Bed Nucleus Research Articles

Neural correlates of beneficial effects of young plasma treatment in aged mice: PET-SPM analyses and neuro-behavioural/molecular biological studies.

To investigate the in vivo neurofunctional changes and therapeutic effects of young blood plasma (YBP) in aged mice, as well as the molecular mechanisms underlying the therapeutic effects of YBP ex vivo and in vitro. Aged C57/BL6 mice received systemic administrations of phosphate-buffered saline (PBS) or YBP twice a week, for 4weeks. In vivo 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) under conscious state and cognitive behavioural tests were performed after 4-week treatment. In addition, an in vitro senescent model was established, and the expressions of key cognition-associated proteins and/or the alterations of key neuronal pathways were analysed in both brain tissues and cultured cells. Aged mice treated with YBP demonstrated higher glucose metabolism in the right hippocampus and bilateral somatosensory cortices, and lower glucose metabolism in the right bed nucleus of stria terminalis and left cerebellum. YBP treatment exerted beneficial effects on the spatial and long-term social recognition memory, and significantly increased the expressions of several cognition-related proteins and altered the key neuronal signalling pathways in the hippocampus and somatosensory cortex. Further in vitro studies suggested that YBP but not aged blood plasma significantly upregulated the expressions of several cognition-associated proteins. Our results highlight the role of the hippocampus and somatosensory cortex in YBP-induced beneficial effects on recognition memory in aged mice. 18F-FDG PET imaging under conscious state provides a new avenue for exploring the mechanisms underlying YBP treatment against age-related cognitive decline.

Distribution of androgen receptor mRNA in the prepubertal male and female mouse brain.

Androgens are steroid hormones that play a critical role in brain development and sexual maturation by acting upon both androgen receptors (AR) and estrogen receptors (ERα/β) after aromatization. The contribution of estrogens from aromatized androgens in brain development and the central regulation of metabolism, reproduction, and behavior is well defined, but the role of androgens acting on AR has been unappreciated. Here, we map the sex specific expression of Ar in the adult and developing mouse brain. Postnatal days (PND) 12 and 21 were used to target a critical window of prepubertal development. Consistent with previous literature in adults, sex‐specific differences in Ar expression were most profound in the bed nucleus of the stria terminalis (BST), medial amygdala (MEA) and medial preoptic area (MPO). Ar expression was also high in these areas at PND 12 and 21 in both sexes. In addition, we describe extra‐hypothalamic and extra‐limbic areas that show moderate, consistent and similar Ar expression in both sexes at both prepubertal time points. Briefly, Ar expression was observed in olfactory areas of the cerebral cortex, the hippocampus, several thalamic nuclei, and cranial nerve nuclei involved in autonomic sensory and motor function. To further characterize forebrain populations of Ar expressing neurons and determine whether they also coexpress estrogen receptors, we examined expression of Ar, Esr1 and Esr2 in prepubertal mice in selected nuclei. We found populations of neurons in the BST, MEA and MPO that coexpress Ar, but not Esr1 or Esr2, whereas others express a combination of the three receptors. Our findings indicate that various brain areas express Ar during prepubertal development and may play an important role in female neuronal development and physiology.

Ontogeny of the Projections From the Dorsomedial Division of the Anterior Bed Nucleus of the Stria Terminalis to Hypothalamic Nuclei.

The bed nucleus of the stria terminalis (BNST) is a telencephalic structure well-connected to hypothalamic regions known to control goal-oriented behaviors such as feeding. In particular, we showed that the dorsomedial division of the anterior BNST innervate neurons of the paraventricular (PVH), dorsomedial (DMH), and arcuate (ARH) hypothalamic nuclei as well as the lateral hypothalamic area (LHA). While the anatomy of these projections has been characterized in mice, their ontogeny has not been studied. In this study, we used the DiI-based tract tracing approach to study the development of BNST projections innervating several hypothalamic areas including the PVH, DMH, ARH, and LHA. These results indicate that projections from the dorsomedial division of the anterior BNST to hypothalamic nuclei are immature at birth and substantially reach the PVH, DMH, and the LHA at P10. In the ARH, only sparse fibers are observed at P10, but their density increased markedly between P12 and P14. Collectively, these findings provide new insight into the ontogeny of hypothalamic circuits, and highlight the importance of considering the developmental context as a direct modulator in their proper formation.

