Sex-specific effects on elements of the social brain neural network in Wistar rats from perinatal exposure to FireMaster 550 or its components.

Developmental exposure to chemical flame retardants (FRs) has been linked to a variety of neurodevelopmental disorders and abnormal socioemotional behaviors in human and laboratory animal studies. We have previously shown in Wistar rats that gestational and lactational exposure to the FR mixture Firemaster 550 (FM 550) or its brominated or organophosphate ester (OPFR) components (at 2,000µg, 1,000µg, and 1,000µg oral to the dam respectively) results in increased anxiety-like behaviors in females and decreased sociality in both sexes. Using their siblings, this study characterized sex and chemical specific targets of disruption in brain regions underlying each behavioral phenotype. Offspring were exposed across gestation and lactation then prepared for either immunohistochemistry or autoradiography at postnatal day 90 to quantify expression of serotonin, estrogen receptor α (ERα), and oxytocin receptor (OTR) in multiple brain regions. No effect of exposure was found in males for any biological target. In females, serotonin innervation was increased in the medial amygdala of FM 550 exposed animals while ERα expression in the bed nucleus of the stria terminalis (BNST) was reduced by FM 550 and OPFR. Evidence of disrupted OTR was observed in males, particularly the BNST but considered an exploratory finding given the small sample size. These results begin to shed light on the mechanisms by which developmental FR exposure alters socioemotional behaviors of relevance to neurodevelopmental disorders.

Neuroticism/Negative Emotionality Is Associated with Increased Reactivity to Uncertain Threat in the Bed Nucleus of the Stria Terminalis, Not the Amygdala.

Neuroticism/negative emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and well-being. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are nonfungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for refining mechanistic research.

Activation of NPY Receptors in the BLA Inhibits Projections to the Bed Nucleus of the Stria Terminalis and Buffers Stress-Induced Decreases in Social Interaction in Male Rats.

Neuropeptide Y (NPY) increases resilience and buffers behavioral stress responses in male rats in part through decreasing the excitability of principal output neurons in the basolateral amygdala (BLA). Intra-BLA administration of NPY acutely increases social interaction (SI) through activation of either Y1 or Y5 receptors, whereas repeated NPY (rpNPY) injections (once daily for 5 d) produce persistent increases in SI through Y5 receptor-mediated neuroplasticity in the BLA. In this series of studies, we characterized the neural circuits from the BLA that underlie these behavioral responses to NPY. Using neuronal tract tracing, NPY Y1 and Y5 receptor immunoreactivity was identified on subpopulations of BLA neurons projecting to the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA). Inhibition of BLA→BNST, but not BLA→CeA, neurons using projection-restricted, cre-driven designer receptors exclusively activated by designer drug-Gi expression increased SI and prevented stress-induced decreases in SI produced by a 30 min restraint stress. This behavioral profile was similar to that seen after both acute and rpNPY injections into the BLA. Intracellular recordings of BLA→BNST neurons demonstrated NPY-mediated inhibition via suppression of H currents, as seen previously. Repeated intra-BLA injections of NPY, which are associated with the induction of BLA neuroplasticity, decreased the activity of BLA→BNST neurons and decreased their dendritic complexity. These results demonstrate that NPY modulates the activity of BNST-projecting BLA neurons, suggesting that this pathway contributes to the stress-buffering actions of NPY and provides a novel substrate for the proresilient effects of NPY.

A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat.

Temporal dynamics play a central role in models of emotion: "fear" is widely conceptualized as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Yet the underlying human neurobiology remains contentious. Leveraging an ethnoracially diverse sample, translationally relevant paradigm, and theory-driven modeling approach, we demonstrate that certain and uncertain threat recruit a shared threat-anticipation circuit. This cortico-subcortical circuit exhibits persistently elevated activation when anticipating uncertain-threat encounters and a transient burst of activation in the moments before certain encounters. For many scientists and clinicians, feelings are the defining feature of human fear and anxiety. Here we used an independently validated brain signature to covertly decode the momentary dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research.

The role and mechanism of 5-HTDRN-BNST neural circuit in anxiety and fear lesions.

