Activation of VGluT2-expressing neurons in the bed nuclei of the stria terminalis produces mouse manic-like behaviors.
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ABSTRACT:
SUBMITTER: Liu TT
PROVIDER: S-EPMC7816202 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Activation of VGluT2-expressing neurons in the bed nuclei of the stria terminalis produces mouse manic-like behaviors.
Liu Ting-Ting TT Lin Wei W Zhang Yu-Qiu YQ
CNS neuroscience & therapeutics 20201227 2
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Project description:Corticotropin-releasing factor (CRF) in the anterior bed nucleus of the stria terminalis (aBNST) is associated with chronic stress and avoidance behavior. However, CRF + BNST neurons project to reward- and motivation-related brain regions, suggesting a potential role in motivated behavior. We used chemogenetics to selectively activate CRF+ aBNST neurons in male and female CRF-ires-Cre mice during an effort-related choice task and a concurrent choice task. In both tasks, mice were given the option either to exert effort for high value rewards or to choose freely available low value rewards. Acute chemogenetic activation of CRF+ aBNST neurons reduced barrier climbing for a high value reward in the effort-related choice task in both males and females. Furthermore, acute chemogenetic activation of CRF+ aBNST neurons also reduced effortful lever pressing in high-performing males in the concurrent choice task. These data suggest a novel role for CRF+ aBNST neurons in effort-based decision and motivation behaviors.
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Project description:There is extensive evidence that glucocorticoid hormones enhance memory consolidation, helping to ensure that emotionally significant events are well remembered. Prior findings suggest that the anteroventral region of bed nuclei of the stria terminalis (avBST) regulates glucocorticoid release, suggesting the potential for avBST activity to influence memory consolidation following an emotionally arousing learning event. To investigate this issue, male Sprague-Dawley rats underwent inhibitory avoidance training and repeated measurement of stress hormones, immediately followed by optogenetic manipulations of either the avBST or its projections to downstream regions, and 48 h later were tested for retention. The results indicate that avBST inhibition augmented posttraining pituitary-adrenal output and enhanced the memory for inhibitory avoidance training. Pretreatment with a glucocorticoid synthesis inhibitor blocked the memory enhancement as well as the potentiated corticosterone response, indicating the dependence of the memory enhancement on glucocorticoid release during the immediate posttraining period. In contrast, posttraining avBST stimulation decreased retention yet had no effect on stress hormonal output. Subsequent experiments revealed that inhibition of avBST input to the paraventricular hypothalamus enhanced stress hormonal output and subsequent retention, whereas stimulation did not affect either. Conversely, stimulation-but not inhibition-of avBST input to the ventrolateral periaqueductal gray impaired consolidation, whereas neither manipulation affected glucocorticoid secretion. These findings indicate that divergent pathways from the avBST are responsible for the mnemonic effects of avBST inhibition versus stimulation and do so via glucocorticoid-dependent and -independent mechanisms, respectively.
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Project description:The bed nucleus of the stria terminalis (BNST) and the laterobasal nucleus (LB), centromedial nucleus (CM), and superficial nucleus (SF) of the amygdala form an interconnected dynamical system, whose combined activity mediates a variety of behavioral and autonomic responses in reaction to homeostatic challenges. Although previous research provided deeper insight into the structural and functional connections between these nuclei, studies investigating their resting-state functional magnetic resonance imaging (fMRI) connectivity were solely based on undirected connectivity measures. Here, we used high-quality data of 391 subjects from the Human Connectome Project to estimate the effective connectivity (EC) between the BNST, the LB, CM, and SF through spectral dynamic causal modeling, the relation of the EC estimates with age and sex as well as their stability over time. Our results reveal a time-stable asymmetric EC structure with positive EC between all amygdala nuclei, which strongly inhibited the BNST while the BNST exerted positive influence onto all amygdala nuclei. Simulation of the impulse response of the estimated system showed that this EC structure shapes partially antagonistic (out of phase) activity flow between the BNST and amygdala nuclei. Moreover, the BNST-LB and BNST-CM EC parameters were less negative in males. In conclusion, our data points toward partially separated information processing between BNST and amygdala nuclei in the resting-state.
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Project description:Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNST→LH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNST→LH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.
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Project description:Dysregulation of the dopamine (DA) system is a hallmark of substance use 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 GABA neurons (BNST vgat Drd2) and interrogated the impact on alcohol-related behaviors. In male mice, reduced BNST vgat Drd2 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 BNST vgat Drd2 knockdown also increased sucrose intake in male mice. Interestingly, reduction in BNST vgat Drd2 expression 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.
