The goal of the Pleil Lab is to delineate the circuit and synaptic mechanisms of alcohol/drug use and stress responsivity, as well as the plasticity in these mechanisms that contributes to the development co-expressed neuropsychiatric disorders such as alcohol/substance use disorder, anxiety, and affective disorders. We have a particular focus on the roles of sex and stress steroid hormones and neuropeptides in 1) the organization and function of behaviorally-relevant limbic circuits, 2) the activity and synaptic transmission of cell type- and projection-defined neuronal populations within these circuits, and 3) the membrane receptor-mediated signaling interactions between these neuromodulators at critical synaptic nodes. We further examine how the synthesis and signaling of these endogenous signaling molecules across the body and brain undergo stress- and alcohol-induced plasticity to confer sex-biased disease susceptibility. Using complementary techniques including ex vivo slice electrophysiology and in vivo behavior combined with optogenetics, pharmacogenetics, RNA interference, and biosensor imaging, we analyze mechanisms of neuropsychiatric disease states at the anatomical, molecular, cellular, synaptic, circuit, and behavioral levels. We also maintain productive collaborations with other WCM and external labs with complementary expertise in areas including epigenetics, whole-brain mapping, hepatic physiology, ligand target identification, and single cell sequencing to broaden these avenues of investigation.
Research Projects
Genomic and nongenomic mechanisms for ovarian estrogen regulation of alcohol drinking, stress, and emotional behaviors
The sex steroid hormone estrogen is a critical endogenous signaling molecule that controls adaptive behaviors across the menstrual/estrous cycle to promote survival and reproduction in females. Several converging projects in the lab are teasing apart the coordinated genomic and nongenomic mechanisms by which estrogen across the estrous cycle in female mice regulates these adaptive behaviors and can be utilized to control maladaptive behaviors like alcohol consumption through interactions with neuropeptide signaling and circuit function. These mechanisms include both rapid nongenomic signaling of estrogen at membrane-associated estrogen receptors that influences synaptic transmission and neuronal excitability, as well as genomic signaling in the nucleus that affects broad transcriptional programming, within neuropeptidergic brain circuits.
Effects of chronic alcohol on steroid hormone metabolism in the liver and liver-blood-brain axis function
Steroid hormones signal in the liver to combat steatosis, inflammation, and oxidative stress to maintain homeostasis in health and in response to metabolic burdens including alcohol and other dietary/physiological stressors. Our lab is studying how chronic alcohol use alters the synthesis and signaling of these hormones in the liver to affect liver pathology and the broad bioavailability of these hormones across the body and brain.
Relationships between synaptic and epigenetic plasticity in neuropsychiatric disease states
Stress- and experience-dependent neural plasticity in development and adulthood changes behavior and contributes to neuropsychiatric disease phenotypes, including anxiety and drug abuse. Several projects are studying the relationships between broad epigenetic modifications, transcriptional reprogramming, and plasticity in synaptic function and neuronal excitability within limbic circuits critical for learning and memory and emotional behaviors that occur across development stress/alcohol exposure or adult opioid use.