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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 -
Cell Reports Jul 2023The dorsal bed nucleus of stria terminalis (dBNST) is a pivotal hub for stress response modulation. Dysfunction of dopamine (DA) network is associated with chronic...
The dorsal bed nucleus of stria terminalis (dBNST) is a pivotal hub for stress response modulation. Dysfunction of dopamine (DA) network is associated with chronic stress, but the roles of DA network of dBNST in chronic stress-induced emotional disorders remain unclear. We examine the role of dBNST Drd1 and Drd2 neurons in post-weaning social isolation (PWSI)-induced behavior deficits. We find that male, but not female, PWSI rats exhibit negative emotional phenotypes and the increase of excitability and E-I balance of dBNST Drd2 neurons. More importantly, hypofunction of dBNST Drd2 receptor underlies PWSI-stress-induced male-specific neuronal plasticity change of dBNST Drd2 neurons. Furthermore, chemogenetic activation of dBNST Drd2 neurons is sufficient to induce anxiogenic effects, while Kir4.1-mediated chronic inhibition of dBNST Drd2 neurons ameliorate PWSI-induced anxiety-like behaviors. Our findings reveal an important neural mechanism underlying PWSI-induced sex-specific behavioral abnormalities and potentially provide a target for the treatment of social stress-related emotional disorder.
Topics: Female; Male; Rats; Animals; Anxiety; Neurons; Septal Nuclei; Stress, Psychological; Social Isolation; Receptors, Dopamine D2
PubMed: 37453056
DOI: 10.1016/j.celrep.2023.112799 -
Molecules and Cells Feb 2021The bed nucleus of the stria terminalis (BNST)-a key part of the extended amygdala-has been implicated in the regulation of diverse behavioral states, ranging from... (Review)
Review
The bed nucleus of the stria terminalis (BNST)-a key part of the extended amygdala-has been implicated in the regulation of diverse behavioral states, ranging from anxiety and reward processing to feeding behavior. Among the host of distinct types of neurons within the BNST, recent investigations employing cell type- and projection-specific circuit dissection techniques (such as optogenetics, chemogenetics, deep-brain calcium imaging, and the genetic and viral methods for targeting specific types of cells) have highlighted the key roles of glutamatergic and GABAergic neurons and their axonal projections. As anticipated from their primary roles in excitatory and inhibitory neurotransmission, these studies established that the glutamatergic and GABAergic subpopulations of the BNST oppositely regulate diverse behavioral states. At the same time, these studies have also revealed unexpected functional specificity and heterogeneity within each subpopulation. In this Minireview, we introduce the body of studies that investigated the function of glutamatergic and GABAergic BNST neurons and their circuits. We also discuss unresolved questions and future directions for a more complete understanding of the cellular diversity and functional heterogeneity within the BNST.
Topics: Animals; Behavior; GABAergic Neurons; Glutamates; Humans; Models, Biological; Septal Nuclei
PubMed: 33594012
DOI: 10.14348/molcells.2021.0006 -
Human Brain Mapping Apr 2021Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the...
Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.
Topics: Adult; Central Amygdaloid Nucleus; Cerebral Cortex; Connectome; Female; Humans; Magnetic Resonance Imaging; Male; Multifactorial Inheritance; Nerve Net; Pedigree; Septal Nuclei; Thalamus
PubMed: 33314443
DOI: 10.1002/hbm.25314 -
The Journal of Neuroscience : the... Aug 2016Early work stressed the differing involvement of the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) in the genesis of fear versus anxiety,... (Review)
Review
Early work stressed the differing involvement of the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) in the genesis of fear versus anxiety, respectively. In 2009, Walker, Miles, and Davis proposed a model of amygdala-BNST interactions to explain these functional differences. This model became extremely influential and now guides a new wave of studies on the role of BNST in humans. Here, we consider evidence for and against this model, in the process highlighting central principles of BNST organization. This analysis leads us to conclude that BNST's influence is not limited to the generation of anxiety-like responses to diffuse threats, but that it also shapes the impact of discrete threatening stimuli. It is likely that BNST-CeA interactions are involved in modulating responses to such threats. In addition, whereas current views emphasize the contributions of the anterolateral BNST region in anxiety, accumulating data indicate that the anteromedial and anteroventral regions also play a critical role. The presence of multiple functional subregions within the small volume of BNST raises significant technical obstacles for functional imaging studies in humans.
