About

William A. Carlezon is a Professor of Psychiatry at McLean Hospital, with a research focus on the biological basis and treatment of psychiatric illnesses. His Behavioral Genetics Laboratory, founded in 1998, aims to understand how the environment affects behavior and brain biology, exploring factors such as stress, drugs, trauma, toxins, and illness. His work is relevant to neuropsychiatric disorders including depression, anxiety, PTSD, addiction, and autism. Dr. Carlezon’s lab employs behavioral tests in rats and mice to model key signs of psychiatric conditions, using strategies like genetic engineering to establish cause-effect relationships. His team has made significant contributions, including the first report that kappa-opioid receptor antagonists have antidepressant, anti-anxiety, and anti-stress effects, leading to advanced clinical trials for treatment-resistant depression. The lab collaborates with other scientists at McLean and the Broad Institute to develop novel kappa antagonists through high-throughput screening and medicinal chemistry.

Research topics

• Psychology
• Neuroscience
• Medicine
• Computer Science
• Biology
• Psychiatry
• Internal medicine
• Clinical psychology
• Chemistry
• Endocrinology

Selected publications

• Neurophysiological and Behavioral Signatures of Reward Responsiveness and Learning are Concordant between Humans and Rats

  OSF Preprints (OSF Preprints) · 2026-03-16

  otherOpen access

  This project was a replication and extension of a prior study that used a probabilistic reversal learning task aligned between humans and rats to probe behavioral, neurophysiological, and computational markers of reward processing across species (Humans and Rats).

  Publisher

• Identification of conserved frontal neurophysiological markers of cognitive flexibility in humans and rats

  OSF Preprints (OSF Preprints) · 2026-03-13

  otherOpen access

  This project used versions of a probabilistic reversal learning task aligned between humans and rats to conduct a a systematic cross-species comparison of behavioral, neurophysiological, and computational markers of cognitive flexibility.

  Publisher

• 230. Fine-Mapping of PTSD Gwas in the Amygdala Reveals Role of Foxp2 in the Regulation of Fear Learning

  Biological Psychiatry · 2026-04-25

  article
  PublisherDOI

• Stress-induced adaptations in nucleus accumbens dopamine D1 receptor-expressing cells correspond to social avoidance behavior in male mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-24

  articleOpen accessSenior authorCorresponding

  ABSTRACT Stress can cause or exacerbate psychiatric illness, and effects on the transcription factor CREB within the nucleus accumbens (NAc) are critically involved. In rodents, stress-induced activation of NAc CREB produces elevations in dynorphin (DYN), an endogenous opioid expressed in dopamine D1-receptor (D1R)-expressing medium spiny neurons (MSNs). In turn, elevated DYN signaling produces features of mood and anxiety disorders via actions at kappa-opioid receptors (KORs). Although individual differences in stress sensitivity have been described—with some appearing susceptible and others resilient—the contribution of NAc DYN to these phenotypes is unclear. Here we examined relationships between social behavior and DYN in D1R-expressing MSNs in mice exposed to chronic social defeat stress (CSDS). We used quantitative (q)RNAscope to assess co-expression of genes encoding CREB ( Creb1 ), D1Rs ( Drd1 ), and DYN ( Pdyn ) within the NAc. To leverage individual variability, we performed regression analyses across all mice, revealing negative correlations between social interaction behavior and expression of Drd1 and Pdyn , linking higher social avoidance with higher expression of these genes. There was no correlation with Creb1 , suggesting stress-induced elevations in Pdyn depend on CREB activation (phosphorylation). These findings suggest that stress-induced elevations in D1R-associated DYN signaling within the NAc is a biomarker of susceptibility.

  PublisherOA PDFDOI

• Early life stress induces social behavioral deficits and peripheral biomarker alterations in adolescence that perpetuate intergenerationally

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-01

  preprintOpen accessSenior authorCorresponding

  Early life stress (ELS) increases the likelihood of developing chronic health problems including mental illness. In humans, deficits in social behavior often emerge during adolescence and correlate with later-life psychiatric diagnoses. We examined in mice the effects of a limited bedding and nesting (LBN) model of ELS on pup ultrasonic vocalizations (USVs) during postnatal days 3-9 (P3-P9). Then on P30, an adolescent timepoint, we assessed social behavior as well as thymus involution and adrenal hypertrophy, both biomarkers of stress. We found reductions in USVs as early as P3, resembling low levels normally seen later in development. There were few changes in SI, with deficits observed only after restraint stress in female LBN mice. Surprisingly, thymus weights were augmented and adrenal glands were smaller in LBN adolescent mice, opposite to alterations typically observed after chronic adult stress. LBN also produced signs of precocious puberty in both sexes, especially in cohorts of LBN-exposed offspring bred to create second-generation LBN offspring that subsequently underwent LBN, indicating perpetuation across generations. Together, these data suggest that stress in early life has distinct and diverse effects, including accelerating several processes, and that some of these effects persist intergenerationally.

