cells in the bed nucleus of the stria terminalis. The wild rats also had approximately 300% greater spleen and adrenal weights, and more than a six-fold increase in corticosterone levels than observed in laboratory rats. Further research on neurobiological variables in wild vs. lab animals will inform the extensive neurobiological knowledge base derived from laboratory investigations using selectively bred rodents in laboratory environments, knowledge that will enhance the translational value of preclinical laboratory rodent studies.

Neural basis for anxiety and anxiety-related physiological responses during a driving situation: an fMRI study.

Although the exteroceptive and interoceptive prediction of a negative event increases a person’s anxiety in daily life situations, the relationship between the brain mechanism of anxiety and the anxiety-related autonomic response has not been fully understood. In this functional magnetic resonance imaging (fMRI) study, we examined the neural basis of anxiety and anxiety-related autonomic responses in a daily driving situation. Participants viewed a driving video clip in the first-person perspective. During the video clip, participants were presented with a cue to indicate whether a subsequent crash could occur (attention condition) or not (safe condition). Enhanced activities in the anterior insula, bed nucleus of the stria terminalis, thalamus, and periaqueductal gray, and higher sympathetic nerve responses (pupil dilation and peripheral arterial stiffness) were triggered by the attention condition but not with the safe condition. Autonomic response-related functional connectivity was detected in the visual cortex, cerebellum, brainstem, and MCC/PCC with the right anterior insula and its adjacent regions as seed regions. Thus, the right anterior insula and adjacent regions, in collaboration with other regions play a role in eliciting anxiety based on the prediction of negative events, by mediating anxiety-related autonomic responses according to interoceptive information.

Aversive Contexts Reduce Activity in the Ventral Subiculum- BNST Pathway

Many anxiety disorders can be characterized by abnormalities in detecting and learning about threats, and the inability to reduce fear responses in non-threatening environments. PTSD may be the most representative of context processing pathology, as intrusive memories are experienced in “safe” contexts. The ventral subiculum (vSUB), the main output of the ventral hippocampus, encodes environmental cues and is critical for context processing. The bed nucleus of the stria terminalis (BNST) contributes to anxiety-like behaviors as well as context fear conditioning. Given the important roles of the BNST and the vSUB in these anxiety and fear-related behaviors, and the anatomical connections between the two brain regions, the major aims of this study were to characterize the anatomy and function of the vSUB–BNST pathway. First, using the retrograde tracer cholera toxin, we mapped the topographical arrangement of the vSUB–BNST pathway. Dual retrograde tracing experiments revealed neurons projecting to the BNST and those projecting to the basolateral amygdala are distinct populations. Second, we assessed whether activity in this pathway, as indexed by FOS immunohistochemistry, was modulated by context fear conditioning. Our data reveal less activation of the vSUB–BNST pathway in both males and females in aversive contexts and the greatest activation when animals explored a neutral familiar context. In addition, the vSUB of females contained fewer GABAergic neurons compared to males. These findings suggest that the vSUB–BNST pathway is involved in eliciting appropriate responses to contexts.

The Elusive "Switch Process" in Bipolar Disorder and Photoperiodism: A Hypothesis Centering on NADPH Oxidase-Generated Reactive Oxygen Species Within the Bed Nucleus of the Stria Terminalis.

One of the most striking and least understood aspects of mood disorders involves the “switch process” which drives the dramatic state changes characteristic of bipolar disorder. In this paper we explore the bipolar switch mechanism as deeply grounded in forms of seasonal switching (for example, from summer to winter phenotypes) displayed by many mammalian species. Thus we develop a new and unifying hypothesis that involves four specific claims, all converging to demonstrate a deeper affinity between the bipolar switch process and the light-sensitive (photoperiodic) nonhuman switch sequence than has been appreciated. First, we suggest that rapid eye movement (REM) sleep in both human and nonhuman plays a key role in probing for those seasonal changes in length of day that trigger the organism's characteristic involutional response (in certain animals, hibernation) to shorter days. Second, we claim that this general mammalian response requires the integrity of a neural circuit centering on the anterior bed nucleus of the stria terminalis. Third, we propose that a key molecular mediator of the switch process in both nonhumans and seasonal humans involves reactive oxygen species (ROS) of a particular provenance, namely those created by the enzyme NADPH oxidase (NOX). This position diverges from one currently prominent among students of bipolar disorder. In that tradition, the fact that patients afflicted with bipolar-spectrum disorders display indices of oxidative damage is marshaled to support the conclusion that ROS, escaping adventitiously from mitochondria, have a near-exclusive pathological role. Instead, we believe that ROS, originating instead in membrane-affiliated NOX enzymes upstream from mitochondria, take part in an eminently physiological signaling process at work to some degree in all mammals. Fourth and finally, we speculate that the diversion of ROS from that purposeful, genetically rooted seasonal switching task into the domain of human pathology represents a surprisingly recent phenomenon. It is one instigated mainly by anthropogenic modifications of the environment, especially “light pollution.”

