Biology subjects

Becker, H. C.

Publications and source records attributed to Becker, H. C..

7 recordsLinked to original sources

bioRxiv2026

Functional remodeling of the parasubthalamic nucleus drives alcohol drinking escalation in dependence

The neurocircuitry changes mediating the development and maintenance of an alcohol use disorder are complex and dynamic. The parasubthalamic nucleus (PSTN), a small nucleus of the posterior lateral hypothalamus best known for suppressing appetite, is interconnected with brain regions disrupted in addiction; yet its potential role in the regulation of alcohol consumption had never been examined. Here we show that the PSTN exerts potent control over alcohol drinking in mice. Remarkably, the influence of endogenous PSTN activity on voluntary alcohol consumption switches from inhibitory to stimulatory upon induction of alcohol dependence. Among PSTN cells, Crh neurons represent a unique subpopulation that promotes alcohol drinking and fires more in dependent mice. Alcohol intake escalation driven by PSTN Crh neurons involves thalamic output and behavioral disinhibition. Based on our results, PSTN Crh neurons could represent a critical node in the brain circuitry overactive in alcohol addiction driven by reward seeking in humans.

neuroscience↗

bioRxiv2025

Tirzepatide attenuates dopamine reward signaling and suppresses alcohol drinking and relapse-like behaviors in rodents

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioral assays, alcohol intake paradigms, and molecular analyses in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release. Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption, prevented binge and relapse-like drinking, and maintained efficacy during repeated administration. Finally, tirzepatide induced sustained synaptic depression in the lateral septum and further altered histone regulatory proteins in this region, suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight, adipose tissue mass, hepatic triglycerides and circulating pro-inflammatory cytokines. Together, our findings suggest tirzepatide modulates alcohol-related behaviors through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatides established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. SIGNIFICANCE STATEMENTExisting treatments for alcohol use disorder show limited effectiveness, leaving patients without viable therapeutic options. We demonstrate that tirzepatide, a long-acting gut peptide-based drug already approved for diabetes and obesity, substantially reduces alcohol consumption and prevents relapse-like behavior across multiple preclinical models. Tirzepatide appears to work by influencing brain reward systems while simultaneously affecting metabolic complications common in alcohol disorders. Given tirzepatides clinical availability, these findings suggest repurposing a recently approved drug to tackle one of medicines more persistent treatment challenges.

neuroscience↗

bioRxiv2022

Transcriptome analysis of alcohol dependence and stress interactions in the nucleus of the solitary tract

Stress exposure contributes to the development of drug and alcohol use disorders. In animal models, stress exacerbates escalations in alcohol consumption in alcohol-dependent animals. The nucleus of the solitary tract (NTS) is a critical brainstem region for integrating and relaying peripheral signals to regulate stress responses. To define the molecular adaptions within this brain region that may contribute to stress-induced alcohol drinking, we exposed animals to chronic intermittent bouts of ethanol vapor (CIE), forced swim stress (FSS), or both (CIE + FSS) and then transcriptionally profiled the NTS at three different timepoints after the last vapor exposure (0-hr, 72-hr, and 186-hr). We identified interferon (IFN) signaling as a critical gene network correlated with alcohol consumption levels. Using a likelihood ratio test, we identified genes that were differentially expressed across time and between groups. Clustering analysis of these genes to identify unique expression patterns identified a subset of genes that fail to normalize in the CIE + FSS group, but not the others. These genes were enriched for cell-to-cell interaction and cellular movement pointing to long-term structural and functional changes in this brain region caused by the unique interaction of alcohol dependence and stress. Specific genes of interest identified in this group include Aqp4, Il16, Reln, Grm4, Gabrd, and Gabra6. We also compared gene expression changes in the NTS to the PFC and found a significant overlap of genes between the two brain regions. Overlapping NTS/PFC genes in the CIE + FSS group were enriched for type I IFN signaling. Finally, we tested the hypothesis that activation of type I IFN signaling increases alcohol consumption based on the three lines of evidence identifying type I IFN signaling as critical for escalations in alcohol intake. Mice treated with recombinant IFN{beta} showed significantly elevated levels of alcohol intake in a two-bottle choice procedure compared to saline-treated controls. Overall, these results define the transcriptomic changes across time in the NTS that may be critical to the development of stress-induced increases in alcohol consumption and alcohol dependence.

molecular biology↗

bioRxiv2021

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA-approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.