Solitary Nitric Oxide Signaling Mediates Mild Stress-Induced Anxiety and Norepinephrine Release in the Bed Nucleus of the Stria Terminalis during Protracted Ethanol Withdrawal.

Ethanol withdrawal (EtOHW) alters the pattern of neurohormonal and behavioral response toward internal and external stimuli, which mediates relapse to alcohol use even after a long period of abstinence. Increased noradrenergic signaling from the nucleus tractus solitarius (NTS) to the bed nucleus of the stria terminalis (BNST) during EtOHW underlies withdrawal-induced anxiety, while nitric oxide synthase (NOS) inhibitors injected into the periaqueductal area attenuate EtOHW-induced anxiety. Therefore, this study investigated the involvement of NOS within the NTS in anxiety and increased norepinephrine (NE) release in the BNST during protracted EtOHW in rats exposed to a mild stress. Rats were intraperitoneally administered 3 g/kg/day EtOH for 21 days followed by 28 days of withdrawal, and on the 28th day of withdrawal, the rats were subjected to restraint stress for 7 minutes. The elevated plus maze test was employed to evaluate anxiety-like behavior in rats, and in vivo microdialysis was used to measure the extracellular NE level in the BNST. In elevated plus maze tests, EtOHW rats but not EtOH-naive rats exhibited anxiety-like behavior when challenged with 7-minute mild restraint stress, which was, respectively, mitigated by prior intra-NTS infusion of the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or selective neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI). Each of these agents also decreased the plasma corticosterone levels in EtOHW rats. In in vivo microdialysis, prior intra-NTS infusion of carboxy-PTIO, L-NAME, or 7-NI attenuated the mild stress-induced NE release in the BNST of EtOHW rats. Additionally, EtOHW rats showed increased solitary nNOS gene and protein expression. Moreover, the anxiolytic effect of intra-NTS administration of 7-NI was abolished by subsequent intra-NTS administration of sodium nitroprusside. These results suggest that elevation of solitary nitric oxide signaling derived from nNOS mediates stress-precipitated anxiety and norepinephrine release in the BNST during protracted EtOHW.

Functional Connectivity Differences Between Two Culturally Distinct Prairie Vole Populations: Insights Into the Prosocial Network

BackgroundThe goal of this study was to elucidate the fundamental connectivity—resting-state connectivity—within and between nodes in the olfactory and prosocial (PS) cores, which permits the expression of social monogamy in males; and how differential connectivity accounts for differential expression of prosociality and aggression. MethodsUsing resting-state functional magnetic resonance imaging, we integrated graph theory analysis to compare functional connectivity between two culturally/behaviorally distinct male prairie voles (Microtusochrogaster). ResultsIllinois males display significantly higher levels of prosocial behavior and lower levels of aggression than KI (Kansas dam and Illinois sire) males, which are associated with differences in underlying neural mechanisms and brain microarchitecture. Shared connectivity 1) between the anterior hypothalamic area and the paraventricular nucleus and 2) between the medial preoptic area and bed nucleus of the stria terminalis and the nucleus accumbens core suggests essential relationships required for male prosocial behavior. In contrast, Illinois males displayed higher levels of global connectivity and PS intracore connectivity, a greater role for the bed nucleus of the stria terminalis and anterior hypothalamic area, which were degree connectivity hubs, and greater PS and olfactory intercore connectivity. ConclusionsThese findings suggest that behavioral differences are associated with PS core degree of connectivity and postsignal induction. This transgenerational system may serve as powerful mental health and drug abuse translational model in future studies.

