Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

Rodriguez, Larry; Kirson, Dean; Wolfe, Sarah A.; Patel, Reesha R.; Varodayan, Florence P.; Snyder, Angela E.; Gandhi, Pauravi J.; Khom, Sophia; Vlkolinský, Roman; Bajo, Michal; Steinman, Michael Q.

doi:10.3390/ijms23147842

Cited by 6 publications

(3 citation statements)

References 54 publications

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“…However, it is important to note that CeA neurons from female rats and mice are largely insensitive to the acute effects of ethanol on GABA release. 75 , 76 , 77 Since this phenotype was observed in male Brsk1 −/− brain slices, but male Brsk1 −/− mice did not show altered ethanol intake, the PKCε signalling pathways that regulate these two phenotypes can be dissociated, with GABA release being BRSK1‐dependent and ethanol consumption being BRSK1‐independent in male mice. Future studies are needed to shed light on the mechanisms underlying these differences.…”

Section: Discussionmentioning

confidence: 99%

Brain‐specific serine/threonine‐protein kinase 1 is a substrate of protein kinase C epsilon involved in sex‐specific ethanol and anxiety phenotypes

Dugan,

Maiya,

Fleischer

et al. 2024

Addiction Biology

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Protein kinase C epsilon (PKCε) regulates behavioural responses to ethanol and plays a role in anxiety‐like behaviour, but knowledge is limited on downstream substrates of PKCε that contribute to these behaviours. We recently identified brain‐specific serine/threonine‐protein kinase 1 (BRSK1) as a substrate of PKCε. Here, we test the hypothesis that BRSK1 mediates responses to ethanol and anxiety‐like behaviours that are also PKCε dependent. We used in vitro kinase assays to further validate BRSK1 as a substrate of PKCε and used Brsk1−/− mice to assess the role of BRSK1 in ethanol‐ and anxiety‐related behaviours and in physiological responses to ethanol. We found that BRSK1 is phosphorylated by PKCε at a residue identified in a chemical genetic screen of PKCε substrates in mouse brain. Like Prkce−/− mice, male and female Brsk1−/− mice were more sensitive than wild‐type to the acute sedative‐hypnotic effect of alcohol. Unlike Prkce−/− mice, Brsk1−/− mice responded like wild‐type to ataxic doses of ethanol. Although in Prkce−/− mice ethanol consumption and reward are reduced in both sexes, they were reduced only in female Brsk1−/− mice. Ex vivo slice electrophysiology revealed that ethanol‐induced facilitation of GABA release in the central amygdala was absent in male Brsk1−/− mice similar to findings in male Prkce−/− mice. Collectively, these results indicate that BRSK1 is a target of PKCε that mediates some PKCε‐dependent responses to ethanol in a sex‐specific manner and plays a role distinct from PKCε in anxiety‐like behaviour.

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Section: Discussionmentioning

confidence: 99%

Brain‐specific serine/threonine‐protein kinase 1 is a substrate of protein kinase C epsilon involved in sex‐specific ethanol and anxiety phenotypes

Dugan,

Maiya,

Fleischer

et al. 2024

Addiction Biology

Self Cite

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“…It is well established that the amygdala has a role in alcohol drinking. Both the BLA and CEA show dysregulation of corticotropin releasing factor (CRF) circuitry (34)(35)(36)(37)(38)(39)(40)(41)(42). The CEA has known roles in regulating negative affective states, which has been shown to relate alcohol drinking and dependence (43).…”

Section: Sex Differences In Frontloading: Do Males and Females Binge ...mentioning

confidence: 99%

Sex Differences in Neural Networks Recruited by Frontloaded Binge Alcohol Drinking