Central 5-hydroxytryptaminergic dorsal raphe nucleus (5-HTDRN)-bed nucleus of stria terminalis (BNST) neural circuit dysfunction is one of the important neurobiological basis of anxiety and fear disorders. Under stress, 5-hydroxytryptamine (5-HT) neurons act on BNST receptors to attenuate anxiety and fear responses or enhance anxiety and fear. In BNST, corticotropin releasing factor neurons play a role in regulating emotions by reversely regulating excitatory or inhibitory 5-HT neurons. The composition of 5-HTDRN-BNST neural circuit, the pathological changes of 5-HTDRN-BNST neural circuit function damage under stress, and the effects of 5-HTDRN-BNST neural circuit on anxiety disorder, panic disorder and post-traumatic stress disorder were analyzed and are summarized in this paper. The characteristics of functional changes of the neural circuit and its effects on brain functional activities provide a basis and ideas for the treatment of anxiety and fear disorders through the regulation of 5-HTDRN-BNST neural circuit, and they also provide a new perspective for understanding the pathological mechanism of such diseases.

Single cocaine exposure attenuates the intrinsic excitability of CRH neurons in the ventral BNST via Sigma-1 receptors.

The ventral bed nucleus of the stria terminalis (vBNST) plays a key role in cocaine addiction, especially relapse. However, the direct effects of cocaine on corticotropin-releasing hormone (CRH) neurons in the vBNST remain unclear. Here, we identify that cocaine exposure can remarkably attenuate the intrinsic excitability of CRH neurons in the vBNST in vitro. Accumulating studies reveal the crucial role of Sigma-1 receptors (Sig-1Rs) in modulating cocaine addiction. However, to the authors' best knowledge no investigations have explored the role of Sig-1Rs in the vBNST, let alone CRH neurons. Given that cocaine acts as a type of Sig-1Rs agonist, and the dramatic role of Sig-1Rs played in intrinsic excitability of neurons as well as cocaine addiction, we employ BD1063 a canonical Sig-1Rs antagonist to block the effects of cocaine, and significantly recover the excitability of CRH neurons. Together, we suggest that cocaine exposure leads to the firing rate depression of CRH neurons in the vBNST via binding to Sig-1Rs.

Early morphological and neurochemical changes of the bed nucleus of stria terminalis (BNST) in gestational protein-restricted male offspring.

BACKGROUND: The bed nucleus of the stria terminalis (BNST) is a structure with a peculiar neurochemical composition involved in modulating anxietylike behavior and fear. AIM: The present study investigated the effects on the BNST neurochemical composition and neuronal structure in critical moments of the postnatal period in gestational protein-restricted male rats' offspring. METHODS: Dams were maintained during the pregnancy on isocaloric rodent laboratory chow with standard protein content [NP, 17%] or low protein content [LP, 6%]. BNST from male NP and age-matched LP offspring was studied using the isotropic fractionator method, Neuronal 3D reconstruction, dendritic-tree analysis, blotting analysis, and high-performance liquid chromatography. RESULTS: Serum corticosterone levels were higher in male LP offspring than NP rats in 14-day-old offspring, without any difference in 7-day-old progeny. The BNST total cell number and anterodorsal BNST division volume in LP progeny were significantly reduced on the 14th postnatal day compared with NP offspring. The BNST HPLC analysis from 7 days-old LP revealed increased norepinephrine levels compared to NP progeny. The BNST blot analysis from 7-day-old LP revealed reduced levels of GR and BDNF associated with enhanced CRF1 expression compared to NP offspring. 14-day-old LP offspring showed reduced expression of MR and 5HT1A associated with decreased DOPAC and DOPA turnover levels relative to NP rats. In Conclusion, the BNST cellular and neurochemical changes may represent adaptation during development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition alters the BNST content and structure and contributes to already-known behavioral changes.

Association between social dominance hierarchy and PACAP expression in the extended amygdala, corticosterone, and behavior in C57BL/6 male mice.

