Dataset Information

Inhibiting CRF Projections from the Central Amygdala to Lateral Hypothalamus and Amygdala Deletion of CRF Alters Binge-Like Ethanol Drinking in a Sex-Dependent Manner.

ABSTRACT:

Background

Binge alcohol drinking is a dangerous pattern of consumption that can contribute to the development of more severe alcohol use disorders (AUDs). Importantly, the rate and severity of AUDs has historically differed between men and women, suggesting that there may be sex differences in the central mechanisms that modulate alcohol (ethanol) consumption. Corticotropin releasing factor (CRF) is a centrally expressed neuropeptide that has been implicated in the modulation of binge-like ethanol intake, and emerging data highlight sex differences in central CRF systems.

Methods

In the present report we characterized CRF+ neurocircuitry arising from the central nucleus of the amygdala (CeA) and innervating the lateral hypothalamus (LH) in the modulation of binge-like ethanol intake in male and female mice.

Results

Using chemogenetic tools we found that silencing the CRF+ CeA to LH circuit significantly blunted binge-like ethanol intake in male, but not female, mice. Consistently, genetic deletion of CRF from neurons of the CeA blunted ethanol intake exclusively in male mice. Furthermore, pharmacological blockade of the CRF type-1 receptor (CRF1R) in the LH significantly reduced binge-like ethanol intake in male mice only, while CRF2R activation in the LH failed to alter ethanol intake in either sex. Finally, a history of binge-like ethanol drinking blunted CRF mRNA in the CeA regardless of sex.

Conclusions

These observations provide novel evidence that CRF+ CeA to LH neurocircuitry modulates binge-like ethanol intake in male, but not female mice, which may provide insight into the mechanisms that guide known sex differences in binge-like ethanol intake.

SUBMITTER: Bendrath SC

PROVIDER: S-EPMC11030312 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Publications

Inhibiting CRF Projections from the Central Amygdala to Lateral Hypothalamus and Amygdala Deletion of CRF Alters Binge-Like Ethanol Drinking in a Sex-Dependent Manner.

Bendrath Sophie C SC Méndez Hernán G HG Dankert Anne M AM Lerma-Cabrera Jose Manuel JM Carvajal Francisca F Dornellas-Loper Ana Paula AP Lee Sophia S Neira Sofia S Haun Harold H Delpire Eric E Navarro Montserrat M Kash Thomas L TL Thiele Todd E TE

bioRxiv : the preprint server for biology 20240413

<h4>Background</h4>Binge alcohol drinking is a dangerous pattern of consumption that can contribute to the development of more severe alcohol use disorders (AUDs). Importantly, the rate and severity of AUDs has historically differed between men and women, suggesting that there may be sex differences in the central mechanisms that modulate alcohol (ethanol) consumption. Corticotropin releasing factor (CRF) is a centrally expressed neuropeptide that has been implicated in the modulation of binge-l ...[more]

PMID: 38645149

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Project description:Orexin in both the lateral hypothalamus (LH) and medial septum (MS) is involved in sleep- and consciousness-related conditions. Since orexin modulates the intoxicating as well as rewarding effects of ethanol, this study focused on the role of orexin-projecting neurons from the LH to the MS, and this neurocircuit's role in mediating the sedative effects of alcohol. Drinking-in-the-Dark (DID) behavior was also assessed as a measure of the role of the LH-MS pathway in modulating binge-like ethanol intake, with a particular focus on sex differences in both behavioral paradigms. Male and female Hcrt-ires-cre mice received cannulation in the MS, while the LH was injected bilaterally with cre-dependent excitatory (Gq) Designer Receptor Exclusively Activated by Designer Drug (DREADD), inhibitory (Gi) DREADD or control virus. All subjects received a 3.75 g/kg dose of 20 % ethanol intraperitoneally and the sedative effect was assessed by the loss of righting reflex (LORR). After behavioral testing, brains were used for c-Fos immunohistochemistry analyses. A separate cohort of mice was used for a 2-week DID protocol using excitatory (Gq) DREADD and control virus. Gq DREADD-induced activation of the orexin neurocircuitry from the LH to the MS significantly reduced sedation time in both female and male mice. Furthermore, CNO treatment failed to alter ethanol sedation times in both animals expressing Gi DREADDs and control virus. There were no significant differences in blood ethanol concentrations (BECs) in any experimental group, suggesting that changes in sedation were not due to treatment-induced alterations of ethanol metabolism. Interestingly, in the DID study, only male mice decreased their ethanol consumption when Gq DREADDs were activated. These results provide novel evidence on the role played by this orexinergic LH to MS circuit on the sedative effects of ethanol and ethanol consumption in a sex-dependent manner. Thus, the MS should be considered further as a novel sexually dimorphic target.

Dataset Information

Inhibiting CRF Projections from the Central Amygdala to Lateral Hypothalamus and Amygdala Deletion of CRF Alters Binge-Like Ethanol Drinking in a Sex-Dependent Manner.

Background

Methods

Results

Conclusions

Publications

Inhibiting CRF Projections from the Central Amygdala to Lateral Hypothalamus and Amygdala Deletion of CRF Alters Binge-Like Ethanol Drinking in a Sex-Dependent Manner.

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