Lateral habenula-projecting central amygdala circuits expressing GABA and NPY Y1 receptor modulate binge-like ethanol intake in mice

Companion, Michel A.; González, David Alejandro; Robinson, Stacey L.; Herman, Melissa A.; Thiele, Todd E.

doi:10.1016/j.addicn.2022.100019

Cited by 9 publications

(7 citation statements)

References 53 publications

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“…We found anti-correlation during morphine context exposure, and vice-versa during saline context exposure. Ethanol addiction, binge-like intake of ethanol in mice, reveals enhanced activity of inhibitory projections from CeA to LHb (Companion et al, 2022). While we cannot ascertain the direction of this functional connection, and it is unclear whether negative correlations indeed reflect inhibitory processes at the cellular or circuit level (Becerra et al, 2006; Goelman et al, 2014), we consider plausible that the anti-correlation we found reflects the activity of such inhibitory synapse, resulting in silencing of antireward activity in LHb.…”

Section: Discussionmentioning

confidence: 99%

Mapping functional traces of opioid memories in the rat brain

Gomes-Ribeiro,

Martins,

Sereno

et al. 2023

Preprint

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Addiction to psychoactive substances is a maladaptive learned behavior. Contexts surrounding drug use integrate this aberrant mnemonic process and hold strong relapse triggering ability. Here we asked where context and salience might be concurrently represented in the brain, and found circuitry hubs specific to morphine-related contextual information storage. Starting with a classical rodent morphine-conditioned place preference (CPP) apparatus, we developed a CPP protocol that allows stimuli presentation inside a magnetic resonance imaging scanner, to allow the investigation of whole brain activity during retrieval of drug-context paired associations, as well as resting state functional connectivity under the effect of morphine conditioning. Using fMRI we found context-specific responses to stimulus onset in multiple brain regions, namely limbic, sensory, and striatal. Furthermore, we found increased functional connectivity of lateral septum with regions within and beyond a proposed limbic network, and of the lateral habenula with hippocampal CA1 region, in response to repeated pairings of drug and context. Subsequent exposure to either morphine or saline-conditioned contexts led to significant, context-specific, functional interconnectivity among amygdala, lateral habenula, and lateral septum. Resting-state connectivity of the lateral habenula and amygdala, and that during saline-paired context presentation significantly predicted inter-individual CPP score differences. In sum, our findings show that drug- and saline-paired contexts form distinct memory traces in overlapping functional brain microcircuits, and intrinsic connectivity of habenula, septum, and amygdala likely influences the maladaptive contextual learning in response to opioids. We identify functional mechanisms involved in the acquisition and retrieval of drug-related memories that might be behind the relapse-triggering ability of opioid-associated sensory/contextual cues.

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Section: Discussionmentioning

confidence: 99%

Mapping functional traces of opioid memories in the rat brain

Gomes-Ribeiro,

Martins,

Sereno

et al. 2023

Preprint

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“…CRF is also coexpressed in GABAergic interneurons within the CeA, which may underlie the ability of CRF-neuronal silencing to reduce binge-like consumption (Day et al, 1999; Nie et al, 2009; Roberto et al, 2010), especially given our previous finding that CRF-1 receptor antagonism within the CeA reduced consumption (Lowery et al, 2010). Interestingly, we recently reported that chemogenetic silencing of GABAergic and neuropeptide Y (NPY) Y1 receptor expressing neurons arising from the CeA and innervating the lateral habenula (LHb) significantly blunted binge-like ethanol intake in male and female mice (Companion et al, in press). As CRF is coexpressed with GABA in the CeA, it is possible that blunted binge-like ethanol intake stemming from silencing CRF neurons of the CeA in the present study was modulated by reduced GABA/CRF signaling in the LHb.…”

Section: Discussionmentioning

confidence: 99%

“…Neuronal inhibition of CRF-positive cells within the CeA curbed excessive ethanol consumption. Future studies should examine the specific pathways that underlie the effect within the CeA, as it could be mediated by projections to the LHb, BNST, or VTA (Companion et al, in press; McBride, 2002; Rinker et al, 2017). By inactivating the CRF-neurons, we may be reducing consumption by preventing ethanol’s disinhibition properties as CeA CRF neurons coexpress GABA (Gilpin et al, 2015; Roberto et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic inhibition of corticotropin-releasing factor neurons in the central amygdala alters binge-like ethanol consumption in male mice.