The brain of the tree pangolin (Manis tricuspis). VIII. The subpallial telencephalon.

The current study provides a detailed architectural analysis of the subpallial telencephalon of the tree pangolin. In the tree pangolin, the subpallial telencephalon was divided into septal and striatopallidal regions. The septal region contained the septal nuclear complex, diagonal band of Broca, and the bed nuclei of the stria terminalis. The striatopallidal region comprised of the dorsal (caudate, putamen, internal and external globus pallidus) and ventral (nucleus accumbens, olfactory tubercle, ventral pallidum, nucleus basalis, basal part of the substantia innominata, lateral stripe of the striatum, navicular nucleus, and the major island of Calleja) striatopallidal complexes. In the tree pangolin, the organization and numbers of nuclei forming these regions and complexes, their topographical relationships to each other, and the cyto‐, myelo‐, and chemoarchitecture, were found to be very similar to that observed in commonly studied mammals. Minor variations, such as less nuclear parcellation in the bed nuclei of the stria terminalis, may represent species‐specific variations, or may be the result of the limited range of stains used. Given the overall similarity across mammalian species, it appears that the subpallial telencephalon of the mammalian brain is highly conserved in terms of evolutionary changes detectable with the methods used. It is also likely that the functions associated with these nuclei in other mammals can be translated directly to the tree pangolin, albeit with the understanding that the stimuli that produce activity within these regions may be specific to the life history requirements of the tree pangolin.

Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors

The serotonin system modulates a wide variety of emotional behaviors and states, including reward processing, anxiety, and social interaction. To reveal the underlying patterns of neural activity, we visualized serotonergic neurons in the dorsal raphe nucleus (DRN5-HT) of mice using miniaturized microscopy during diverse emotional behaviors. We discovered ensembles of cells with highly correlated activity and found that DRN5-HT neurons are preferentially recruited by emotionally salient stimuli as opposed to neutral stimuli. Individual DRN5-HT neurons responded to diverse combinations of salient stimuli, with some preference for valence and sensory modality. Anatomically defined subpopulations projecting to either a reward-related structure (the ventral tegmental area) or an anxiety-related structure (the bed nucleus of the stria terminalis) contained all response types but were enriched in reward- and anxiety-responsive cells, respectively. Our results suggest that the DRN serotonin system responds to emotional salience using ensembles with mixed selectivity and biases in downstream connectivity.

1308-P: Role of Medial Amygdala Neurons in Regulating the Metabolic Responses to Homeostatic Challenge

Neural signals play a critical role in metabolic regulation by controlling behavior and coordinating glucose production and uptake in peripheral organs. Physiological and psychological stimuli that disrupt homeostasis - stressors - result in metabolic and behavioral adaptations but our understanding of the precise circuits underlying these adaptations remains incomplete. Here we used in vivo calcium imaging, viral tracing and neural manipulation to determine the contribution of medial amygdala (MeA) circuits to the metabolic responses to stress. Social and psychological stressors result in hyperglycemia. These stressors also rapidly increased fluorescence of genetic calcium indicators (GCamp) in MeA neurons. Chemogenetic activation of MeA neurons significantly increased blood glucose without altering pancreatic hormone release and suppressed feeding. Viral tracing revealed distinct MeA subpopulations projecting to the bed nucleus of the stria terminalis (BNST) and to the ventromedial hypothalamus (VMH) . Chemogenetic stimulation of MeA projections to the VMH but not BNST increased blood glucose during glucose tolerance testing via sympathetic activation of hepatic gluconeogenesis, without effects on pancreatic or adrenal hormones. Conversely, silencing of MeA neurons projecting to the VMH blunted stress-induced hyperglycemia. Together these findings suggest a crucial role for MeA circuits in the metabolic response to stressors with dissociation of sympathetic, hormonal, and behavioral adaptations to homeostatic challenge. Disclosure K.Devarakonda: None. R.O’connor: None. A.Alvarsson: None. R.Y.Li: None. M.Jimenez gonzalez: None. P.Kenny: None. S.Stanley: None. Funding American Diabetes Association (1-17-ACE-31) ; National Institutes of Health (R01NS097184, OT2OD024912, F31DK129016 and R01DK124461) National Science Foundation (1930163) Department of Defense (W81XWH-20-1-0156, W81XWH-20-1-0345) Naomi Berries Diabetes Center Russell Berrie Foundation AwardRevson Foundation

