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Behavioural Brain Research Jan 2021Accurate discrimination between safe and dangerous stimuli is essential for survival. Prior research has begun to uncover the neural structures that are necessary for...
Accurate discrimination between safe and dangerous stimuli is essential for survival. Prior research has begun to uncover the neural structures that are necessary for learning this discrimination, but exploration of brain regions involved in this learning process has been mostly limited to males. Recent findings show sex differences in discrimination learning, with reduced fear expression to safe cues in females compared to males. Here, we used male and female Sprague Dawley rats to explore neural activation, as measured by Fos expression, in fear and safety learning related brain regions. Neural activation after fear discrimination (Discrimination) was compared between males and females, as well as with fear conditioned (Fear Only) and stimulus presented (Control) conditions. Correlations of discrimination ability and neural activation were also calculated. We uncovered a correlation between central amygdala (CeA) activation and discrimination abilities in males and females. Anterior medial bed nucleus of the stria terminalis (BNST) was the only region where sex differences in Fos counts were observed in the Discrimination condition, and the only region where neural activation significantly differed between Fear Only and Discrimination conditions. Together, these findings indicate the importance of fear expression circuitry in mediating discrimination responses and generate important questions for future investigation.
Topics: Animals; Behavior, Animal; Central Amygdaloid Nucleus; Conditioning, Classical; Discrimination Learning; Fear; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Septal Nuclei; Sex Characteristics
PubMed: 32871228
DOI: 10.1016/j.bbr.2020.112884 -
NeuroImage Aug 2014Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in... (Comparative Study)
Comparative Study
Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analyzed using septal probabilistic maps and DARTEL toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p<.001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region.
Topics: Adolescent; Adult; Automation; Brain Mapping; Epilepsy, Temporal Lobe; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Observer Variation; Septal Nuclei; Young Adult
PubMed: 24736183
DOI: 10.1016/j.neuroimage.2014.04.026 -
Cell Reports Nov 2022Stress is a risk factor for emotion and energy metabolism disorders. However, the neurocircuitry mechanisms for emotion initiation and glucose mobilization underlying...
Stress is a risk factor for emotion and energy metabolism disorders. However, the neurocircuitry mechanisms for emotion initiation and glucose mobilization underlying stress responses are unclear. Here we demonstrate that photoactivation of Gad2+ projection from the anterior bed nucleus of the stria terminalis (aBNST) to the arcuate nucleus (ARC) induces anxiety-like behavior as well as acute hyperglycemia. Photoinhibition of the circuit is anxiolytic and blocks hyperglycemia induced by restraint stress. Pharmacogenetic inhibition of the ARC→raphe obscurus nucleus (ROb) and photoactivation of the aBNST→ARC circuits simultaneously leads to significant hypoglycemia and anxiety-like behavior. Pharmacogenetic inhibition of the ARC→nucleus of the solitary tract (NTS) whilst photoactivation of the aBNST→ARC circuit only induces hyperglycemia. Our results reveal that the aBNST→ARC→ROb circuit is recruited for the stress response of rapid glucose mobilization and the aBNST→ARC→NTS circuit for behavioral symptoms of stress response. This study identifies a possible general strategy for neurocircuitry structural organization dealing with multiple organs involved in responses, with potential therapeutic targets for emotion and energy metabolism disorders underlying psychiatric disorders.
Topics: Humans; Glucose; Septal Nuclei; Anxiety; Arcuate Nucleus of Hypothalamus; Hyperglycemia
PubMed: 36351404
DOI: 10.1016/j.celrep.2022.111586 -
NeuroImage Apr 2020The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use...
The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.
Topics: Adolescent; Adult; Cerebral Cortex; Diffusion Tensor Imaging; Echo-Planar Imaging; Female; Humans; Male; Middle Aged; Nerve Net; Septal Nuclei; Sex Characteristics; Sex Factors; Young Adult
PubMed: 31954845
DOI: 10.1016/j.neuroimage.2020.116555 -
The European Journal of Neuroscience May 2022The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic, neuropeptide-rich node of the extended amygdala that has been implicated in responses to stress,... (Review)
Review
The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic, neuropeptide-rich node of the extended amygdala that has been implicated in responses to stress, drugs of abuse, and natural rewards. Its function is dysregulated in neuropsychiatric disorders that are characterized by stress- or drug-induced alterations in mood, arousal, motivation, and social behavior. However, compared to the BNST's role in mood, arousal, and motivation, its role in social behavior has remained relatively understudied. Moreover, the precise cell types and circuits underlying the BNST's role in social behavior have only recently begun to be explored using modern neuroscience techniques. Here, we systematically review the existing literature investigating the neurobiological substrates within the BNST that contribute to the coordination of various sex-dependent and sex-independent social behavioral repertoires, focusing largely on pharmacological and circuit-based behavioral studies in rodents. We suggest that the BNST coordinates social behavior by promoting appropriate assessment of social contexts to select relevant behavioral outputs and that disruption of socially relevant BNST systems by stress and drugs of abuse may be an important factor in the development of social dysfunction in neuropsychiatric disorders.