Marshall¹,

Robinson²,

Ebert³

et al. 2022

Behavioral Neuroscience

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Repetitive bouts of binge drinking can lead to neuroplastic events that alter ethanol’s pharmacologic effects and perpetuate excessive consumption. The corticotropin-releasing factor (CRF) system is an example of ethanol-induced neuroadaptations that drive excessive ethanol consumption. Our laboratory has previously shown that CRF antagonist, when infused into the central amygdala (CeA), reduces binge-like ethanol consumption. The present study extends this research by assessing the effects of silencing CRF-producing neurons in CeA on binge-like ethanol drinking stemming from “Drinking in the Dark” (DID) procedures. CRF-ires-Cre mice underwent surgery to infuse Gi/o-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus or a control virus into either the CeA or basolateral amygdala (BLA). Gi/o-DREADD-induced CRF-neuronal inhibition in the CeA resulted in a 33% decrease in binge-like ethanol consumption. However, no effect on ethanol consumption was seen after DREADD manipulation in the BLA. Moreover, CeA CRF-neuronal inhibition had no effect on sucrose consumption. The effects of silencing CRF neurons in the CeA on ethanol consumption are not secondary to changes in motor function or anxiety-like behaviors as assessed in the open-field test (OFT). Finally, the DREADD construct’s functional ability to inhibit CRF-neuronal activity was demonstrated by reduced ethanol-induced c-Fos following DREADD activation. Together, these data suggest that the CRF neurons in the CeA play an important role in binge ethanol consumption and that inhibition of the CRF-signaling pathway remains a viable target for manipulating binge-like ethanol consumption.

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“…Y1 receptors have also been implicated in alcohol consumption, with the inhibition of lateral habenula projecting Y1 receptor containing CeA neurons leading to a reduction in binge-like alcohol consumption, with no effect on sucrose (Companion et al, 2022). Even though the inhibition of Y1 receptor containing CeA neurons projecting to the lateral habenula had a behavioral effect, there were no changes to the inhibitory currents in these neurons after one 4-day cycle of binge-like alcohol consumption (Companion et al, 2022). Overall, these findings show the involvement of NPY on alcohol related behavioral and physiological effects (for a more comprehensive review of the effect of NPY CRFR1 and CRFR2 required to block effect of alcohol on glutamatergic transmission in CeA CRFR1 antagonists reduce alcohol consumption (Finn et al, 2007;Lowery-Gionta et al, 2012;Weera et al, 2020;Walker, 2021) Neuropeptide Y (NPY) CeA M Projections to and from intercalated neurons, BNST…”

Section: Neuropeptide Ymentioning

confidence: 99%

“…Interestingly, both systemic and intra-CeA inhibition of Y2 receptors did not influence alcohol self-administration in alcohol dependent and non-dependent rats ( Kallupi et al, 2014c ). Y1 receptors have also been implicated in alcohol consumption, with the inhibition of lateral habenula projecting Y1 receptor containing CeA neurons leading to a reduction in binge-like alcohol consumption, with no effect on sucrose ( Companion et al, 2022 ). Even though the inhibition of Y1 receptor containing CeA neurons projecting to the lateral habenula had a behavioral effect, there were no changes to the inhibitory currents in these neurons after one 4-day cycle of binge-like alcohol consumption ( Companion et al, 2022 ).…”

Section: Modulators Of Proposed Circuitmentioning

confidence: 99%

Subregional Differences in Alcohol Modulation of Central Amygdala Neurocircuitry

Melkumyan

Silberman

2022

Front. Mol. Neurosci.

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Alcohol use disorder is a highly significant medical condition characterized by an impaired ability to stop or control alcohol use, compulsive alcohol seeking behavior, and withdrawal symptoms in the absence of alcohol. Understanding how alcohol modulates neurocircuitry critical for long term and binge-like alcohol use, such as the central amygdala (CeA), may lead to the development of novel therapeutic strategies to treat alcohol use disorder. In clinical studies, reduction in the volume of the amygdala has been linked with susceptibility to relapse to alcohol use. Preclinical studies have shown the involvement of the CeA in the effects of alcohol use, with lesions of the amygdala showing a reduction in alcohol drinking, and manipulations of cells in the CeA altering alcohol drinking. A great deal of work has shown that acute alcohol, as well as chronic alcohol exposure via intake or dependence models, alters glutamatergic and GABAergic transmission in the CeA. The CeA, however, contains heterogeneous cell populations and distinct subregional differences in neurocircuit architecture which may influence the mechanism by which alcohol modulates CeA function overall. The current review aimed to parse out the differences in alcohol effects on the medial and lateral subregions of the CeA, and what role neuroinflammatory cells and markers, the endocannabinoid system, and the most commonly studied neuropeptide systems play in mediating these effects. A better understanding of alcohol effects on CeA subregional cell type and neurocircuit function may lead to development of more selective pharmacological interventions for alcohol use disorder.

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Lateral habenula-projecting central amygdala circuits expressing GABA and NPY Y1 receptor modulate binge-like ethanol intake in mice

Cited by 9 publications

References 53 publications

Mapping functional traces of opioid memories in the rat brain

Mapping functional traces of opioid memories in the rat brain

Chemogenetic inhibition of corticotropin-releasing factor neurons in the central amygdala alters binge-like ethanol consumption in male mice.

Subregional Differences in Alcohol Modulation of Central Amygdala Neurocircuitry

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