Activation of Lateral Parabrachial Nucleus (LPBn) PACAP-Expressing Projection Neurons to the Bed Nucleus of the Stria Terminalis (BNST) Enhances Anxiety-like Behavior.

Anxiety disorders are among the most common psychiatric disorders, and understanding the underlying neurocircuitry of anxiety- and stress-related behaviors may be important for treatment. The bed nucleus of the stria terminalis (BNST) has been studied for its role in many stress-related pathologies, such as anxiety, pain, depression, and addiction. Our prior work has demonstrated that pituitary adenylate cyclase-activating polypeptide (PACAP) receptor activation in the BNST mediates many of the behavioral consequences of chronic stress. While the BNST contains local PACAP-expressing neurons, a major source of afferent PACAP is the lateral parabrachial nucleus (LPBn), and excitotoxic lesions of the LPBn substantially decreasess PACAP immunostaining in the BNST. Here, we first assessed Cre-dependent reporter expression by injecting AAV2-hSyn-DIO-mCherry into the LPBn of PACAP-IRES-Cre mice for circuit mapping studies and identified PACAP projections to the BNST, lateral capsular central nucleus of the amygdala (CeLC), and ventromedial hypothalamus (VMH). In a second study, we assessed the effects of chemogenetically activating LPBn PACAP afferents in the BNST by injecting AAV2-hSyn-DIO-hM3D(Gq)-mCherry into the LPBn of PACAP-IRES-Cre mice for Cre-dependent expression of excitatory designer receptors exclusively activated by designer drugs (DREADDs). Before behavioral testing, clozapine-N-oxide (CNO), the selective agonist of our DREADD, was infused directly into the BNST. We found that after specific activation of LPBn PACAP afferents in the BNST, mice had increased anxiety-like behavior compared with controls, while total locomotor activity was unaffected. These results indicate that activation of PACAPergic LPBn projections to the BNST may play an important role in producing anxiety-like behavior.

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

ObjectiveThe paraventricular nucleus of hypothalamus (PVN), an integrative center in the brain, orchestrates a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the input–output organization of PVNMC4R+ neurons and test their physiological functions beyond feeding. MethodsUsing a combination of viral tools, we mapped PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding. ResultsWe found that PVNMC4R+ neurons innervate many different brain regions that are known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure, and brown adipose tissue temperature. These physiological changes accompanied acute transient hyperactivity followed by hypoactivity and resting-like behavior. ConclusionsOur results elucidate the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermoregulation, cardiovascular function, and biphasic behavioral activation.

Repeated exposure with short-term behavioral stress resolves pre-existing stress-induced depressive-like behavior in mice

Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated daily five-minute restraint resolves pre-existing stress-induced depressive-like behavior in mice. Repeated injection of glucocorticoids in low doses mimics the anti-depressive effects of short-term stress. Repeated exposure to short-term stress and injection of glucocorticoids activate neurons in largely overlapping regions of the brain, as shown by c-Fos staining, and reverse distinct stress-induced gene expression profiles. Chemogenetic inhibition of neurons in the prelimbic cortex projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis results in anti-depressive effects similarly to short-term stress exposure, while only inhibition of neurons in the prelimbic cortex projecting to the bed nucleus of the stria terminalis rescues defective glucocorticoid release. In summary, we show that short-term stress can reverse adaptively altered stress gains and resolve stress-induced depressive-like behavior.

Bed nucleus of the stria terminalis and amygdala responses to unpredictable threat in children.