Topics: Amygdala; Neuropeptides; Septal Nuclei; Social Behavior
PubMed: 33006806
DOI: 10.1111/ejn.14991 -
Frontiers in Endocrinology 2022Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a pleiotropic neuropeptide, is widely distributed throughout the body. The abundance of PACAP expression in... (Review)
Review
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a pleiotropic neuropeptide, is widely distributed throughout the body. The abundance of PACAP expression in the central and peripheral nervous systems, and years of accompanying experimental evidence, indicates that PACAP plays crucial roles in diverse biological processes ranging from autonomic regulation to neuroprotection. In addition, PACAP is also abundantly expressed in the hypothalamic areas like the ventromedial and arcuate nuclei (VMN and ARC, respectively), as well as other brain regions such as the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and ventral tegmental area (VTA) - suggesting that PACAP is capable of regulating energy homeostasis both the homeostatic and hedonic energy balance circuitries. The evidence gathered over the years has increased our appreciation for its function in controlling energy balance. Therefore, this review aims to further probe how the pleiotropic actions of PACAP in regulating energy homeostasis is influenced by sex and dynamic changes in energy status. We start with a general overview of energy homeostasis, and then introduce the integral components of the homeostatic and hedonic energy balance circuitries. Next, we discuss sex differences inherent to the regulation of energy homeostasis these two circuitries, as well as the activational effects of sex steroid hormones that bring about these intrinsic disparities between males and females. Finally, we explore the multifaceted role of PACAP in regulating homeostatic and hedonic feeding through its actions in regions like the NAc, BNST, and in particular the ARC, VMN and VTA that occur in sex- and energy status-dependent ways.
Topics: Energy Metabolism; Female; Homeostasis; Humans; Hypothalamus; Male; Pituitary Adenylate Cyclase-Activating Polypeptide; Septal Nuclei
PubMed: 35721722
DOI: 10.3389/fendo.2022.877647 -
NeuroImage Jun 2022Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural...
Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.
Topics: Animals; Hippocampus; Humans; Hypothalamo-Hypophyseal System; Macaca; Pituitary-Adrenal System; Septal Nuclei
PubMed: 35304264
DOI: 10.1016/j.neuroimage.2022.119096 -
Neuropsychopharmacology : Official... Jan 2016The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress... (Review)
Review
The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress leads to long-term maladaptive changes that increase vulnerability to psychiatric disorders, such as anxiety and addiction. These two disorders are the most prevalent psychiatric disorders in the United States, and are typically chronic, disabling, and highly comorbid. Emerging evidence implicates a tiny brain region-the bed nucleus of the stria terminalis (BNST)-in the body's stress response and in anxiety and addiction. Rodent studies provide compelling evidence that the BNST plays a central role in sustained threat monitoring, a form of adaptive anxiety, and in the withdrawal and relapse stages of addiction; however, little is known about the role of BNST in humans. Here, we review current evidence for BNST function in humans, including evidence for a role in the production of both adaptive and maladaptive anxiety. We also review preliminary evidence of the role of BNST in addiction in humans. Together, these studies provide a foundation of knowledge about the role of BNST in adaptive anxiety and stress-related disorders. Although the field is in its infancy, future investigations of human BNST function have tremendous potential to illuminate mechanisms underlying stress-related disorders and identify novel neural targets for treatment.
Topics: Animals; Anxiety; Behavior, Addictive; Fear; Humans; Septal Nuclei
PubMed: 26105138
DOI: 10.1038/npp.2015.185 -
Molecules and Cells Jan 2015Recent technical developments have transformed how neuroscientists can probe brain function. What was once thought to be difficult and perhaps impossible, stimulating a... (Review)
Review
Recent technical developments have transformed how neuroscientists can probe brain function. What was once thought to be difficult and perhaps impossible, stimulating a single set of long range inputs among many, is now relatively straight-forward using optogenetic approaches. This has provided an avalanche of data demonstrating causal roles for circuits in a variety of behaviors. However, despite the critical role that neuropeptide signaling plays in the regulation of behavior and physiology of the brain, there have been remarkably few studies demonstrating how peptide release is causally linked to behaviors. This is likely due to both the different time scale by which peptides act on and the modulatory nature of their actions. For example, while glutamate release can effectively transmit information between synapses in milliseconds, peptide release is potentially slower [See the excellent review by Van Den Pol on the time scales and mechanisms of release (van den Pol, 2012)] and it can only tune the existing signals via modulation. And while there have been some studies exploring mechanisms of release, it is still not as clearly known what is required for efficient peptide release. Furthermore, this analysis could be complicated by the fact that there are multiple peptides released, some of which may act in contrast. Despite these limitations, there are a number of groups making progress in this area. The goal of this review is to explore the role of peptide signaling in one specific structure, the bed nucleus of the stria terminalis, that has proven to be a fertile ground for peptide action.
Topics: Animals; Humans; Neurons; Neuropeptides; Septal Nuclei; Signal Transduction
PubMed: 25475545
DOI: 10.14348/molcells.2015.2261 -
Nature Communications Mar 2023Binge alcohol consumption induces discrete social and arousal disturbances in human populations that promote increased drinking and accelerate the progression of Alcohol...
Binge alcohol consumption induces discrete social and arousal disturbances in human populations that promote increased drinking and accelerate the progression of Alcohol Use Disorder. Here, we show in a mouse model that binge alcohol consumption disrupts social recognition in females and potentiates sensorimotor arousal in males. These negative behavioral outcomes were associated with sex-specific adaptations in serotonergic signaling systems within the lateral habenula (LHb) and the bed nucleus of the stria terminalis (BNST), particularly those related to the receptor 5HT. While both BNST and LHb neurons expressing this receptor display potentiated activation following binge alcohol consumption, the primary causal mechanism underlying the effects of alcohol on social and arousal behaviors appears to be excessive activation of LHb neurons. These findings may have valuable implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brain's serotonin system.
Topics: Humans; Male; Female; Mice; Animals; Alcoholism; Binge Drinking; Serotonin; Neurons; Alcohol Drinking; Arousal; Ethanol; Septal Nuclei
PubMed: 37002196
DOI: 10.1038/s41467-023-36808-2