Biology subjects

Platt, D. M.

Publications and source records attributed to Platt, D. M..

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↗

bioRxiv2023

An Automated Scientist to Design and Optimize Microbial Strains for the Industrial Production of Small Molecules

Engineering microbes to synthesize molecules of societal value has historically been a time consuming and artisanal process, with the synthesis of each new non-native molecule typically warranting its own separate publication. Because most microbial strain engineering efforts leverage a finite number of common metabolic engineering design tactics, we reasoned that automating these design steps would help create a pipeline that can quickly, cheaply, and reliably generate so-called microbial factories. In this work we describe the design and implementation of a computational system, an Automated Scientist we call Lila, which handles all metabolic engineering design and optimization through the design-build-test-learn (DBTL) paradigm. Lila generates metabolic routes, identifies relevant genetic elements for perturbation, and specifies the design and re-design of microbial strains in a matter of seconds to minutes. Strains specified by Lila are then built and subsequently phenotyped as part of a largely automated in-house pipeline. Humans remain in-the-loop to curate choices made by the system, helping for example to refine the metabolic model or suggest custom protein modifications. Lila attempted to build strains that could produce 454 biochemically diverse molecules with precursors located broadly throughout the metabolism of two microbial hosts, Saccharomyces cerevisiae and Escherichia coli. Notably, we observed the highest published titers for the molecule naringenin, the metabolic precursor to flavonoids. In total we created hundreds of thousands of microbial strains capable of overproducing 242 molecules, of which 180 are not native to S. cerevisiae or E. coli.

synthetic biology↗