Substantial evidence from studies in humans suggests the amygdala is pivotal for anxiety. Findings from animal models and translational studies suggests the bed nucleus of the stria terminalis (BNST) is also critical for anxiety and the anticipation of unpredictable threat in adults. However, it remains unknown whether the BNST is involved in unpredictable threat anticipation in children. Forty-two 8-10-year-olds completed resting-state functional magnetic resonance imaging (fMRI) scans and an unpredictable threat fMRI task in which they were trained to associate cues with images. Intrinsic connectivity analyses were performed to establish functional BNST and amygdala networks. BNST and amygdala activation to cues and images was tested. Significant findings were followed by task-based functional connectivity analyses. Children showed evidence for BNST and amygdala intrinsic connectivity that was similar to previous patterns observed in adults. In response to unpredictable cues relative to neutral face cues, children had a significant amygdala response but no response in the BNST. The amygdala, but not the BNST, also showed a significantly greater response to fear face images relative to neutral images. Thus, unpredictable threat activated the amygdala, but not BNST, in children. This finding is contrary to studies showing robust BNST activation to unpredictable threat in adults and may suggest that the BNST's role in threat processing emerges later in development.

Haloperidol and aripiprazole affects CRH system and behaviour of animals exposed to chronic mild stress

CRH system integrates responses to stress challenges, whereas antipsychotics may impinge on this process. Effect of haloperidol (HAL) and aripiprazole (ARI) on chronic mild stress (CMS) induced neurobehavioral and CRH/CRHR1 system changes was studied in functionally interconnected rat brain areas including prefrontal cortex (PFC), bed nucleus of the stria terminalis (BNST), hypothalamic paraventricular nucleus (PVN), hippocampus (HIP), and amygdala (AMY). Animals were exposed to CMS for 3-weeks and since the 7th day of CMS injected with vehicle (VEH), HAL (1 mg/kg) or ARI (10 mg/kg) for 4-weeks. Expression levels of CRH, CRHR1, and c-fos genes and anxiety-like and anhedonia behavioural patterns were evaluated. CMS in VEH animals suppressed CRH gene expression in the PFC and BNST, c-fos expression in all areas, except HIP, and increased CRHR1 gene expression in the HIP. Antipsychotics decreased CRH gene expression in all areas, except HIP and by CMS elevated CRHR1 expression in the HIP (ARI also in AMY). CMS and antipsychotics decreased the sucrose preference. Aripiprazole prevented CRH expression decrease in the BNST and sucrose preference induced by CMS. Haloperidol increased time spent in the EPM open arms. These data indicate that HAL and ARI selectively influenced behavioural parameters and CRH/CRHR1 gene expression levels in CMS animals.

Estrogen signaling modulates behavioral selection toward pups and amygdalohippocampal area in the rhomboid nucleus of the bed nucleus of the stria terminalis circuit

Gonadal steroid hormone influences behavioral choice of adult animals toward pups, parental or aggressive. We previously reported that long-term administration of 17β-estradiol (E2) to male mice during sexual maturation induces aggressive behavior toward conspecific pups, which is called “infanticide,” and significantly enhanced excitatory synaptic transmission in the rhomboid nucleus of bed nucleus of the stria terminalis (BSTrh), which is an important brain region for infanticide. However, it is unclear how estrogen receptor–dependent signaling after sexual maturity regulates neural circuits including the BSTrh. Here we revealed that E2 administration to gonadectomized mice in adulthood elicited infanticidal behavior and enhanced excitatory synaptic transmission in the BSTrh by increasing the probability of glutamate release from the presynaptic terminalis. Next, we performed whole-brain mapping of E2-sensitive brain regions projecting to the BSTrh and found that amygdalohippocampal area (AHi) neurons that project to the BSTrh densely express estrogen receptor 1 (Esr1). Moreover, E2 treatment enhanced synaptic connectivity in the AHi-BSTrh pathway. Together, these results suggest that reinforcement of excitatory inputs from AHi neurons into the BSTrh by estrogen receptor–dependent signaling may contribute to the expression of infanticide.

Robust BOLD Responses to Faces But Not to Conditioned Threat: Challenging the Amygdala's Reputation in Human Fear and Extinction Learning.