The natural alignment of animals into social dominance hierarchies produces adaptive, and potentially maladaptive, changes in the brain that influence health and behavior. Aggressive and submissive behaviors assumed by animals through dominance interactions engage stress-dependent neural and hormonal systems that have been shown to correspond with social rank. Here, we examined the association between social dominance hierarchy status established within cages of group-housed mice and the expression of the stress peptide PACAP in the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). We also examined the relationship between social dominance rank and blood corticosterone (CORT) levels, body weight, motor coordination (rotorod) and acoustic startle. Male C57BL/6 mice were ranked as either Dominant, Submissive, or Intermediate based on counts of aggressive/submissive encounters assessed at 12 weeks-old following a change in homecage conditions. PACAP expression was significantly higher in the BNST, but not the CeA, of Submissive mice compared to the other groups. CORT levels were lowest in Submissive mice and appeared to reflect a blunted response following events where dominance status is recapitulated. Together, these data reveal changes in specific neural/neuroendocrine systems that are predominant in animals of lowest social dominance rank, and implicate PACAP in brain adaptations that occur through the development of social dominance hierarchies.

Father's Absence in the Mongolian gerbil (Meriones unguiculatus) is associated with alterations in paternal behavior, T, cort, presence of ERα, and AR in mPOA/ BNST.

Testosterone (T), estrogen receptor alpha (ERα), and androgen receptor (AR) play a significant role in the regulation of paternal behavior. We determined the effects of deprivation of paternal care on alterations in paternal behavior, T concentrations in plasma, and the presence of ERα and AR in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST), medial amygdala (MeA), and olfactory bulb (OB), as well as the corticosterone (CORT) concentrations in plasma caused by deprivation of paternal care in the Mongolian gerbil (Meriones unguiculatus). Twenty pairs of gerbils were formed; the pups were deprived of paternal care (DPC) in 10 pairs. In another 10 pairs, the pups received paternal care (PC). Ten males raised in DPC condition and 10 males raised in PC conditions were mated with virgin females. When they became fathers, each DPC male and PC male was subjected to tests of paternal behavior on day three postpartum. Blood samples were obtained to quantify T and CORT concentrations, and the brains were removed for ERα and AR immunohistochemistry analyses. DPC males gave less care to their pups than PC males, and they had significantly lower T concentrations and levels of ERα and AR in the mPOA and BNST than PC males. DPC males also had higher CORT concentrations than PC males. These results suggest that in the Mongolian gerbil father's absence causes a decrease in paternal care in the offspring, which is associated with alterations in the neuroendocrine mechanisms that regulate it.

Development of activity-based anorexia requires PKC-δ neurons in two central extended amygdala nuclei.

Anorexia nervosa (AN) is a serious psychiatric disease, but the neural mechanisms underlying its development are unclear. A subpopulation of amygdala neurons, marked by expression of protein kinase C-delta (PKC-δ), has previously been shown to regulate diverse anorexigenic signals. Here, we demonstrate that these neurons regulate development of activity-based anorexia (ABA), a common animal model for AN. PKC-δ neurons are located in two nuclei of the central extended amygdala (EAc): the central nucleus (CeA) and oval region of the bed nucleus of the stria terminalis (ovBNST). Simultaneous ablation of CeAPKC-δ and ovBNSTPKC-δ neurons prevents ABA, but ablating PKC-δ neurons in the CeA or ovBNST alone is not sufficient. Correspondingly, PKC-δ neurons in both nuclei show increased activity with ABA development. Our study shows how neurons in the amygdala regulate ABA by impacting both feeding and wheel activity behaviors and support a complex heterogeneous etiology of AN.

Forced Abstinence from Volitional Ethanol Intake Drives a Vulnerable Period of Hyperexcitability in BNST-Projecting Insular Cortex Neurons.

The insular cortex (IC) integrates sensory and interoceptive cues to inform downstream circuitry executing adaptive behavioral responses. The IC communicates with areas involved canonically in stress and motivation. IC projections govern stress and ethanol recruitment of bed nucleus of the stria terminalis (BNST) activity necessary for the emergence of negative affective behaviors during alcohol abstinence. Here, we assess the impact of the chronic drinking forced abstinence (CDFA) volitional home cage ethanol intake paradigm on synaptic and excitable properties of IC neurons that project to the BNST (IC→BNST). Using whole-cell patch-clamp electrophysiology, we investigated IC→BNST circuitry 24 h or 2 weeks following forced abstinence (FA) in female C57BL6/J mice. We find that IC→BNST cells are transiently more excitable following acute ethanol withdrawal. In contrast, in vivo ethanol exposure via intraperitoneal injection, ex vivo via ethanol wash, and acute FA from a natural reward (sucrose) all failed to alter excitability. In situ hybridization studies revealed that at 24 h post FA BK channel mRNA expression is reduced in IC. Further, pharmacological inhibition of BK channels mimicked the 24 h FA phenotype, while BK activation was able to decrease AP firing in control and 24 h FA subjects. All together these data suggest a novel mechanism of homeostatic plasticity that occurs in the IC→BNST circuitry following chronic drinking.