239-LB: Single-Cell Analysis Identified Inhibitory Neurons Associated with High-Fat Diet in the Bed Nucleus of the Stria Terminalis

Obesity occurs due to inadequate homeostatic function controlled by the central nervous system (CNS) . Outside of a few brain areas, little information is available on structures, such as the bed nucleus of the stria terminalis (BST) and preoptic area (POA) , that are essential for body weight regulation. To better understand BST and POA mechanisms involved in obesity, we overlayed deep sequencing results collected from obese (by Echo MRI) and diabetic (by glucose tolerance test) mice on high fat diet (HFD) with a previously published single cell RNA-seq data set. We identified neural subtypes using Seurat (Fig. 1A) and deconvoluted the RNA-seq with CIBERSORT. The Inhibitory 1 subtype had a lower proportion in HFD BST than control BST (Fig. 1B, p=0.035) but no difference was found between BST and POA (Fig. 1C, p=0.505) . We performed differential gene expression analysis to identify Inhibitory 1 markers and associated pathways. Aminobutyric acid (GABA) -ergic synapse pathway was enriched (Fig. 1D,E, p< 0.0001) , which is essential to the CNS control of body weight. HFD induced strong transcriptional changes in BST Inhibitory 1 markers between HFD and control diet (Fig. 1F) . One gene of particular interest was Glutathione Peroxidase 3 (GPX3, p<0.0001) . GPX3, localized to the BST and POA (Fig. 1G) , is down-regulated in both prostate and adipose tissues during HFD and implicated in neurodegenerative disease, but not yet been studied in the brain and obesity. Future studies will investigate BST GPX3 in obesity. Disclosure X. Yang: None. J. Flak: Research Support; Eli Lilly and Company. T. S. Johnson: Research Support; Eli Lilly and Company.

A narrative review on invasive brain stimulation for treatment-resistant depression.

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Social Interactions Increase Activation of Vasopressin-Responsive Neurons in the Dorsal Raphe

Social interactions play an important role in our daily lives and can profoundly impact our health for better and worse. To better understand the neural circuitry underlying social behavior, we focused on neural circuits involving vasopressin neurons of the bed nucleus of the stria terminalis (BNST) and serotonin neurons of the dorsal raphe (DR). Previous research shows that BNST vasopressin neurons are activated in male mice by interaction with a female and that vasopressin indirectly excites serotonin neurons. In our studies, we tested the hypothesis that specific social interactions would also activate neurons in the DR, specifically vasopressin 1A receptor (Avpr1a)-expressing neurons, which may be direct targets of the BNST vasopressin neurons. Using in separate experiments immunohistochemistry and in situ hybridization, we found that male and female subjects exposed to a female conspecific show activation in the DR, and the activated neurons include populations of Avpr1a-expressing and other non-serotonergic, non-Avpr1a neurons in roughly equal numbers. Avpr1a neurons in the DR constitute a largely undocumented neuron population. Electrophysiological data suggest that most DR Avpr1a neurons behave like fast spiking interneurons found in other brain regions. Examination of RNAseq and in situ hybridization data suggests that there are glutamatergic, GABAergic, and serotonergic subtypes of Avpr1a neurons in the DR. Together our data support a model in which a subset of vasopressin-responsive interneurons in the DR may relay stimulus specific social signals from the forebrain BNST to the serotonergic DR system, which could help direct prosocial stimulus specific behavioral responses.

Oxytocin receptor behavioral effects and cell types in the bed nucleus of the stria terminalis

Oxytocin is a neuropeptide that can produce anxiolytic effects and promote social approach. However, emerging evidence shows that under some conditions, oxytocin can instead induce anxiety-related behaviors. These diverse effects of oxytocin appear to be mediated by circuit-specific actions. Recent data showed that inhibition of oxytocin receptors (OTRs) in the bed nucleus of the stria terminalis (BNST) was sufficient to increase social approach and decrease social vigilance in female California mice (Peromyscus californicus) exposed to social defeat stress. As a member of the G-protein coupled receptor family, OTRs can induce distinct downstream pathways by coupling to different G-protein isoforms. We show that infusion of carbetocin, a biased OTR-Gq agonist, in the BNST reduced social approach in both female and male California mice. In both females and males, carbetocin also increased social vigilance. To gain insight into cell types that could be mediating this effect, we analyzed previously published single-cell RNAseq data from the BNST and nucleus accumbens (NAc). In the NAc, we and others showed that OTR activation promotes social approach behaviors. In the BNST, Oxtr was expressed in over 40 cell types, that span both posterior and anterior subregions of the BNST. The majority of Oxtr-expressing neurons were GABAergic. In the anterior regions of BNST targeted in our carbetocin experiments, Cyp26b1-expressing neurons had high average Oxtr expression. In the NAc, most Oxtr+ cells were D1 dopamine receptor-expressing neurons and interneurons. These differences in Oxtr cell type distribution may help explain how activation of OTR in BNST versus NAc can have different effects on social approach and social vigilance.

