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Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors.

Sleep is fundamental to life, and poor sleep quality is linked to the suboptimal function of the neural circuits that process and respond to emotional stimuli. Wakefulness (“arousal”) is chiefly regulated by circadian and homeostatic forces, but affective mood states also strongly impact the balance between sleep and wake. Considering the bidirectional relationships between sleep/wake changes and emotional dynamics, we use the term “emotional arousal” as a representative characteristic of the profound overlap between brain pathways that: (1) modulate wakefulness; (2) interpret emotional information; and (3) calibrate motivated behaviors. Interestingly, many emotional arousal circuits communicate using specialized signaling molecules called neuropeptides to broadly modify neural network activities. One major neuropeptide-enriched brain region that is critical for emotional processing and has been recently implicated in sleep regulation is the bed nuclei of stria terminalis (BNST), a core component of the extended amygdala (an anatomical term that also includes the central and medial amygdalae, nucleus accumbens shell, and transition zones betwixt). The BNST encompasses an astonishing diversity of cell types that differ across many features including spatial organization, molecular signature, biological sex and hormonal milieu, synaptic input, axonal output, neurophysiological communication mode, and functional role. Given this tremendous complexity, comprehensive elucidation of the BNST neuropeptide circuit mechanisms underlying emotional arousal presents an ambitious set of challenges. In this review, we describe how rigorous investigation of these unresolved questions may reveal key insights to enhancing psychiatric treatments and global psychological wellbeing.

BackgroundComorbidity of anxiety disorders, stressor- and trauma-related disorders, and substance use disorders is extremely common. Moreover, therapies that reduce pathological fear and anxiety on the one hand, and drug-seeking on the other, often prove short-lived and are susceptible to relapse. Considerable advances have been made in the study of the neurobiology of both aversive and appetitive extinction, and this work reveals shared neural circuits that contribute to both the suppression and relapse of conditioned responses associated with trauma or drug use.ObjectivesThe goal of this review is to identify common neural circuits and mechanisms underlying relapse across domains of addiction biology and aversive learning in preclinical animal models. We focus primarily on neural circuits engaged during the expression of relapse.Key findingsAfter extinction, brain circuits involving the medial prefrontal cortex and hippocampus come to regulate the expression of conditioned responses by the amygdala, bed nucleus of the stria terminalis, and nucleus accumbens. During relapse, hippocampal projections to the prefrontal cortex inhibit the retrieval of extinction memories resulting in a loss of inhibitory control over fear- and drug-associated conditional responding.ConclusionsThe overlapping brain systems for both fear and drug memories may explain the co-occurrence of fear and drug-seeking behaviors.

Purpose The aim of this study was to evaluate cognitive effects 12 months after Deep Brain Stimulation (DBS) of the Bed Nucleus of Stria Terminalis (BNST) in patients with refractory Obsessive–Compulsive Disorder (OCD). Methods Eight patients (5 female; mean ± SD age 36 ± 15) with OCD were included. A neuropsychological test battery covering verbal and spatial episodic memory, executive function, and attention was administered preoperatively and 12 months after surgery. Medical records were used as a source for descriptive data to probe for any changes not covered by standardized checklists and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the primary outcome measure. Results At 12 months, seven patients showed response to DBS: three were full responders (i.e., Y-BOCS ≥ 35% improvement), and four were partial responders (Y-BOCS 25–34% improvement). Relative to baseline, there was a slight decline on visuo-spatial learning (p = 0.027), and improved performance on the Color-Word Interference inhibition/switching subtest (p = 0.041), suggesting improvement in cognitive flexibility. Conclusions DBS in the BNST for treatment refractory OCD generates very few adverse cognitive effects and improves cognitive flexibility after 12 months of stimulation. The improvement in Y-BOCS and the absence of major cognitive side effects support the BNST as a potential target for DBS in severe OCD.

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 (BNST ALG ) 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 BNST ALG as well as their electrophysiological and morphological properties, amongst other differences. Given this tremendous complexity on multiple levels, the comprehensive elucidation of the BNST ALG 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 BNST ALG structure, functional connectivity, the electrophysiological and morphological properties, and neuropeptidergic profiles of BNST ALG neurons between species with the aim to facilitate future studies of this important nucleus in relation to human disease.

This study aims to investigate the underlying neurobiological mechanisms that regulate natural reward seeking behaviors, specifically in the context of sexual behavior and sucrose self-administration. The role of CaMKIIa+ neurons in the bed nucleus of the stria terminalis (BNST) was explored using chemogenetic silencing and -stimulation. Additionally, the study examined how these effects interacted with the internal state of the animals. Through detailed behavioral analysis, it was demonstrated that CaMKIIa+ neurons in the BNST play a significant role in the regulation of both sexual behavior and sucrose self-administration. Although the behavioral outcome measures differed between the two behaviors, the regulatory role of the CaMKIIa+ neurons in the BNST was found to converge on the modulation of the pacing of engagement in these behaviors in male rats. Moreover, our study confirmed that the internal physiological state of the animal affects how the BNST modulates these behaviors. These findings suggest that different types of natural rewards may recruit a similar brain circuitry to regulate the display of motivated behaviors. Overall, this research provides valuable insights into the neural mechanisms underlying natural reward seeking and sheds light on the interconnected nature of reward-related behaviors in male rats.