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala.

Neuroticism/Negative Emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment and divorce to mental illness and premature death. Work in animals suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to the human brain and temperament have remained unclear. Here we used a combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is selectively associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to 'threat-related' faces. Implicit in much of the neuroimaging literature is the assumption that different threat paradigms are statistically interchangeable probes of individual differences in neural function, yet our results revealed negligible evidence of convergence between popular threat-anticipation and emotional-face tasks. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing the next generation of mechanistic research.

Chronic stress and its effects on behavior, RNA expression of the bed nucleus of the stria terminalis, and the M-current of NPY neurons.

Mood disorders, like major depressive disorder, can be precipitated by chronic stress and are more likely to be diagnosed in cisgender women than in cisgender men. This suggests that stress signaling in the brain is sexually dimorphic. We used a chronic variable mild stress paradigm to stress female and male mice for 6 weeks, followed by an assessment of avoidance behavior: the open field test, the elevated plus maze, the light/dark box emergence test, and the novelty suppressed feeding test. Additional cohorts were used for bulk RNA-Sequencing of the anterodorsal bed nucleus of the stria terminalis (adBNST) and whole-cell patch clamp electrophysiology in NPY-expressing neurons of the adBNST to record stress-sensitive M-currents. Our results indicate that females are more affected by chronic stress as indicated by an increase in avoidance behaviors, but that this is also dependent on the estrous stage of the animals such that diestrus females show more avoidant behaviors regardless of stress treatment. Results also indicate that NPY-expressing neurons of the adBNST are not major mediators of chronic stress as the M-current was not affected by treatment. RNA-Sequencing data suggests sex differences in estrogen signaling, serotonin signaling, and orexin signaling in the adBNST. Our results indicate that chronic stress influences behavior in a sex- and estrous stage-dependent manner but NPY-expressing neurons in the BNST are not the mediators of these effects.

Case report: Clinical efficacy of deep brain stimulation contacts corresponds to local field potential signals in a patient with obsessive-compulsive disorder.

Introduction: Deep brain stimulation (DBS) is often effective in treating severe obsessive-compulsive disorder (OCD) when traditional therapeutic approaches have failed. However, optimizing DBS programming is a time-consuming process. Recent research in movement disorders suggests that local field potentials can dramatically speed up the process of identifying the optimal contacts for stimulation, but this has not yet been tested in a patient with OCD. Methods: In a patient with severe OCD, we first determined the optimal contact for stimulation for each hemisphere using traditional monopolar and bipolar review and then tested whether the clinically optimal contact in each hemisphere corresponded to local field potential signals. Results: Overall, we found that clinical efficacy corresponded with the contacts that showed the strongest local field potential signals across multiple frequency bands. Discussion: Our findings are the first indication that local field potentials could guide contact selection in patients with OCD. If validated in a larger sample, this methodology could decrease time to clinical benefit and improve accuracy in patients that are difficult to assess using traditional methods. Further research is needed to determine whether local field potentials could be used to guide finer resolution in programming parameters.

Deep brain stimulation for treatment resistant obsessive compulsive disorder; an observational study with ten patients under real-life conditions.