Effect of orexin and its antagonist on the organization of emotional and exploratory behavior of rats in a model of psychic trauma

BACKGROUND: A number of recent studies have revealed the role of orexins in regulating emotional behavior and emotional memory. The rationale for this role of orexin regulation is the close bi-directional interaction of orexin neurons with emotional structures of the brain, such as the bed nucleus of the stria terminalis, locus ceruleus, central and dorsomedial amygdala, hippocampus, medial prefrontal cortex. There is experimental and clinical evidence that an endogenous or induced deficiency of orexin effects accelerates the elimination of traumatic memory.
 AIM: To study the effect of the OX1R Orexin Receptor Antagonist SB408124 and orexin on the emotional and exploratory behavior of animals after predator-induced stress.
 MATERIALS AND METHODS: The experiments were made with 36 male Wistar rats, divided into 4 groups of 8 animals. Animals of 3 groups were exposed to single simulation of post-traumatic stress disorder by exposition with the indian python and subsequent death of one rat as a result of predator activity. The rats of 2 experimental groups received SB408124 OX1R antagonist in a dose of 20 l of 0.1% solution and Orexin A in the same dose intranasally. The other animals received physiological solution in a dose of 20 l intranasally. Behavior tests was made 7 days after the modeling of psychotrauma. A panel of behavioral tests was used: an elevated X-maze, an open field test, and an residentintruder test. The obtained data were statistically processed using the Student t-test and ANOVA dispersion analysis. The differences were considered statistically significant at p 0.01.
 RESULTS: Orexin antagonist SB408124 showed anxiolytic effects. SB408124 showed anxiolytic properties in stressed rats. It restored the time spent in the light arm of the elevated X-maze to the intact level. In the open field test SB408124 increased (p 0.01) the orientation behavior and reduced the frequency of freezing in stressed animals. Orexin A suppressed (p 0,01) locomotor activity of animals in the open field. In the residentintruder test in stressed animals SB408124 restored suppressed communication activity (p 0,01). Orexin A reduced communicative behavior and increased aggression of animals.
 CONCLUSIONS: The work shows a moderate anxiolytic action of SB408124 in the post-traumatic stress model in rats.

Somatostatin neurons in the bed nucleus of the stria terminalis play a sex-dependent role in binge Drinking

Alcohol use disorder (AUD) is characterized by alcohol use coupled with chronic relapse and involves brain regions including the bed nucleus of the stria terminalis (BNST). Here, we explore whether a subpopulation of BNST neurons, somatostatin (SST) expressing GABAergic neurons, play a role in an animal model of binge-like alcohol consumption, the Drinking in the Dark (DID) model. Chemogenetic activation of BNST SST neurons reduced binge alcohol consumption in female but not male SST-Cre mice, while inhibition of these neurons in the same mice had no effect. In addition, chemogenetic activation of these neurons did not cause apparent changes in models of anxiety-like behavior in either sex. Basal SST cell counts and intrinsic excitability of SST neurons were compared to attempt to understand sex differences in DREADD-induced changes in drinking, and while males had a greater number of BNST SST neurons, this effect went away when normalizing for total BNST volume. Together, these results suggest SST neurons in the BNST should be further explored as a potential neuronal subtype modulated by AUD, and for their therapeutic potential.

Developmental-Based Classification of Enkephalin and Somatostatin Containing Neurons of the Chicken Central Extended Amygdala.