animal behavior and cognition↗

bioRxiv2019

Inhibition of the Ventral Hippocampus Increases Alcohol Drinking

The function of the ventral hippocampus (vHC) supports many behaviors, including those related to reward seeking behaviors and drug addiction. We used a mouse model of alcohol dependence and relapse to investigate the role of the vHC in alcohol (ethanol) drinking. One experiment used a chemogenetic approach to inhibit vHC function while ethanol dependent and non-dependent mice had access to ethanol. Interestingly, the non-dependent mice expressing an inhibitory DREADD in the VHC showed a significant increase in ethanol drinking ([~]30%) after hM4Di DREADD activation with clozapine-n-oxide (CNO; 3 mg/kg, ip.) compared to vehicle. On the other hand, ethanol dependent mice, which were already drinking significantly more ethanol than non-dependent mice, only had a slight, non-significant increase in drinking after CNO challenge. In a separate group of dependent and non-dependent mice, GCaMP6f calcium-dependent activity was recorded in the vHC while mice were actively drinking ethanol. These data showed that once mice were rendered ethanol dependent and were drinking more ethanol than the non-dependent mice, calcium signaling in the ventral hippocampus decreased ([~]45%) in the ethanol dependent mice compared to the non-dependent mice. Together, these findings suggest that ethanol dependence reduces activity of the ventral hippocampus and that reduced function of this brain region contributes to increased ethanol drinking.

neuroscience↗

bioRxiv2019

Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

Anxiety and mood disorders are often comorbid with alcohol use disorder (AUD) and are considered critical in the development, maintenance, and reinstatement of alcohol dependence and harmful alcohol-seeking behaviors. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy ethanol drinking and anxiety-related behaviors. We used a model of stress-induced escalation of drinking in ethanol dependent C57BL/6J mice to measure anxiety-like behaviors on the marble burying and novelty-suppressed feeding task (NSFT) during abstinence. In order to identify novel pharmacogenetic targets that may lead to more effective treatment, a targeted bioinformatics analysis was used to quantify the expression of K+ channel genes in the amygdala that covary with anxiety-related phenotypes in the well phenotyped and fully sequenced family of BXD strains. A pharmacological approach was used to validate the key bioinformatics finding in ethanol-dependent, stressed C57BL/6J mice during the NSFT. Amygdalar expression of Kcnn3 correlated significantly with just over 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors in this family. Kcnn3 expression in the amygdala correlated negatively with binge-like and voluntary ethanol drinking. C57BL/6J mice treated with chronic intermittent ethanol exposure and repeated swim stress consumed more ethanol in their home cages and showed hypophagia on the NSFT during prolonged abstinence. Pharmacologically targeting KCNN3 protein with the KCa2 channel positive modulator 1-EBIO decreased ethanol drinking and reduced latency to approach food during the NSFT in ethanol-dependent, stressed mice. Collectively these validation studies provide central nervous system mechanistic links into to the covariance of stress, anxiety, and AUD in the BXD strains. Further this analytical approach is effective in defining targets for treating alcohol dependence and comorbid mood and anxiety disorders.

neuroscience↗

bioRxiv2019

Brain Regional Gene Expression Network Analysis Identifies Unique Interactions Between Chronic Ethanol Exposure and Consumption

Progressive increases in ethanol consumption is a hallmark of alcohol use disorder (AUD). Persistent changes in brain gene expression are hypothesized to underlie the altered neural signaling producing abusive consumption in AUD. To identify brain regional gene expression networks contributing to progressive ethanol consumption, we performed microarray and scale-free network analysis of expression responses in a C57BL/6J mouse model utilizing chronic intermittent ethanol by vapor chamber (CIE) in combination with limited access oral ethanol consumption. This model has previously been shown to produce long-lasting increased ethanol consumption, particularly when combining oral ethanol access with repeated cycles of intermittent vapor exposure. The interaction of CIE and oral consumption was studied by expression profiling and network analysis in medial prefrontal cortex, nucleus accumbens, hippocampus, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain region expression networks were analyzed for ethanol-responsive gene expression, correlation with ethanol consumption and functional content using extensive bioinformatics studies. In all brain-regions studied the largest number of changes in gene expression were seen when comparing ethanol naive mice to those exposed to CIE and drinking. In the prefrontal cortex, however, unique patterns of gene expression were seen compared to other brain-regions. Network analysis identified modules of co-expressed genes in all brain regions. The prefrontal cortex and nucleus accumbens showed the greatest number of modules with significant correlation to drinking behavior. Across brain-regions, however, many modules with strong correlations to drinking, both baseline intake and amount consumed after CIE, showed functional enrichment for synaptic transmission and synaptic plasticity.

genomics↗