Testicular androgens during the perinatal period play an important role in the sexual differentiation of the brain of rodents. Testicular androgens transported into the brain act via androgen receptors or are the substrate of aromatase, which synthesizes neuroestrogens that act via estrogen receptors. The latter that occurs in the perinatal period significantly contributes to the sexual differentiation of the brain. The preoptic area (POA) and the bed nucleus of the stria terminalis (BNST) are sexually dimorphic brain regions that are involved in the regulation of sex-specific social behaviors and the reproductive neuroendocrine system. Here, we discuss how neuroestrogens of testicular origin act in the perinatal period to organize the sexually dimorphic structures of the POA and BNST. Accumulating data from rodent studies suggest that neuroestrogens induce the sex differences in glial and immune cells, which play an important role in the sexually dimorphic formation of the dendritic synapse patterning in the POA, and induce the sex differences in the cell number of specific neuronal cell groups in the POA and BNST, which may be established by controlling the number of cells dying by apoptosis or the phenotypic organization of living cells. Testicular androgens in the peripubertal period also contribute to the sexual differentiation of the POA and BNST, and thus their aromatization to estrogens may be unnecessary. Additionally, we discuss the notion that testicular androgens that do not aromatize to estrogens can also induce significant effects on the sexually dimorphic formation of the POA and BNST.

RationaleAlcohol exposure during adolescence has been linked to long-lasting behavioral consequences, contributing to the development of alcohol use disorder. Negative affect and chronic pain during alcohol withdrawal are critical factors influencing problematic alcohol use and relapse. Our previous research demonstrated that adolescent intermittent ethanol (AIE) vapor exposure elicits sex-specific negative affect-like behavior in adult mice following stress exposure. Additionally, AIE induces persistent mechanical hypersensitivity, which is accompanied by increased activation of corticotropin-releasing factor receptor type 1 (CRFR1) neurons in the dorsolateral bed nucleus of the stria terminalis (dlBNST).ObjectivesThis study extends previous work by investigating plasma corticosterone levels and CRFR1 protein expression in the dlBNST following restraint stress exposure in adult mice with an AIE history. We also aim to explore the role of dlBNST CRFR1 signaling in mediating negative affect-like behavior and mechanical hypersensitivity.ResultsFemale mice exhibited elevated plasma corticosterone levels compared to males following restraint stress. Moreover, females with AIE history showed higher expression of CRFR1 protein in the dlBNST compared to air controls. Antagonism of CRFR1 in the dlBNST blocked AIE-induced mechanical hypersensitivity in adult females but did not affect stress-induced negative affect-like behavior. In alcohol-naïve females, intra-dlBNST administration of a CRFR1 agonist induced mechanical hypersensitivity.ConclusionsThese findings provide new insights into the neurobiological mechanisms underlying stress-induced negative affect and pain-related behavior, both influenced by a history of adolescent alcohol exposure. The results suggest that CRFR1 antagonists warrant further investigation for their potential in addressing alcohol-related chronic pain.

The paraventricular nucleus of the hypothalamus (PVN) is uniquely capable of proximal control over autonomic and neuroendocrine stress responses, and the bed nucleus of the stria terminalis (BNST) directly modulates PVN function, as well as playing an important role in stress control itself. The dorsal BNST (dBNST) is predominantly preautonomic, while the ventral BNST (vBNST) is predominantly viscerosensory, receiving dense noradrenergic signaling. Distinguishing the dBNST and vBNST, along with the PVN, may facilitate our understanding of dynamic interactions among these regions. T1-weighted MPRAGE and high resolution gradient echo (GRE) modalities were acquired at 7T. GRE was coregistered to MPRAGE and segmentations were performed in MRIcroGL based on their Atlas of the Human Brain depictions. The dBNST, vBNST and PVN were manually segmented in 25 participants; 10 images were rated by 2 raters. These segmentations were normalized and probabilistic atlases for each region were generated in MNI space, now available as resources for future research. We found moderate–high inter-rater reliability [ n  = 10; Mean Dice (SD); PVN = 0.69 (0.04); dBNST = 0.77 (0.04); vBNST = 0.62 (0.04)]. Probabilistic atlases were reverse normalized into native space for six additional participants that were segmented but not included in the original 25. We also found moderate to moderate–high reliability between the probabilistic atlases and manual segmentations [ n  = 6; Mean Dice (SD); PVN = 0.55 (0.12); dBNST = 0.60 (0.10); vBNST = 0.47 (0.12 SD)]. By isolating these hypothalamic and BNST subregions using ultra-high field MRI modalities, more specific delineations of these regions can facilitate greater understanding of mechanisms underlying stress-related function and psychopathology.

Regulation of gene expression is considered a plausible mechanism of drug addiction, given the stability of behavioural abnormalities that define an addicted state. Among many transcription factors known to influence the addiction process, one of the best characterized is ΔFosB, which is induced in the brain's reward regions by chronic exposure to virtually all drugs of abuse and mediates sensitized responses to drug exposure. Since ΔFosB is a highly stable protein, it represents a mechanism by which drugs produce lasting changes in gene expression long after the cessation of drug use. Studies are underway to explore the detailed molecular mechanisms by which ΔFosB regulates target genes and produces its behavioural effects. We are approaching this question using DNA expression arrays coupled with the analysis of chromatin remodelling-changes in the posttranslational modifications of histones at drug-regulated gene promoters-to identify genes that are regulated by drugs of abuse via the induction of ΔFosB and to gain insight into the detailed molecular mechanisms involved. Our findings establish chromatin remodelling as an important regulatory mechanism underlying drug-induced behavioural plasticity, and promise to reveal fundamentally new insight into how ΔFosB contributes to addiction by regulating the expression of specific target genes in brain reward pathways.