Biology subjects

Pareek, T.

Publications and source records attributed to Pareek, T..

3 recordsLinked to original sources

bioRxiv2025

Cross-Species Evidence for Hippocampal CACNA1C as a Therapeutic Target for Alcohol Use Disorder

Context-induced relapse is a major barrier to recovery from alcohol use disorder (AUD). Identifying molecular targets involved in contextual memories associated with alcohol use may serve as novel pharmacotherapies. Our RNAseq profiling study of the hippocampus from rhesus monkeys with chronic alcohol use identified the voltage-gated calcium channel CACNA1C as a promising therapeutic target. However, data regarding CACNA1C expression in AUD and whether inhibition of CACNA1C can attenuate ethanol contextual memories remains limited. We tested the hypothesis that hippocampal CACNA1C expression is increased in human and nonhuman primates (NHPs) with chronic alcohol use. Further, we used a mouse conditioned place preference (CPP) paradigm to test the hypothesis that Nifedipine, a CACNA1C-selective L-type calcium channel antagonist, can attenuate ethanol-induced CPP. CACNA1C mRNA expression was increased in the hippocampus of subjects with AUD (p<0.03). Increased densities of CACNA1C neurons (p<0.01) and glia (p<0.02) were observed in rhesus monkeys with chronic alcohol use. Ethanol-treated mice spent more time in the ethanol-paired chamber compared to the vehicle animals (p<0.04), demonstrating ethanol-induced CPP. This effect was attenuated by Nifedipine, as time spent in the ethanol-paired chamber in the ethanol + Nifedipine group was not significantly different from the vehicle group. These findings demonstrate that chronic alcohol use increases CACNA1C expression in the hippocampus across species and that a CACNA1C subtype-selective antagonist reduces ethanol-induced CPP. Together, these results support CACNA1C as a promising therapeutic target for context-induced relapse in AUD.

neuroscience↗

bioRxiv2025

Altered molecular signaling pathways in the hippocampus of rhesus monkeys following chronic alcohol use

Context-induced relapse is a significant factor limiting recovery from alcohol use disorder (AUD). However, the molecular processes in the hippocampus, a critical region for contextual memory impacted by chronic alcohol use, remain poorly understood. We used a non-human primate model to test the hypothesis that chronic alcohol use impacts hippocampal molecular pathways that may serve as therapeutic targets for context-induced relapse and memory processing issues associated with chronic alcohol use. We conducted RNAseq profiling on hippocampal samples from adult male rhesus monkeys with chronic alcohol use (n=7) and controls (n=5) from the Monkey Alcohol Tissue Research Resource (MATRR). We identified 2,575 differentially expressed genes (DEGs) in subjects with chronic alcohol use, including genes implicated in genome-wide association studies (GWAS) of alcohol dependence, such as GLP2R and GABBR2. Downregulated pathways included chemical synaptic transmission, trans-synaptic signaling, and neuron development, and upregulated pathways involved mitochondrial function. Targeted pathway analysis highlighted significant downregulation of synaptic signaling (e.g., axonal fasciculation) and upregulation of mitochondrial processes (e.g., electron transport). Leading-edge gene analysis revealed several downregulated genes involved in synaptic signaling including GRIN2B, CACNA1C, and NLGN1 as well as upregulated genes such as NDUFS3 and MT-ND1 involved in mitochondrial processes. Drug repurposing analysis identified several targets including epidermal growth factor receptor (EGFR) inhibitors, and L-type calcium channel blockers as potential therapeutic targets. Our results provide critical insights into molecular pathways underlying hippocampal pathology in chronic alcohol use, emphasizing the roles of mitochondrial function, synaptic regulation and calcium channels, and offering potential novel therapeutic targets.

neuroscience↗

bioRxiv2025

Sleep Deprivation Alters Hippocampal Dendritic Spines in a Contextual Fear Memory Engram

Sleep is critically involved in strengthening memories. However, our understanding of the morphological changes underlying this process is still emerging. Recent studies suggest that specific subsets of dendritic spines are strengthened during sleep in specific neurons involved in recent learning. Contextual memories associated with traumatic experiences are involved in post-traumatic stress disorder (PTSD) and represent recent learning that may be strengthened during sleep. We tested the hypothesis that dendritic spines encoding contextual fear memories are selectively strengthened during sleep. Furthermore, we tested how sleep deprivation after initial fear learning impacts dendritic spines following re-exposure to fear conditioning. We used ArcCreERT2 mice to visualize neurons that encode contextual fear learning (Arc+ neurons), and concomitantly labeled neurons that did not encode contextual fear learning (Arc-neurons). Dendritic branches of Arc+ and Arc-neurons were sampled using confocal imaging to assess spine densities using three-dimensional image analysis from either sleep deprived (SD) or control mice allowed to sleep normally. Mushroom spines in Arc+ branches displayed decreased density in SD mice, indicating upscaling of mushroom spines during sleep following fear learning. In comparison, no changes were observed in dendritic spines from Arc-branches. When animals were re-exposed to contextual fear conditioning 4 weeks later, we observed lower density of mushroom spines in both Arc+ and Arc-branches, as well as lower density of thin spines in Arc-branches in mice that were SD following the initial fear conditioning trial. Our findings indicate that sleep strengthens dendritic spines in neurons that recently encoded fear memory, and sleep deprivation following initial fear learning impairs dendritic spine strengthening initially and following later re-exposure. SD following a traumatic experience thus may be a viable strategy in weakening the strength of contextual memories associated with trauma and PTSD.

neuroscience↗