Biology subjects

Stanhope, C.

Publications and source records attributed to Stanhope, C..

4 recordsLinked to original sources

bioRxiv2026

The role of serotonin in the orbitofrontal cortex in alcohol consumption

Binge alcohol drinking is a public health concern that can dramatically increase the risk for development of alcohol use disorder (AUD). Continued alcohol drinking in the face of negative consequences is another key feature of AUD. A better understanding of the neural circuitry that regulates these behaviors could provide insight as to novel treatments for AUD. Serotonin is a neurotransmitter that has been implicated in alcohol consumption in both human studies and animal models. The orbitofrontal cortex (OFC) is a brain region that both receives serotonergic input from the dorsal raphe and has been implicated in AUD. However, how volitional alcohol consumption impacts serotonin signaling within the OFC and how this contributes to alcohol related behaviors is unknown. Here, we show that a history of alcohol consumption alters the ability of 5-HT to hyperpolarize OFC pyramidal neurons in mice and monkeys. Consistent with this, a history of binge alcohol consumption decreases the expression of the 5-HT1A but not 5-HT2A receptor in the OFC from mice. Next, we show that deletion of the 5-HT1A receptor from the OFC increased alcohol intake and preference in male, but not female mice. Finally, we found that 5-HT1A receptor deletion led to increased quinine-adulterated alcohol intake, a measure of aversion-resistant drinking, in both male and female mice. Altogether, we identified serotonin signaling in the OFC as key target for modulation of binge and compulsive alcohol consumption.

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↗

bioRxiv2021

Delineation of dynorphin and kappa opioid receptor circuit elements in alcohol consumption

Alcohol use disorder is complex and multi-faceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry. Significance StatementThe insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we utilize converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.

neuroscience↗

bioRxiv2018

Longitudinal studies at birth and age 7 reveal strong effects of genetic variation on ancestry-associated DNA methylation patterns in blood cells from ethnically admixed children

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results not only indicate that race-associated DNAm patterns in blood are present at birth and are primarily genetically, and not environmentally, determined, but also that DNAm in blood cells overall is robust to many environmental exposures during the first 7 years of life.

genomics↗