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Project description:Neurovascular coupling is understood to be the underlying mechanism of functional hyperemia, but the actions of the neurotransmitters involved are not well characterized. Here we investigate the local role of the neurotransmitter norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat by measuring O₂, which is delivered during functional hyperemia. Extracellular changes in norepinephrine and O₂ were simultaneously monitored using fast-scan cyclic voltammetry. Introduction of norepinephrine by electrical stimulation of the ventral noradrenergic bundle or by iontophoretic ejection induced an initial increase in O₂ levels followed by a brief dip below baseline. Supporting the role of a hyperemic response, the O₂ increases were absent in a brain slice containing the vBNST. Administration of selective pharmacological agents demonstrated that both phases of this response involve β-adrenoceptor activation, where the delayed decrease in O₂ is sensitive to both α- and β-receptor subtypes. Selective lesioning of the locus coeruleus with the neurotoxin DSP-4 confirmed that these responses are caused by the noradrenergic cells originating in the nucleus of the solitary tract and A1 cell groups. Overall, these results support that non-coerulean norepinephrine release can mediate activity-induced O₂ influx in a deep brain region.
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Project description:Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II+ (CaMKII+) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRNDA → dBNSTCaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.
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Project description:The activity of neurons in the anterolateral cell group of the bed nucleus of the stria terminalis (BNST(ALG)) plays a critical role in anxiety- and stress-related behaviors. Histochemical studies have suggested that multiple distinct neuronal phenotypes exist in the BNST(ALG). Consistent with this observation, the physiological properties of BNST(ALG) neurons are also heterogeneous, and three distinct cell types can be defined (Types I-III) based primarily on their expression of four key membrane currents, namely I(h), I(A), I(T), and I(K(IR)). Significantly, all four channels are multimeric proteins and can comprise of more than one pore-forming α subunit. Hence, differential expression of α subunits may further diversify the neuronal population. However, nothing is known about the relative expression of these ion channel α subunits in BNST(ALG) neurons. We have addressed this lacuna by combining whole-cell patch-clamp recording together with single-cell reverse transcriptase polymerase chain reaction (scRT-PCR) to assess the mRNA transcript expression for each of the subunits for the four key ion channels in Type I-III neurons of the BNST(ALG.) Here, cytosolic mRNA from single neurons was probed for the expression of transcripts for each of the α subunits of I(h) (HCN1-HCN4), I(T) (Ca(v)3.1-Ca(v)3.3), I(A) (K(v)1.4, K(v)3.4, K(v)4.1-K(v) 4.3) and I(K(IR)) (Kir2.1-Kir2.4). An unbiased hierarchical cluster analysis followed by discriminant function analysis revealed that a positive correlation exists between the physiological and genetic phenotype of BNST(ALG) neurons. Thus, the analysis segregated BNST(ALG) neurons into 3 distinct groups, based on their α subunit mRNA expression profile, which positively correlated with our existing electrophysiological classification (Types I-III). Furthermore, analysis of mRNA transcript expression in Type I-Type III neurons suggested that, whereas Type I and III neurons appear to represent genetically homologous cell populations, Type II neurons may be further subdivided into three genetically distinct subgroups. These data not only validate our original classification scheme, but further refine the classification at the molecular level, and thus identifies novel targets for potential disruption and/or pharmacotherapeutic intervention in stress-related anxiety-like behaviors.
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Project description:As stressful environment is a potent modulator of feeding, we seek in the present work to decipher the neuroanatomical basis for an interplay between stress and feeding behaviors. For this, we combined anterograde and retrograde tracing with immunohistochemical approaches to investigate the patterns of projections between the dorsomedial division of the bed nucleus of the stria terminalis (BNST), well connected to the amygdala, and hypothalamic structures such as the paraventricular (PVH) and dorsomedial (DMH), the arcuate (ARH) nuclei and the lateral hypothalamic areas (LHA) known to control feeding and motivated behaviors. We particularly focused our study on afferences to proopiomelanocortin (POMC), agouti-related peptide (AgRP), melanin-concentrating-hormone (MCH) and orexin (ORX) neurons characteristics of the ARH and the LHA, respectively. We found light to intense innervation of all these hypothalamic nuclei. We particularly showed an innervation of POMC, AgRP, MCH and ORX neurons by the dorsomedial and dorsolateral divisions of the BNST. Therefore, these results lay the foundation for a better understanding of the neuroanatomical basis of the stress-related feeding behaviors.
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Project description:The basolateral amygdala (BLA) is thought to be essential for fear learning. However, extensive training can overcome the loss of conditional fear evident following lesions and inactivation of the BLA. Such results suggest the existence of a primary BLA-dependent and a compensatory BLA-independent neural circuit. We tested the hypothesis that the bed nuclei of the stria terminalis (BST) provides this compensatory plasticity. Using extensive context-fear conditioning, we demonstrate that combined BLA and BST lesions prevented fear acquisition and expression. Additionally, protein synthesis in the BST was critical only for consolidation of BLA-independent but not BLA-dependent fear. Moreover, fear acquired after BLA lesions resulted in greater activation of BST regions that receive hippocampal efferents. These results suggest that the BST is capable of functioning as a compensatory site in the acquisition and consolidation of context-fear memories. Unlocking such neural compensation holds promise for understanding situations when brain damage impairs normal function or failure to regulate compensatory sites leads to anxiety disorders.
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