About

Kristen Pleil is a professor in the Department of Pharmacology at Weill Cornell Medicine. Her lab studies how the synthesis and signaling of steroid hormones in the brain and body regulate brain circuit function, physiology, and behavior through interactions with neuropeptides. The primary focus of her research is understanding how peripheral and central hormone actions regulate neuropeptidergic neural circuits that control neuropsychiatric disease-related behaviors, including alcohol and drug intake, anxiety, and mood. Her work emphasizes the mechanisms contributing to sex-dependent behavioral expression and aberrant plasticity that confer sexually dimorphic disease susceptibility, with the goal of identifying novel therapeutic targets for prevention and intervention.

Research topics

• Neuroscience
• Psychology
• Biology
• Medicine
• Genetics
• Developmental psychology
• Physiology
• Internal medicine
• Endocrinology
• Psychiatry
• Clinical psychology

Selected publications

• Alcohol dysregulation of adaptive estrogen signaling in the limbic thalamus

  Alcohol · 2026-04-07

  article1st authorCorresponding
  PublisherDOI

• Adverse gestational environment configures a subpopulation of ventral dentate granule cells for recruitment to drive innate anxiety

  Cell Reports · 2025-09-01 · 2 citations

  articleOpen access

  An adverse gestational environment is a risk factor for the development of psychiatric disorders. Although studies have implicated modifications in neuronal DNA and chromatin, how these changes come about and lead to abnormal behaviors is not known. We sought to identify persistent DNA/chromatin and transcriptomic signatures induced by a proinflammatory gestational environment in the ventral dentate gyrus (vDG), a hippocampal region linked to anxiety. A proinflammatory environment shifted DNA methylation of enhancers and promoters and altered synapse-related gene expression, resulting in transcriptional heterogeneity in the vDG. In animals with prior adversity, exposure to a threatening environment recruited vDG neurons with the greatest transcriptional changes, notably in synapse-relevant genes that also tended to be differentially methylated. Finally, vDG activity was increased during transition from a safe to a threatening environment in animals with prior adversity but not in controls, suggesting their enhanced perception of a potential threat. Our data outline a proinflammatory gestational environment-induced neurobiological sequence that leads to anxiety.

  PublisherDOI

• Prenatal adversity configures a subpopulation of ventral dentate granule cells for recruitment to drive innate anxiety

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-02

  preprint

  ABSTRACT Adverse prenatal environment is a risk factor for the development of psychiatric disorders. Although studies have implicated epigenetic mechanisms, little is known about how epigenomic changes come about and lead to abnormal behaviors in affected individuals. We sought to identify epigenomic and transcriptomic signatures induced by a proinflammatory gestational environment in the ventral dentate gyrus (vDG), a hippocampal region linked to avoidance of threatening contexts, that persist and promote anxiety-like behavior in mice. Here we show that adversity shifted the methylation of enhancers and promoters with intermediate methylation and altered synapse-related gene expression, resulting in epigenetic and transcriptional heterogeneity in the vDG. Exposure to an anxiogenic environment recruited vDG neurons with the most transcriptional alterations. Differentially expressed synapse-relevant genes in ensemble neurons tended to be differentially methylated. Finally, this ensemble exhibited higher activity in threatening than safe environment suggesting a prenatal adversity-induced epigenetic and neurobiological sequence that leads to anxiety.

  PublisherDOI

• Chronic alcohol consumption alters sex-dependent BNST neuron function in rhesus macaques

  Neurobiology of Stress · 2024-04-30 · 3 citations

  articleOpen access1st authorCorresponding

  Repeated alcohol drinking contributes to a number of neuropsychiatric diseases, including alcohol use disorder and co-expressed anxiety and mood disorders. Women are more susceptible to the development and expression of these diseases with the same history of alcohol exposure as men, suggesting they may be more sensitive to alcohol-induced plasticity in limbic brain regions controlling alcohol drinking, stress responsivity, and reward processing, among other behaviors. Using a translational model of alcohol drinking in rhesus monkeys, we examined sex differences in the basal function and plasticity of neurons in the bed nucleus of the stria terminalis (BNST), a brain region in the extended amygdala shown to be a hub circuit node dysregulated in individuals with anxiety and alcohol use disorder. We performed slice electrophysiology recordings from BNST neurons in male and female monkeys following daily “open access” (22 hr/day) to 4% ethanol and water for more than one year or control conditions. We found that BNST neurons from control females had reduced overall current density, hyperpolarization-activated depolarizing current (Ih), and inward rectification, as well as higher membrane resistance and greater synaptic glutamatergic release and excitatory drive, than those from control males, suggesting that female BNST neurons are more basally excited than those from males. Chronic alcohol drinking produced a shift in these measures in both sexes, decreasing current density, Ih, and inward rectification and increasing synaptic excitation. In addition, network activity-dependent synaptic inhibition was basally higher in BNST neurons of males than females, and alcohol exposure increased this in both sexes, a putative homeostatic mechanism to counter hyperexcitability. Altogether, these results suggest that the rhesus BNST is more basally excited in females than males and chronic alcohol drinking produces an overall increase in excitability and synaptic excitation. These results shed light on the mechanisms contributing to the female-biased susceptibility to neuropsychiatric diseases including co-expressed anxiety and alcohol use disorder.