Most of our knowledge about human emotional memory comes from animal research. Based on this work, the amygdala is often labeled the brain's “fear center”, but it is unclear to what degree neural circuitries underlying fear and extinction learning are conserved across species. Neuroimaging studies in humans yield conflicting findings, with many studies failing to show amygdala activation in response to learned threat. Such null findings are often treated as resulting from MRI-specific problems related to measuring deep brain structures. Here we test this assumption in a mega-analysis of three studies on fear acquisition (n = 98; 68 female) and extinction learning (n = 79; 53 female). The conditioning procedure involved the presentation of two pictures of faces and two pictures of houses: one of each pair was followed by an electric shock [a conditioned stimulus (CS+)], the other one was never followed by a shock (CS–), and participants were instructed to learn these contingencies. Results revealed widespread responses to the CS+ compared with the CS– in the fear network, including anterior insula, midcingulate cortex, thalamus, and bed nucleus of the stria terminalis, but not the amygdala, which actually responded stronger to the CS–. Results were independent of spatial smoothing, and of individual differences in trait anxiety and conditioned pupil responses. In contrast, robust amygdala activation distinguished faces from houses, refuting the idea that a poor signal could account for the absence of effects. Moving forward, we suggest that, apart from imaging larger samples at higher resolution, alternative statistical approaches may be used to identify cross-species similarities in fear and extinction learning.SIGNIFICANCE STATEMENT The science of emotional memory provides the foundation of numerous theories on psychopathology, including stress and anxiety disorders. This field relies heavily on animal research, which suggests a central role of the amygdala in fear learning and memory. However, this finding is not strongly corroborated by neuroimaging evidence in humans, and null findings are too easily explained away by methodological limitations inherent to imaging deep brain structures. In a large nonclinical sample, we find widespread BOLD activation in response to learned fear, but not in the amygdala. A poor signal could not account for the absence of effects. While these findings do not disprove the involvement of the amygdala in human fear learning, they challenge its typical portrayals and illustrate the complexities of translational science.

Retraction: Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice.

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here, we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.

FKBP51 in the Oval Bed Nucleus of the Stria Terminalis Regulates Anxiety-Like Behavior.

The cochaperone FKBP51, encoded by the Fkbp5 gene, has been identified as central risk factor for anxiety-related disorders and stress system dysregulation. In the brain, the oval bed nucleus of the stria terminalis (ovBNST) has been implicated in stress-induced anxiety. However, the role of Fkbp5 in the ovBNST and its impact on anxiety-like behavior have remained unknown. Here, we show in mice that Fkbp5 in the ovBNST is reactive to acute stress and coexpressed with the stress-regulated neuropeptides Tac2 and Crh Subsequently, results obtained from viral-mediated manipulation indicate that Fkbp5 overexpression (OE) in the ovBNST results in an anxiolytic-like tendency regarding behavior and endocrinology, whereas a Fkbp5 knock-out (KO) exposed a clear anxiogenic phenotype, indicating that native ovBNST expression and regulation is necessary for normal anxiety-related behavior. Notably, our data suggests that a stress-induced increase of Fkbp5 in the ovBNST may in fact have a protective role, leading to a transient decrease in anxiety and suppression of a future stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation. Together, our findings provide a first insight into the previously unknown relationship and effects of Fkbp5 and the ovBNST on anxiety-like behavior and HPA axis functioning.

Stress and central autonomic network.