Topics: Animals; Anxiety; Fear; Humans; Models, Neurological; Nerve Net; Septal Nuclei; Stress, Psychological
PubMed: 27488624
DOI: 10.1523/JNEUROSCI.0856-16.2016 -
Neurology Jan 2013To measure the volume of basal forebrain septal nuclei in patients with temporal lobe epilepsy (TLE) as compared to patients with extratemporal epilepsy and controls. In...
OBJECTIVE
To measure the volume of basal forebrain septal nuclei in patients with temporal lobe epilepsy (TLE) as compared to patients with extratemporal epilepsy and controls. In animal models of TLE, septal lesions facilitate epileptogenesis, while septal stimulation is antiepileptic.
METHOD
Subjects were recruited from 2 sites and consisted of patients with pharmacoresistant focal epilepsy (20 with TLE and mesial temporal sclerosis [MTS], 24 with TLE without MTS, 23 with extratemporal epilepsy) and 114 controls. Septal volume was measured using high-resolution MRI in association with newly developed probabilistic septal nuclei maps. Septal volume was compared between subject groups while controlling for relevant factors.
RESULTS
Patients with TLE without MTS had significantly larger septal nuclei than patients with extratemporal epilepsy and controls. This was not true for patients with MTS. These results are interpreted with reference to prior studies demonstrating expansion of the septo-hippocampal cholinergic system in animal models of TLE and human TLE surgical specimens.
CONCLUSION
Septal nuclei are enlarged in patients with TLE without MTS. Further investigation of septal nuclei and antiepileptic septo-hippocampal neurocircuitry could be relevant to development of new therapeutic interventions such as septal stimulation for refractory TLE.
Topics: Adolescent; Adult; Epilepsy, Temporal Lobe; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Sclerosis; Septal Nuclei; Statistics as Topic; Temporal Lobe; Young Adult
PubMed: 23303846
DOI: 10.1212/WNL.0b013e31827f0ed7 -
NeuroImage May 2014Anxiety and addiction disorders are two of the most common mental disorders in the United States, and are typically chronic, disabling, and comorbid. Emerging evidence...
Anxiety and addiction disorders are two of the most common mental disorders in the United States, and are typically chronic, disabling, and comorbid. Emerging evidence suggests the bed nucleus of the stria terminalis (BNST) mediates both anxiety and addiction through connections with other brain regions, including the amygdala and nucleus accumbens. Although BNST structural connections have been identified in rodents and a limited number of structural connections have been verified in non-human primates, BNST connections have yet to be described in humans. Neuroimaging is a powerful tool for identifying structural and functional circuits in vivo. In this study, we examined BNST structural and functional connectivity in a large sample of humans. The BNST showed structural and functional connections with multiple subcortical regions, including limbic, thalamic, and basal ganglia structures, confirming structural findings in rodents. We describe two novel connections in the human brain that have not been previously reported in rodents or non-human primates, including a structural connection with the temporal pole, and a functional connection with the paracingulate gyrus. The findings of this study provide a map of the BNST's structural and functional connectivity across the brain in healthy humans. In large part, the BNST neurocircuitry in humans is similar to the findings from rodents and non-human primates; however, several connections are unique to humans. Future explorations of BNST neurocircuitry in anxiety and addiction disorders have the potential to reveal novel mechanisms underlying these disabling psychiatric illnesses.
Topics: Amygdala; Brain; Diffusion Tensor Imaging; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Nerve Net; Neural Pathways; Rest; Septal Nuclei; Sex Characteristics
PubMed: 24444996
DOI: 10.1016/j.neuroimage.2014.01.017 -
Neuropsychopharmacology : Official... Jan 2016The anterior bed nucleus of the stria terminalis (BNST) has been recognized as a critical structure in regulating trait anxiety, contextual fear memory, and appetitive... (Review)
Review
The anterior bed nucleus of the stria terminalis (BNST) has been recognized as a critical structure in regulating trait anxiety, contextual fear memory, and appetitive behavior, and is known to be sensitive to stress manipulations. As one of the most complex structures in the central nervous system, the intrinsic circuitry of the BNST is largely unknown; however, recent technological developments have allowed researchers to begin to untangle the internal connections of the nucleus. This research has revealed the possibility of two opposing circuits, one anxiolytic and one anxiogenic, within the BNST, the relative strength of which determines the behavioral outcome. The balance of these pathways is critical in maintaining a normal physiological and behavioral state; however, stress and drugs of abuse can differentially affect the opposing circuitry within the nucleus to shift the balance to a pathological state. In this review, we will examine how stress interacts with the neuromodulators, corticotropin-releasing factor, norepinephrine, dopamine, and serotonin to affect the circuitry of the BNST as well as how synaptic plasticity in the BNST is modulated by stress, resulting in long-lasting changes in the circuit and behavioral state.