The central extended amygdala, including the lateral bed nucleus of the stria terminalis and the central amygdala, plays a key role in stress response. To understand how the central extended amygdala regulates stress it is essential to dissect this structure at molecular, cellular and circuit levels. In mammals, the central amygdala contains two distinct cell populations that become active (on cells) or inactive (off cells) during the conditioned fear response. These two cell types inhibit each other and project mainly unidirectionally to output cells, thus providing a sophisticated regulation of stress. These two cell types express either protein kinase C-delta/enkephalin or somatostatin, and were suggested to originate in different embryonic domains of the subpallium that respectively express the transcription factors Pax6 or Nkx2.1 during development. The regulation of the stress response by the central extended amygdala is poorly studied in non-mammals. Using an evolutionary developmental neurobiology approach, we previously identified several subdivisions in the central extended amygdala of chicken. These contain Pax6, Islet1 and Nkx2.1 cells that originate in dorsal striatal, ventral striatal or pallidopreoptic embryonic divisions, and also contain neurons expressing enkephalin and somatostatin. To know the origin of these cells, in this study we carried out multiple fluorescent labeling to analyze coexpression of different transcription factors with enkephalin or somatostatin. We found that many enkephalin cells coexpress Pax6 and likely derive from the dorsal striatal division, resembling the off cells of the mouse central amygdala. In contrast, most somatostatin cells coexpress Nkx2.1 and derive from the pallidal division, resembling the on cells. We also found coexpression of enkephalin and somatostatin with other transcription factors. Our results show the existence of multiple cell types in the central extended amygdala of chicken, perhaps including on/off cell systems, and set the basis for studying the role of these cells in stress regulation.

Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours

Sepsis is a life-threatening condition induced by a deregulated host response to severe infection. Post-sepsis syndrome includes long-term psychiatric disorders, such as persistent anxiety and post-traumatic stress disorder, whose neurobiological mechanisms remain unknown.Using a reference mouse model of sepsis, we showed that mice that recovered from sepsis further developed anxiety-related behaviours associated with an exaggerated fear memory. In the brain, sepsis induced an acute pathological activation of a specific neuronal population of the central nucleus of the amygdala, which projects to the ventral bed nucleus of the stria terminalis. Using viral-genetic circuit tracing and in vivo calcium imaging, we observed that sepsis induced persistent changes in the connectivity matrix and in the responsiveness of these central amygdala neurons projecting to the ventral bed nucleus of the stria terminalis. The transient and targeted silencing of this subpopulation only during the acute phase of sepsis with a viral pharmacogenetic approach, or with the anti-epileptic and neuroprotective drug levetiracetam, prevented the subsequent development of anxiety-related behaviours.Specific inhibition of brain anxiety and fear circuits during the sepsis acute phase constitutes a preventive approach to preclude the post-infection psychiatric outcomes.

Odor blocking of stress hormone responses

Scents have been employed for millennia to allay stress, but whether or how they might do so is largely unknown. Fear and stress induce increases in blood stress hormones controlled by hypothalamic corticotropin releasing hormone neurons (CRHNs). Here, we report that two common odorants block mouse stress hormone responses to three potent stressors: physical restraint, predator odor, and male–male social confrontation. One odorant inhibits restraint and predator odor activation of excitatory neurons upstream of CRHNs in the bed nucleus of the stria terminalis (BNSTa). In addition, both activate inhibitory neurons upstream of CRHNs in the hypothalamic ventromedial nucleus (VMH) and silencing of VMH inhibitory neurons hinders odor blocking of stress. Together, these findings indicate that odor blocking can occur via two mechanisms: (1) Inhibition of excitatory neurons that transmit stress signals to CRHNs and (2) activation of inhibitory neurons that act directly or indirectly to inhibit stressor activation of CRHNs.

The neural distribution of the avian homologue of oxytocin, mesotocin, in two songbird species, the zebra finch and the canary: A potential role in song perception and production.

The avian homologue of oxytocin (OT), formerly called mesotocin, influences social behaviors in songbirds and potentially song production. We sought to characterize the distribution of OT peptide in the brain of two songbird species: canaries (Serinus canaria) and zebra finches (Taeniopygia guttata). To visualize OT, we performed immunocytochemistry using an antibody previously shown to identify OT in avian species. In both canaries and zebra finches, dense OT‐ir perikarya were located in the paraventricular nucleus (PVN), preoptic area (POA), supraoptic nucleus (SON), and medial bed nucleus of the stria terminalis (BNSTm). We also observed morphologically distinct OT‐ir cells scattered throughout the mesopallium. OT‐ir fibers were observed in the PVN, ventral medial hypothalamus (VMH), periaqueductal gray (PAG), intercollicular nucleus (ICo), and ventral tegmental area (VTA). We also observed punctate OT‐ir fibers in the song control nucleus HVC. In both male and female canaries, OT‐ir fibers were present in the lateral septum (LS), but innervation was greater in males. We did not observe this sex difference in zebra finches. Much of the OT staining observed is consistent with general distributions within the vertebrate hypothalamus, indicating a possible conserved function. However, some extra‐hypothalamic distributions, such as perikarya in the mesopallium, may be specific to songbirds and play a role in song perception and production. The presence of OT‐ir fibers in HVC and song control nuclei projecting dopaminergic regions provides anatomical evidence in support of the idea that OT can influence singing behavior—either directly via HVC or indirectly via the PAG, VTA, or POA.