The central autonomic network (CAN) plays a critical role in the stress response, which is triggered by challenges on the homeostasis (physiological stressors) or unpleasant social or environmental situations. This review focuses on the role of areas of the CAN including the insular and anterior cingulate cortices, extended amygdala, hypothalamus, periaqueductal gray and locus coeruleus in the stress response. These areas are interconnected and affect sympathetic or parasympathetic output via their influence on premotor or preganglionic autonomic neurons in the lower brainstem and spinal cord. The insula integrates multiple inputs to create a sense of the physiological state of the body, whereas the anterior cingulate initiates predictive visceromotor commands. The amygdala and bed nucleus of the stria terminalis provide automatic emotional tagging and trigger automatic survival responses to threat via their outputs to the hypothalamus, periaqueductal gray, and lower brainstem. Several regions of the hypothalamus, including the paraventricular nucleus, dorsomedial nucleus and lateral hypothalamic area participate in different patterns of stress response according to the type of stimulus and projections to premotor and preganglionic autonomic neurons. The periaqueductal gray initiates different patterns of autonomic, pain modulatory, and motor responses, including the "fight or flight" or "playing dead" responses. The locus coeruleus promotes emotional learning in the amygdala associated with states of anxiety. Neurons of the C1 area of the rostral ventrolateral medulla elicit sympathoexcitatory responses to internal stressors such as hypoxia and inflammation. The ventromedial medulla, including the nucleus raphe pallidus, initiates sympathoexcitatory responses to social and other external stressors.

Non-motor connections of the pedunculopontine nucleus of the rat and human brain

IntroductionThe connections of the pedunculopontine nucleus (PPN) with motor areas of the central nervous system (CNS) are well described in the literature, in contrast relations with non-motor areas are lacking. Thus, the aim of the present study is to define the non-motor connections of the PPN in rats using the fluoro-gold (FG) tracer and compare the presence of these connections in healthy human adults using diffusion tensor tractography (DTI). Materials and MethodsWe injected FG into the PPN of 12 rats. The non-motor connections of the PPN with cortical, subcortical, and brainstem structures were documented. The non-motor connections of the rats were compared with the DTI obtained from 35 healthy adults. ResultsThe results of the tract-tracing study in the rat showed that the PPN was connected to non-motor cortical (cingulate, somatosensory, visual, auditory, medial frontal cortices), subcortical (amygdala, hypothalamus, thalamus, habenular, and bed nucleus of stria terminalis), and brainstem (medullary reticular, trigeminal spinal, external cuneate, pontine reticular, vestibular, superior and inferior colliculus, locus ceruleus, periaqueductal gray, parabrachial, dorsal raphe, pretectal, lateral lemniscus nuclei, and the contralateral PPN) structures. The DTI obtained from healthy adults showed similar PPN non-motor connections as in rats. ConclusionUnderstanding the connections of the PPN with non-motor cortical, subcortical, and brainstem areas of the CNS will enrich our knowledge of its contribution in various circuits and the areas that PPN activity can influence. Further, it will provide insight into the role of Parkinson's disease and related disorders and explain the non-motor complications which occur subsequent to deep brain stimulation (DBS) of the PPN.

Neurochemically distinct populations of the bed nucleus of stria terminalis modulate innate fear response to weak threat evoked by predator odor stimuli

Anxiety and trauma-related disorders are characterized by significant alterations in threat detection, resulting in inadequate fear responses evoked by weak threats or safety stimuli. Recent research pointed out the important role of the bed nucleus of stria terminalis (BNST) in threat anticipation and fear modulation under ambiguous threats, hence, exaggerated fear may be traced back to altered BNST function. To test this hypothesis, we chemogenetically inhibited specific BNST neuronal populations (corticotropin-releasing hormone - BNSTCRH and somatostatin - BNSTSST expressing neurons) in a predator odor-evoked innate fear paradigm. The rationale for this paradigm was threefold: (1) predatory cues are particularly strong danger signals for all vertebrate species evoking defensive responses on the flight-avoidance-freezing dimension (conservative mechanisms), (2) predator odor can be presented in a scalable manner (from weak to strong), and (3) higher-order processing of olfactory information including predatory odor stimuli is integrated by the BNST. Accordingly, we exposed adult male mice to low and high predatory threats presented by means of cat urine, or low- and high-dose of 2-methyl-2-thiazoline (2MT), a synthetic derivate of a fox anogenital product, which evoked low and high fear response, respectively. Then, we tested the impact of chemogenetic inhibition of BNSTCRH and BNSTSST neurons on innate fear responses using crh- and sst-ires-cre mouse lines. We observed that BNSTSST inhibition was effective only under low threat conditions, resulting in reduced avoidance and increased exploration of the odor source. In contrast, BNSTCRH inhibition had no impact on 2MT-evoked responses, but enhanced fear responses to cat odor, representing an even weaker threat stimulus. These findings support the notion that BNST is recruited by uncertain or remote, potential threats, and CRH and SST neurons orchestrate innate fear responses in complementary ways.