Introduction: Obsessive-compulsive disorder (OCD) affects 2-3% of the global population, causing distress in many functioning levels. Standard treatments only lead to a partial recovery, and about 10% of the patients remain treatment-resistant. Deep brain stimulation offers a treatment option for severe, therapy-refractory OCD, with a reported response of about 60%. We report a comprehensive clinical, demographic, and treatment data for patients who were treated with DBS in our institution. Methods: We offered DBS to patients with severe chronic treatment resistant OCD. Severity was defined as marked impairment in functioning and treatment resistance was defined as non-response to adequate trials of medications and psychotherapy. Between 2020 and 2022, 11 patients were implanted bilaterally in the bed nucleus of stria terminalis (BNST). Patients were evaluated with YBOCS, MADRS, GAF, CGI, and WHOQOL-BREF. We performed the ratings at baseline (before surgery), after implantation before the start of the stimulation, after reaching satisfactory stimulation parameters, and at follow-up visits 3, 6, 9, and 12 months after optimized stimulation. Results: One patient has retracted his consent to publish the results of his treatment, thus we are reporting the results of 10 patients (5 males, 5 females, mean age: 37 years). Out of our 10 patients, 6 have shown a clear response indicated by a YBOCS-reduction between 42 and 100 percent at last follow-up. One further patient experienced a subjectively dramatic effect on OCD symptoms, but opted afterwards to stop the stimulation. The other 3 patients showed a slight, non-significant improvement of YBOCS between 8.8 and 21.9%. The overall mean YBOCS decreased from 28.3 at baseline to 13.3 (53% reduction) at the last follow-up. The improvement of the OCD symptoms was also accompanied by an improvement of depressive symptoms, global functioning, and quality of life. Conclusion: Our results suggest that BNST-DBS can be effective for treatment-resistant OCD patients, as indicated by a reduction in symptoms and an overall improvement in functioning. Despite the need for additional research to define the patients' selection criteria, the most appropriate anatomical target, and the most effective stimulation parameters, improved patient access for this therapy should be established.

The neurophysiological basis of stress and anxiety - comparing neuronal diversity in the bed nucleus of the stria terminalis (BNST) across species.

The bed nucleus of the stria terminalis (BNST), as part of the extended amygdala, has become a region of increasing interest regarding its role in numerous human stress-related psychiatric diseases, including post-traumatic stress disorder and generalized anxiety disorder amongst others. The BNST is a sexually dimorphic and highly complex structure as already evident by its anatomy consisting of 11 to 18 distinct sub-nuclei in rodents. Located in the ventral forebrain, the BNST is anatomically and functionally connected to many other limbic structures, including the amygdala, hypothalamic nuclei, basal ganglia, and hippocampus. Given this extensive connectivity, the BNST is thought to play a central and critical role in the integration of information on hedonic-valence, mood, arousal states, processing emotional information, and in general shape motivated and stress/anxiety-related behavior. Regarding its role in regulating stress and anxiety behavior the anterolateral group of the BNST (BNSTALG) has been extensively studied and contains a wide variety of neurons that differ in their electrophysiological properties, morphology, spatial organization, neuropeptidergic content and input and output synaptic organization which shape their activity and function. In addition to this great diversity, further species-specific differences are evident on multiple levels. For example, classic studies performed in adult rat brain identified three distinct neuron types (Type I-III) based on their electrophysiological properties and ion channel expression. Whilst similar neurons have been identified in other animal species, such as mice and non-human primates such as macaques, cross-species comparisons have revealed intriguing differences such as their comparative prevalence in the BNSTALG as well as their electrophysiological and morphological properties, amongst other differences. Given this tremendous complexity on multiple levels, the comprehensive elucidation of the BNSTALG circuitry and its role in regulating stress/anxiety-related behavior is a major challenge. In the present Review we bring together and highlight the key differences in BNSTALG structure, functional connectivity, the electrophysiological and morphological properties, and neuropeptidergic profiles of BNSTALG neurons between species with the aim to facilitate future studies of this important nucleus in relation to human disease.

A neural circuit for male sexual behavior and reward.

Male sexual behavior is innate and rewarding. Despite its centrality to reproduction, a molecularly specified neural circuit governing innate male sexual behavior and reward remains to be characterized. We have discovered a developmentally wired neural circuit necessary and sufficient for male mating. This circuit connects chemosensory input to BNSTprTac1 neurons, which innervate POATacr1 neurons that project to centers regulating motor output and reward. Epistasis studies demonstrate that BNSTprTac1 neurons are upstream of POATacr1 neurons, and BNSTprTac1-released substance P following mate recognition potentiates activation of POATacr1 neurons through Tacr1 to initiate mating. Experimental activation of POATacr1 neurons triggers mating, even in sexually satiated males, and it is rewarding, eliciting dopamine release and self-stimulation of these cells. Together, we have uncovered a neural circuit that governs the key aspects of innate male sexual behavior: motor displays, drive, and reward.