  PublisherDOI

• Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice

  Nature Communications · 2024-12-30 · 13 citations

  articleOpen accessSenior author

  Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen occurred via rapid signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking. Thus, this study demonstrates a rapid, nongenomic signaling mechanism for ovarian-derived estrogen in the brain controlling behavior in gonadally intact females.

  PublisherOA PDFDOI

• Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-04-02 · 2 citations

  preprintOpen access

  Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184's effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.

  PublisherOA PDFDOI

• Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia

  Science Advances · 2024-11-29 · 11 citations

  articleOpen access

  Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments as a complement to opioid-based treatments. Here, we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by cannabinoid receptor 1 (CB1R) within the VTA, as VTA CB1R conditional knockout counteracts JZL184's effects. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together, these findings reveal that 2-AG diminishes the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.

  PublisherDOI

• A Little “Re-Cognition” Goes a Long Way for Pro-Cognitive Therapeutics in Alcohol Studies

  Journal of Pharmacology and Experimental Therapeutics · 2024-05-21 · 1 citations

  letterOpen accessSenior author
  PublisherOA PDFDOI

• Chronic alcohol consumption alters sex-dependent BNST neuron function in rhesus macaques

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-04-15

  preprintOpen access1st authorCorresponding

  Abstract Repeated alcohol drinking contributes to a number of neuropsychiatric diseases, including alcohol use disorder and co-expressed anxiety and mood disorders. Women are more susceptible to the development and expression of these diseases with the same history of alcohol exposure as men, suggesting they may be more sensitive to alcohol-induced plasticity in limbic brain regions controlling alcohol drinking, stress responsivity, and reward processing, among other behaviors. Using a translational model of alcohol drinking in rhesus monkeys, we examined sex differences in the basal function and plasticity of neurons in the bed nucleus of the stria terminalis (BNST), a brain region in the extended amygdala shown to be a hub circuit node dysregulated in individuals with anxiety and alcohol use disorder. We performed slice electrophysiology recordings from BNST neurons in male and female monkeys following daily “open access” (22 hr/day) to 4% ethanol and water for more than one year or control conditions. We found that BNST neurons from control females had reduced overall current density, hyperpolarization-activated depolarizing current (I h ), and inward rectification, as well as higher membrane resistance and greater synaptic glutamatergic release and excitatory drive, than those from control males, suggesting that female BNST neurons are more basally excited than those from males. Chronic alcohol drinking produced a shift in these measures in both sexes, decreasing current density, I h , and inward rectification and increasing synaptic excitation. In addition, network activity-dependent synaptic inhibition was basally higher in BNST neurons of males than females, and alcohol exposure increased this in both sexes, a putative homeostatic mechanism to counter hyperexcitability. Altogether, these results suggest that the rhesus BNST is more basally excited in females than males and chronic alcohol drinking produces an overall increase in excitability and synaptic excitation. These results shed light on the mechanisms contributing to the female-biased susceptibility to neuropsychiatric diseases including co-expressed anxiety and alcohol use disorder.

  PublisherOA PDFDOI

• An opioid efficacy switch for reversible optical control of peripheral analgesia

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-20 · 2 citations

  preprintOpen access

  Abstract The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects. Here we design, synthesize, and characterize a reversibly photoswitchable morphinan agonist termed “azo-morphine-3” ( AM-3 ) which interconverts from low to high efficacy in response to different wavelengths of light to enable optical control of MOR signaling. Cryo-EM structures of the low efficacy “ trans ” and high efficacy “ cis ” states of AM-3 bound to the MOR reveal distinct binding modes of the photoswitchable azobenzene moiety, each inducing unique structural dynamics, providing insight into the molecular basis of agonist efficacy. In mice, AM-3 drives reversible and repeatable optical control of anti-nociception with a reduced side effect profile owing to its restriction to the periphery and its ability to be locally activated at the site of pain.

  PublisherOA PDFDOI

Recent grants

• The role of excitatory inputs to BNST CRF neurons in alcohol drinking behavior

  NIH · $228k · 2015–2017

• The role of rapid estrogen signaling in alcohol drinking behavior

  NIH · $3.5M · 2019–2029

• The effect of alcohol drinking on NPY modulation of inhibition in the BNST

  NIH · $156k · 2012–2015

• The DNA methylation code governing the ensemble representation of morphine-context association

  NIH · $465k · 2019–2021

Frequent coauthors

• Thomas L. Kash

  University of North Carolina at Chapel Hill

  51 shared

• Mary Jane Skelly

  Cornell University

  28 shared

• Conor Liston

  24 shared

• Joshua Levitz

  Cornell University

  22 shared

• Chia Li

  National Institute of Diabetes and Digestive and Kidney Diseases

  20 shared

• Emily G. Lowery‐Gionta

  Walter Reed Army Institute of Research

  19 shared

• Jeffrey F. DiBerto

  University of North Carolina at Chapel Hill

  16 shared

• Robert N. Fetcho

  Princeton University

  16 shared