Persistent autism-relevant behavioral phenotype and social neuropeptide alterations in female mice offspring induced by maternal transfer of PBDE congeners in the commercial mixture DE-71

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

Distribution of electric field in patients with obsessive compulsive disorder treated with deep brain stimulation of the bed nucleus of stria terminalis

BackgroundDeep brain stimulation (DBS) is being investigated as a treatment for therapy-refractory obsessive compulsive disorder (OCD). Many different brain targets are being trialled. Several of these targets such as the ventral striatum (including the nucleus accumbens (NAc)), the ventral capsule, the inferior thalamic peduncle, and the bed nucleus of stria terminalis (BNST)) belong to the same network, are anatomically very close to one another, or even overlap. Data is still missing on how various stimulation parameters in a given target will affect surrounding anatomical areas and impact the clinical outcome of DBS.MethodsIn a pilot study of eleven participants with DBS of the BNST, we investigate through patient-specific simulation of electric field, which anatomical areas are affected by the electric field, and if this can be related to the clinical results. Our study combined individual patient’s stimulation parameters at 12- and 24-month follow-up with image data from the preoperative MRI and postoperative CT. These data were used to calculate the distribution of electric field and create individual anatomical models of the field of stimulation.ResultsThe individual electric stimulation fields by stimulation in the BNST were similar at both the 12- and 24-month follow-up, involving mainly anterior limb of the internal capsule (ALIC), genu of the internal capsule (IC), BNST, fornix, anteromedial globus pallidus externa (GPe), and the anterior commissure. A statistical significant correlation (p < 0.05) between clinical effect measured by the Yale-Brown Obsessive Compulsive Scale and stimulation was found at the 12-month follow-up in the ventral ALIC and anteromedial GPe.ConclusionsMany of the targets under investigation for OCD are in anatomical proximity. As seen in our study, off-target effects are overlapping. Therefore, DBS in the region of ALIC, NAc, and BNST may perhaps be considered to be stimulation of the same target.

Sexual dimorphism in the bed nucleus of the stria terminalis, medial preoptic area and suprachiasmatic nucleus in male and female tree shrews.

Sex differences in behaviour partly arise from the sexual dimorphism of brain anatomy between males and females. However, the sexual dimorphism of the tree shrew brain is unclear. In the present study, we examined the detailed distribution of vasoactive intestinal polypeptide-immunoreactive (VIP-ir) neurons and fibres in the suprachiasmatic nucleus (SCN) and VIP-ir fibres in the bed nucleus of the stria terminalis (BST) of male and female tree shrews. The overall volume of the SCN in male tree shrews was comparable with that in females. However, males showed a significantly higher density of VIP-ir cells and fibres in the SCN than females. The shape of the VIP-stained area in coronal sections was arched, elongated or oval in the lateral division (STL) and the anterior part of the medial division (STMA) of the BST and oval or round in the posterior part of the medial division of the BST (STMP). The volume of the VIP-stained BST in male tree shrews was similar to that in females. The overall distribution of VIP-ir fibres was similar between the sexes throughout the BST except within the STMA, where darkly stained fibres were observed in males, whereas lightly stained fibres were observed in females. Furthermore, male tree shrews showed a significantly higher intensity of Nissl staining in the medial preoptic area (MPA) and the ventral part of the medial division of the BST than females. These findings are the first to reveal sexual dimorphism in the SCN, BST and MPA of the tree shrew brain, providing neuroanatomical evidence of sexual dimorphism in these regions related to their roles in sex differences in physiology and behaviour.