Excessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as ...an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.
Turning the tide on obesity? Bulik, Cynthia M; Hardaway, J Andrew
Science (American Association for the Advancement of Science),
08/2023, Volume:
381, Issue:
6657
Journal Article
Peer reviewed
Open access
Genetics, ultraprocessed foods, portion distortion, sweetened beverages, screen time, food addiction, intestinal microbiota, diet culture, weight stigma, food insecurity-all have been implicated in ...the "obesity epidemic." More than a billion people worldwide have obesity, and many more are overweight. With the emergence of new, highly effective weight-loss drugs, might the "fat decades" become a closed chapter in the history of public health?
Eating disorders (anorexia nervosa, bulimia nervosa and binge-eating disorder) are a heterogeneous class of complex illnesses marked by weight and appetite dysregulation coupled with distinctive ...behavioral and psychological features. Our understanding of their genetics and neurobiology is evolving thanks to global cooperation on genome-wide association studies, neuroimaging, and animal models. Until now, however, these approaches have advanced the field in parallel, with inadequate cross-talk. This review covers overlapping advances in these key domains and encourages greater integration of hypotheses and findings to create a more unified science of eating disorders. We highlight ongoing and future work designed to identify implicated biological pathways that will inform staging models based on biology as well as targeted prevention and tailored intervention, and will galvanize interest in the development of pharmacologic agents that target the core biology of the illnesses, for which we currently have few effective pharmacotherapeutics.
Kappa opioid receptors (KORs) are involved in a variety of aversive behavioral states, including anxiety. To date, a circuit-based mechanism for KOR-driven anxiety has not been described. Here, we ...show that activation of KORs inhibits glutamate release from basolateral amygdala (BLA) inputs to the bed nucleus of the stria terminalis (BNST) and occludes the anxiolytic phenotype seen with optogenetic activation of BLA-BNST projections. In addition, deletion of KORs from amygdala neurons results in an anxiolytic phenotype. Furthermore, we identify a frequency-dependent, optically evoked local dynorphin-induced heterosynaptic plasticity of glutamate inputs in the BNST. We also find that there is cell type specificity to the KOR modulation of the BLA-BNST input with greater KOR-mediated inhibition of BLA dynorphin-expressing neurons. Collectively, these results provide support for a model in which local dynorphin release can inhibit an anxiolytic pathway, providing a discrete therapeutic target for the treatment of anxiety disorders.
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•KORs presynaptically inhibit BLA glutamate transmission in the BNST•Optogenentic activation of local dynorphin neurons produces inhibition of glutamate•Deletion of amygdala KORs produces an anxiolytic phenotype in the elevated plus maze
Crowley et al. demonstrate that kappa opioid receptors (KORs) in the bed nucleus of the stria terminalis (BNST) inhibit pathway-specific glutamate transmission and show optogenetic control of dynorphin release in the BNST. The findings indicate that the basolateral amygdala (BLA), BNST, and KORs are important for the control of anxiety-related behaviors.
Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through ...which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT
) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF
) in mice. Specifically, 5-HT
projections to the BNST, via actions at 5-HT
receptors (5-HT
Rs), engage a CRF
inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF
inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF
R, also known as CRHR1), given that CRF
R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT
→CRF
circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.
The central nucleus of the amygdala plays a significant role in alcohol use and other affective disorders; however, the genetically-defined neuronal subtypes and projections that govern these ...behaviors are not well known. Here we show that neurotensin neurons in the central nucleus of the amygdala of male mice are activated by
ethanol consumption and that genetic ablation of these neurons decreases ethanol consumption and preference in non-ethanol-dependent animals. This ablation did not impact preference for sucrose, saccharin, or quinine. We found that the most robust projection of the central amygdala neurotensin neurons was to the parabrachial nucleus, a brain region known to be important in feeding behaviors, conditioned taste aversion, and alarm. Optogenetic stimulation of projections from these neurons to the parabrachial nucleus is reinforcing, and increases ethanol drinking as well as consumption of sucrose and saccharin solutions. These data suggest that this central amygdala to parabrachial nucleus projection influences the expression of reward-related phenotypes and is a novel circuit promoting consumption of ethanol and palatable fluids.
Alcohol use disorder (AUD) is a major health burden worldwide. Although ethanol consumption is required for the development of AUD, much remains unknown regarding the underlying neural circuits that govern initial ethanol intake. Here we show that ablation of a population of neurotensin-expressing neurons in the central amygdala decreases intake of and preference for ethanol in non-dependent animals, whereas the projection of these neurons to the parabrachial nucleus promotes consumption of ethanol as well as other palatable fluids.
Food palatability is one of many factors that drives food consumption, and the hedonic drive to feed is a key contributor to obesity and binge eating. In this study, we identified a population of ...prepronociceptin-expressing cells in the central amygdala (PnocCeA) that are activated by palatable food consumption. Ablation or chemogenetic inhibition of these cells reduces palatable food consumption. Additionally, ablation of PnocCeA cells reduces high-fat-diet-driven increases in bodyweight and adiposity. PnocCeA neurons project to the ventral bed nucleus of the stria terminalis (vBNST), parabrachial nucleus (PBN), and nucleus of the solitary tract (NTS), and activation of cell bodies in the central amygdala (CeA) or axons in the vBNST, PBN, and NTS produces reward behavior but did not promote feeding of palatable food. These data suggest that the PnocCeA network is necessary for promoting the reinforcing and rewarding properties of palatable food, but activation of this network itself is not sufficient to promote feeding.
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•PnocCeA neurons are activated following palatable food consumption•PnocCeA neurons promote palatable food consumption specifically•PnocCeA neuronal projections in the CeA, vBNST, PBN, and NTS promote reward
Eating calorically dense, palatable foods is a major contributor to obesity and binge eating. In this article, Hardaway et al. identify a central amygdala brain circuit expressing the neuropeptide prepronociceptin in mice that promotes palatable food consumption and reward.
Neuropeptide Regulation of Signaling and Behavior in the BNST Kash, T.L., University of North Carolina at Chapel Hill, USA; Pleil, K.E., University of North Carolina at Chapel Hill, USA; Marcinkiewcz, C.A., University of North Carolina at Chapel Hill, USA ...
Molecules and cells,
01/2015, Volume:
38, Issue:
1
Journal Article
Peer reviewed
Open access
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.
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