Topics: Animals; Corticotropin-Releasing Hormone; Dopamine; Humans; Nerve Net; Neuronal Plasticity; Norepinephrine; Septal Nuclei; Serotonin; Stress, Psychological
PubMed: 26096838
DOI: 10.1038/npp.2015.178 -
Frontiers in Neural Circuits 2021The Medial Septum and diagonal Band of Broca (MSDB) was initially studied for its role in locomotion. However, the last several decades were focussed on its intriguing... (Review)
Review
The Medial Septum and diagonal Band of Broca (MSDB) was initially studied for its role in locomotion. However, the last several decades were focussed on its intriguing function in theta rhythm generation. Early studies relied on electrical stimulation, lesions and pharmacological manipulation, and reported an inconclusive picture regarding the role of the MSDB circuits. Recent studies using more specific methodologies have started to elucidate the differential role of the MSDB's specific cell populations in controlling both theta rhythm and behaviour. In particular, a novel theory is emerging showing that different MSDB's cell populations project to different brain regions and control distinct aspects of behaviour. While the majority of these behaviours involve movement, increasing evidence suggests that MSDB-related networks govern the motivational aspect of actions, rather than locomotion . Here, we review the literature that links MSDB, theta activity, and locomotion and propose open questions, future directions, and methods that could be employed to elucidate the diverse roles of the MSDB-associated networks.
Topics: Animals; Diagonal Band of Broca; GABA Agonists; Humans; Locomotion; Motivation; Movement; Nerve Net; Septal Nuclei; Sodium Channel Blockers; Theta Rhythm
PubMed: 34366795
DOI: 10.3389/fncir.2021.699798 -
Journal of Molecular Neuroscience : MN Jul 2019While addiction to drugs of abuse represents a significant health problem worldwide, the behavioral and neural mechanisms that underlie addiction and relapse are largely... (Review)
Review
While addiction to drugs of abuse represents a significant health problem worldwide, the behavioral and neural mechanisms that underlie addiction and relapse are largely unclear. The concept of the dark side of addiction, developed and explored by George Koob and colleagues, describes a systematic decrease in reward-related processing following drug self-administration and subsequent recruitment of anti-reward (i.e., stress) systems. Indeed, the activation of central nervous system (CNS) stress-response systems by drugs of abuse is contributory not only to mood and anxiety-related disorders but critical to both the maintenance of addiction and relapse following abstinence. In both human and animal studies, compounds that activate the bed nucleus of the stria terminalis (BNST) have roles in stress-related behaviors and addiction processes. The activation of pituitary adenylate cyclase-activating peptide (PACAP) systems in the BNST mediates many consequences of chronic stressor exposure that may engage in part downstream corticotropin-releasing hormone (CRH) signaling. Similar to footshock stress, the BNST administration of PACAP or the PAC1 receptor-specific agonist maxadilan can facilitate relapse following extinction of cocaine-seeking behavior. Further, in the same paradigm, the footshock-induced relapse could be attenuated following BNST pretreatment with PAC1 receptor antagonist PACAP6-38, implicating PACAP systems as critical components underlying stress-induced reinstatement. In congruence with previous work, the PAC1 receptor internalization and endosomal MEK/ERK signaling appear contributory mechanisms to the addiction processes. The studies offer new insights and approaches to addiction and relapse therapeutics.
Topics: Animals; Humans; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Septal Nuclei; Signal Transduction; Substance-Related Disorders
PubMed: 30074172
DOI: 10.1007/s12031-018-1147-6