Biology subjects

Haun, H.

Publications and source records attributed to Haun, H..

6 recordsLinked to original sources

bioRxiv2024

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

BackgroundBinge 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. MethodsIn 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. ResultsUsing 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. ConclusionsThese 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.

neuroscience↗

bioRxiv2024

Retrieval of an ethanol-conditioned taste aversion promotes GABAergic plasticity in the insular cortex

Blunted sensitivity to ethanols aversive effects can increase motivation to consume ethanol; yet, the neurobiological circuits responsible for encoding these aversive properties are not fully understood. Plasticity in cells projecting from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for taste aversion learning and retrieval, suggesting this circuits potential involvement in modulating the aversive properties of ethanol. Here, we tested the hypothesis that GABAergic activity onto IC-BLA projections would be facilitated following the retrieval of an ethanol-conditioned taste aversion (CTA). Consistent with this hypothesis, frequency of mIPSCs was increased following retrieval of an ethanol-CTA across cell layers in IC-BLA projection neurons. This increase in GABAergic plasticity occurred in both a circuit-specific and learning-dependent manner. Additionally, local inhibitory inputs onto layer 2/3 IC-BLA projection neurons were greater in number and strength following ethanol-CTA. Finally, DREADD-mediated inhibition of IC parvalbumin-expressing cells blunted the retrieval of ethanol-CTA in male, but not female, mice. Collectively, this work implicates a circuit-specific and learning-dependent increase in GABAergic tone following retrieval of an ethanol-CTA, thereby advancing our understanding of how the aversive effects of ethanol are encoded in the brain. Significance statementSensitivity to the aversive properties of ethanol contributes to motivation to consume alcohol. However, the plasticity-associated mechanisms through which ethanols aversive effects are represented within neural circuits are largely unidentified. In the present study, we used whole-cell patch clamp electrophysiology combined with synaptic input mapping to identify alterations in GABAergic plasticity within the insula, and within cells projecting from the insula to the basolateral amygdala. We demonstrate learning and circuit-specific alterations in GABAergic tone following retrieval of an ethanol-conditioned taste aversion, as well as a male-specific role for Parvalbumin-expressing interneurons in modulating the strength of an ethanol-conditioned taste aversion. Combined, these findings provide novel insights into how the aversive properties of ethanol are encoded within brain circuitry.

neuroscience↗

bioRxiv2024

Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system.

High intensity alcohol drinking during binge episodes overwhelmingly contributes to the socioeconomic burden created by Alcohol Use Disorders (AUD). Novel interventions are needed to add to the current therapeutic toolkit and nociceptin receptor (NOP) antagonists have shown promise in reducing heavy drinking days in patients with an AUD. However, an endogenous locus of nociceptin peptide and discrete sites of NOP action underlying this effect remains understudied. Here we show that the lateral septum (LS), a region contributing to binge drinking, is enriched in neurons expressing mRNA coding for the nociceptin peptide (Pnoc). Pnoc-expressing neurons of the LS (LSPnoc) are tuned to stimuli associated with negative valence and display increased excitability during withdrawal from binge-like alcohol drinking. LSPnoc activation was found to have aversive qualities and also potentiates binge-like drinking behavior, suggesting a convergence of circuitry that promotes aversion and drives alcohol consumption. Viral mediated tracing and functional assessment of LSPnoc projection fields revealed GABAergic synapses locally within the LS, and downstream within the lateral hypothalamus (LH) and supramammillary nucleus (SuM). Genetic deletion of NOP from the LS attenuated binge-like alcohol intake in male mice while NOP deletion from the LH and SuM decrease alcohol intake in females. Together, these findings are the first to demonstrate an endogenous population of nociceptin-expressing neurons that contributes to alcohol consumption and identifies sex-dependent modulation of alcohol drinking by NOP.

neuroscience↗

bioRxiv2023

Disentangling the effects of Corticotrophin Releasing Factor and GABA release from the ventral bed nucleus of the stria terminalis on ethanol self-administration in mice