Ardinger,

Chen,

Kimbrough

et al. 2024

Preprint

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Frontloading is an alcohol drinking pattern where intake is skewed toward the onset of access. The goal of the current study was to identify brain regions involved in frontloading. Whole brain imaging was performed in 63 C57Bl/6J (32 female and 31 male) mice that underwent 8 days of binge drinking using the drinking-in-the-dark (DID) model. On days 1-7, three hours into the dark cycle, mice received 20% (v/v) alcohol or water for two hours. Intake was measured in 1-minute bins using volumetric sippers, which facilitated analyses of drinking patterns. On day 8 mice were perfused 80 minutes into the DID session and brains were extracted. Brains were then processed to stain for Fos protein using iDISCO+. Following light sheet imaging, ClearMap2.1 was used to register brains to the Allen Brain Atlas and detect Fos+ cells. For brain network analyses, day 8 drinking patterns were used to characterize mice as frontloaders or non-frontloaders using a recently developed change-point analysis. Based on this analysis the groups were female frontloaders (n = 20), female non-frontloaders (n = 2), male frontloaders (n = 13) and male non-frontloaders (n = 8). There were no differences in total alcohol intake in animals that frontloaded versus those that did not. Only two female mice were characterized as non-frontloaders, thus preventing brain network analysis of this group. Functional correlation matrices were calculated for each group from log10 Fos values. Euclidean distances were calculated from these R values and hierarchical clustering was used to determine modules (highly connected groups of brain regions). In males, alcohol access decreased modularity (3 modules in both frontloaders and non-frontloaders) as compared to water drinkers (7 modules). In females, an opposite effect was observed. Alcohol access (9 modules for frontloaders) increased modularity as compared to water drinkers (5 modules). These results suggest sex differences in how alcohol consumption reorganizes the functional architecture of neural networks. Next, key brain regions in each network were identified. Connector hubs, which primarily facilitate communication between modules, and provincial hubs, which facilitate communication within modules, were of specific interest for their important and differing roles. In males, 4 connector hubs and 17 provincial hubs were uniquely identified in frontloaders (i.e., were brain regions that did not have this status in male non-frontloaders or water drinkers). These represented a group of hindbrain regions (e.g., locus coeruleus and the pontine gray) functionally connected to striatal/cortical regions (e.g., cortical amygdalar area) by the paraventricular nucleus of the thalamus. In females, 16 connector and 17 provincial hubs were uniquely identified which were distributed across 8 of the 9 modules in the female frontloader alcohol drinker network. Only one brain region (the nucleus raphe pontis) was a connector hub in both sexes, suggesting that frontloading in males and females may be driven by different brain regions. In conclusion, alcohol consumption led to fewer, but more densely connected, groups of brain regions in males but not females, and recruited different hub brain regions between the sexes. These results suggest that alcohol frontloading leads to a reduction in network efficiency in male mice.

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“…CRF1 is found extensively throughout the brain and has been studied in the context of both AUD and affective behaviors. However, most studies focus only on the classical stress regions, such the bed nucleus of the stria terminalis [40][41][42] and the amygdala 41,[43][44][45] despite CRF1 being abundantly expressed in cortical regions [46][47][48] . Indeed, alcohol preferring rats have increased CRF1 levels in the cingulate cortex, motor cortex, and somatosensory cortex 49 .…”

Section: Significance Statementmentioning

confidence: 99%

Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:Tdtomato Transgenic Rats

Quadir

Arleth

Cone

et al. 2022

Preprint

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Alcohol use disorders are complex conditions characterized in part by excessive ethanol (EtOH) drinking and withdrawal-induced malaise. The corticotropin releasing factor-1 receptor (CRF1) has been implicated in EtOH drinking, affective states, and pain sensitivity; often in a sex-dependent manner. The studies presented here investigate the associations between baseline behavior, chronic intermittent EtOH intake, and withdrawal-induced affective behavior in male and female CRF1:cre:tdTomato rats. There were no sex differences in basal affective state or thermal sensitivity, as measured by the splash test, novelty suppressed feeding test, and Hargreaves, respectively. However, female rats displayed increased mechanical sensitivity, measured by the Von Frey test. Following baseline testing, rats underwent voluntary EtOH or water drinking under intermittent access conditions. Female rats consumed significantly more EtOH, but only during the first week. There were no group effects of EtOH on behavioral tests, but all of the rats demonstrated increased malaise upon repeated testing. There were significant individual differences where affective behavior positively correlated with negative affect in both sexes. There were also significant correlations between EtOH intake and CRF1-cFos co-expression in the infralimbic cortex and basolateral amygdala. EtOH decreased CRF1+ expression in the lateral amygdala, but there were no significant group effects of EtOH on cFos or CRF1-cFos co-expression in the medial prefrontal cortex or amygdala. Together, these results illustrate the complex interplay between affect, pain sensitivity, EtOH drinking, and the role of CRF1 containing neurons in mediating these behaviors.

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Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

Cited by 6 publications

References 54 publications

Brain‐specific serine/threonine‐protein kinase 1 is a substrate of protein kinase C epsilon involved in sex‐specific ethanol and anxiety phenotypes

Brain‐specific serine/threonine‐protein kinase 1 is a substrate of protein kinase C epsilon involved in sex‐specific ethanol and anxiety phenotypes

Sex Differences in Neural Networks Recruited by Frontloaded Binge Alcohol Drinking

Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:Tdtomato Transgenic Rats

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