Dissection of the bed nucleus of the stria terminalis neuronal subtypes in feeding regulation.

The bed nucleus of the stria terminalis (BNST) plays an important role in feeding regulation through projections to other brain areas. However, whether functional distinctions exist within different BNST cells is not clear. Here, we found optogenetic activation of LH-projecting BNST neurons induced aversion and significantly reduced consumption of normal chow but not high-fat diets (HFD). In contrast, photoactivation of vlPAG-projecting BNST neurons induced place preference and promoted HFD intake, without affecting normal chow consumption. Moreover, optogenetic silencing of LH-projecting BNST neurons reduced the consumption of normal chow in fasted mice, while photoinhibition of vlPAG-projecting BNST neurons decreased the consumption of HFD in both fed and fasted mice. We then labeled the LH- and vlPAG-projecting BNST neurons using retroAAV-GFP and retroAAV-mCherry, respectively, and found these two populations of neurons have different anatomical distribution and electrophysiological properties. Taken together, we identified vlPAG-projecting and LH-projecting BNST neurons are two distinct populations of cells with significant differences in functional and anatomic characteristics.

Microbial metabolites regulate social novelty via CaMKII neurons in the BNST.

Social novelty is a cognitive process that is essential for animals to interact strategically with conspecifics based on their prior experiences. The commensal microbiome in the gut modulates social behavior through various routes, including microbe-derived metabolite signaling. Short-chain fatty acids (SCFAs), metabolites derived from bacterial fermentation in the gastrointestinal tract, have been previously shown to impact host behavior. Herein, we demonstrate that the delivery of SCFAs directly into the brain disrupts social novelty through distinct neuronal populations. We are the first to observe that infusion of SCFAs into the lateral ventricle disrupted social novelty in microbiome-depleted mice without affecting brain inflammatory responses. The deficit in social novelty can be recapitulated by activating calcium/calmodulin-dependent protein kinase II (CaMKII)-labeled neurons in the bed nucleus of the stria terminalis (BNST). Conversely, chemogenetic silencing of the CaMKII-labeled neurons and pharmacological inhibition of fatty acid oxidation in the BNST reversed the SCFAs-induced deficit in social novelty. Our findings suggest that microbial metabolites impact social novelty through a distinct neuron population in the BNST.

Dopamine D2 receptors in the bed nucleus of the stria terminalis modulate alcohol-related behaviors.

Dysregulation of the dopamine (DA) system is a hallmark of substance abuse disorders, including alcohol use disorder (AUD). Of the DA receptor subtypes, the DA D2 receptors (D2Rs) play a key role in the reinforcing effects of alcohol. D2Rs are expressed in numerous brain regions associated with the regulation of appetitive behaviors. One such region is the bed nucleus of the stria terminalis (BNST), which has been linked to the development and maintenance of AUD. Recently, we identified alcohol withdrawal-related neuroadaptations in the periaqueductal gray/dorsal raphe to BNST DA circuit in male mice. However, the role of D2R-expressing BNST neurons in voluntary alcohol consumption is not well characterized. In this study, we used a CRISPR-Cas9-based viral approach, to selectively reduce the expression of D2Rs in BNST VGAT neurons and interrogated the impact of BNST D2Rs in alcohol-related behaviors. In male mice, reduced D2R expression potentiated the stimulatory effects of alcohol and increased voluntary consumption of 20% w/v alcohol in a two-bottle choice intermittent access paradigm. This effect was not specific to alcohol, as D2R deletion also increased sucrose intake in male mice. Interestingly, cell-specific deletion of BNST D2Rs in female mice did not alter alcohol-related behaviors but lowered the threshold for mechanical pain sensitivity. Collectively, our findings suggest a role for postsynaptic BNST D2Rs in the modulation of sex-specific behavioral responses to alcohol and sucrose.