Excessive alcohol use causes a great deal of harm and negative health outcomes. Corticotrophin releasing factor (CRF), a stress-related neuropeptide, has been implicated in binge ethanol intake and ethanol dependence. CRF containing neurons in the bed nucleus of the stria terminalis (BNSTCRF) can control ethanol consumption. These BNSTCRF neurons also release GABA, raising the question, is it CRF or GABA release or both that is controlling alcohol consumption. Here, we used viral vectors to separate the effects of CRF and GABA release from BNSTCRF neurons on the escalation of ethanol intake in an operant self-administration paradigm in male and female mice. We found that CRF deletion in BNST neurons reduces ethanol intake in both sexes, with a stronger effect in males. For sucrose self-administration there was no effect of CRF deletion. Suppression of GABA release, via knockdown of vGAT, from BNSTCRF produced a transient increase in ethanol operant self-administration following in male mice, and reduced in motivation to work for sucrose on a progressive ratio schedule of reinforcement in a sex-dependent manner. Together, these results highlight how different signaling molecules from the same populations of neurons can bidirectionally control behavior. Moreover, they suggest that BNST CRF release is important for high intensity ethanol drinking that precedes dependence, whereas GABA release from these neurons may play a role in regulating motivation.

neuroscience↗

bioRxiv2022

Alcohol dependence modifies brain networks activated during abstinence and reaccess: a c-fos-based analysis in mice

High-level alcohol consumption causes neuroplastic changes in the brain that lead to negative affective and somatic symptoms when alcohol is withdrawn, promoting relapse drinking. We have some understanding of these plastic changes in defined brain circuits and cell types, but unbiased approaches are needed to explore broader patterns of adaptations. Here, we employed whole-brain c-fos mapping and network analysis to assess how brain-wide patterns of neuronal activity are altered during acute alcohol abstinence and reaccess in a well-characterized model of alcohol dependence. Mice underwent four cycles of chronic intermittent ethanol vapor exposure (CIE) with alternating weeks of voluntary alcohol drinking, and a subset of mice underwent forced swim stress (FSS) prior to drinking sessions to further escalate alcohol consumption. After four CIE cycles, brains were collected from mice in each group either 24 hours (abstinence) or immediately following a one-hour period of alcohol reaccess. Brains from CIE mice during acute abstinence displayed widespread neuronal activation relative to those from AIR mice, independent of FSS, and this increase in c-fos was reversed by reaccess drinking. For network analysis, mice were then classified as high or low drinkers (HD or LD). We computed Pearson correlations for all pairs of brain regions and used graph theoretical methods to identify changes in network properties associated with high-drinking behavior. Network modularity, a measure of network segregation into communities, was increased in HD mice after alcohol reaccess relative to abstinence. Within-community strength and diversity measures were computed for each region and condition, and highly coactive regions were identified. One high-diversity region, the cortical amygdala (COA), was further interrogated using a chemogenetic approach. COA silencing in CIE mice reduced voluntary drinking, validating our network analysis and indicating that this region may play an important but underappreciated role in alcohol dependence.

neuroscience↗

bioRxiv2022

Chronic Alcohol Consumption Alters Home-Cage Behaviors and Responses to Ethologically Relevant Predator Tasks in Mice

Alcohol use disorders (AUD) are the most prevalent substance use disorders worldwide. Considering recent reports indicating an increase in alcohol use particularly in females, it is vital to understand how alcohol history impacts behavior. Animal model research on withdrawal-associated affective states tends to focus on males, forced alcohol paradigms, and a few traditional anxiety/stress tests. While this has been essential, heavy alcohol use triggers adverse withdrawal-related affective states that can influence how people respond to a large variety of life events and stressors. To this end, we show that behaviors in the home-cage, open field, looming disc, and robogator predator threat task, which vary in task demand and intensity, are altered in mice with a history of voluntary alcohol consumption. In alcohol-exposed males, behaviors in the home cage, a low anxiety baseline environment, suggest increased vigilance/exploration. However, in the open field and robogator task, which induce heightened arousal and task demands, a more hesitant/avoidant phenotype is seen. Female alcohol mice show no behavioral alterations in the home cage and open field test, however, in the looming disc task, which mimics an overhead advancing predator and forces a behavioral choice, we see greater escape responses compared to water controls, indicative of active stress coping behaviors. This suggests females may begin to show alcohol-induced alterations as task demands increase. To date, few drugs have advanced past clinical trials for the treatment of AUD, and those that have are predominately used in life-threatening situations only. No treatments exist for ameliorating negative withdrawal related states, which could aid in harm reduction related to heavy alcohol use. Understanding how withdrawal alters a variety of behavioral responses that are linked to stress coping can widen our understanding of alcohol abuse and lead us closer to better therapeutics to help individuals with AUD.

neuroscience↗