  PublisherOA PDFDOI

• Correspondence between sleep patterns and anhedonia in adult male mice exposed to early-life stress

  Translational Psychiatry · 2025-10-06 · 1 citations

  articleOpen accessSenior author

  Early-life stress (ELS) can produce long-lasting effects that increase the risk for mood and anxiety disorders. Transdiagnostic symptoms include anhedonia (reduced reward sensitivity) and sleep disruption, both of which are quantifiable via objective endpoints that can be utilized across species. Here we used a mouse model for ELS-exposure to juvenile chronic social defeat stress (jCSDS)-together with translationally-applicable endpoints to examine correspondence between sleep patterns and anhedonia. These initial studies focused on males, which typically show robust defeat-induced anhedonia phenotypes. Exposure to jCSDS produced reductions in open-field social behavior, an endpoint commonly used in mice to quantify stress effects, during adulthood. Mice were then implanted with wireless transmitters that enable continuous EEG-derived analysis of sleep architecture. Following assessment of baseline sleep patterns, mice were tested in a rodent version of the Probabilistic Reward Task (PRT), a procedure used to quantify reward responsiveness in humans, during the light phase of their diurnal cycle. These studies revealed significant associations between baseline sleep architecture and anhedonic phenotypes in jCSDS-exposed mice: higher anhedonia correlated with less time awake and more time in slow wave sleep (SWS) during the light phase, and more time awake and less time in rapid eye movement (REM) sleep and SWS during the dark (active) phase. Our findings suggest that sleep patterns represent a biomarker that can predict stress-susceptible (higher anhedonia) and resilient (lower anhedonia) phenotypes. This work enhances our understanding of relationships between sleep and anhedonia, and may provide a basis for precision approaches to treat ELS-induced pathophysiology.

  PublisherOA PDFDOI

• Spontaneous oxycodone withdrawal disrupts sleep, diurnal, and electrophysiological dynamics in rats

  PLoS ONE · 2025-01-17 · 1 citations

  articleOpen accessCorresponding

  Opioid dependence is defined by an aversive withdrawal syndrome upon drug cessation that can motivate continued drug-taking, development of opioid use disorder, and precipitate relapse. An understudied but common opioid withdrawal symptom is disrupted sleep, reported as both insomnia and daytime sleepiness. Despite the prevalence and severity of sleep disturbances during opioid withdrawal, there is a gap in our understanding of their interactions. The goal of this study was to establish an in-depth, temporal signature of spontaneous oxycodone withdrawal effects on the diurnal composition of discrete sleep stages and the dynamic spectral properties of the electroencephalogram (EEG) signal in male rats. We continuously recorded EEG and electromyography (EMG) signals for 8 d of spontaneous withdrawal after a 14-d escalating-dose oxycodone regimen (0.5-8.0 mg/kg, 2×d; SC). During withdrawal, there was a profound loss (peaking on days 2-3) and gradual return of diurnal structure in sleep, body temperature, and locomotor activity, as well as decreased sleep and wake bout durations dependent on lights on/off. Withdrawal was associated with significant alterations in the slope of the aperiodic 1/f component of the EEG power spectrum, an established biomarker of arousal level. Early in withdrawal, NREM exhibited an acute flattening and return to baseline of both low (1-4 Hz) and high (15-50 Hz) frequency components of the 1/f spectrum. These findings suggest temporally dependent withdrawal effects on sleep, reflecting the complex way in which the allostatic forces of opioid withdrawal impinge upon sleep and diurnal processes. These foundational data based on continuous tracking of vigilance state, sleep stage composition, and spectral EEG properties provide a detailed construct with which to form and test hypotheses on the mechanisms of opioid-sleep interactions.

  PublisherOA PDFDOI

• Identification of an intrusive-hypervigilant phenotype of posttraumatic stress symptoms with unique stress peptide and amygdala functional connectivity profiles

  Neuropsychopharmacology · 2025-09-15

  preprintOpen access

  Posttraumatic stress disorder (PTSD) is a highly heterogeneous psychiatric disorder, complicating efforts to identify consistent biological markers and develop targeted treatments for individuals exposed to trauma. Recent research has identified a distinct intrusive-hypervigilant (IH) phenotype, which is characterized by heightened intrusive reexperiencing and hypervigilance symptoms along with elevated levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide involved in stress response via amygdala signaling. In an independent sample of 172 symptomatic trauma-exposed adults, we replicated this IH phenotype using latent profile analysis of Clinician-Administered PTSD Scale for DSM-5 symptom severity ratings and expanded its biological characterization using resting-state functional magnetic resonance imaging (rs-fMRI). Consistent with prior work, the identified IH group demonstrated more severe intrusive reexperiencing and hypervigilance symptoms and higher PACAP levels compared to groups with generally High or Low symptom severity. Additionally, the IH phenotype exhibited stronger functional connectivity of the centromedial, but not basolateral, amygdala with regions in the occipital cortex, precuneus, and medial prefrontal cortex - areas primarily within the Default Mode and Visual Networks. Meta-analytic decoding linked these regions to mental imagery, memory processing, fear, and threat perception. These findings support the existence of an IH phenotype of posttraumatic stress that may exhibit a distinct biological profile, characterized by exaggerated interactions between memory, threat, and arousal systems that may be mediated by PACAP and its effects of amygdala connectivity. This phenotype may serve as a promising target for precision psychiatry approaches, including pharmacological and neurotherapeutic interventions that modulate PACAP signaling and amygdala connectivity.

  PublisherDOI

• Associations between PACAP levels and psychophysiological indicators of fear and arousal in adults with posttraumatic stress symptoms

  Journal of Mood and Anxiety Disorders · 2025-05-13 · 3 citations

  articleOpen access

  Posttraumatic stress disorder (PTSD) is associated with heightened fear responding and decreased fear regulation, as demonstrated with psychophysiological measures (e.g., autonomic function) and circulating biomarkers of stress, such as pituitary adenylate cyclase-activating polypeptide (PACAP). The current study examined associations between PACAP levels and psychophysiological indicators of arousal in a sample of 168 trauma-exposed adults with a range of PTSD symptoms. We also examined sex differences in these relationships. Psychophysiological indicators included fear-potentiated startle (FPS), heart rate (HR), and heart rate variability (HRV) during a fear acquisition and extinction paradigm. PACAP levels were derived from fasting blood samples. PACAP levels were positively correlated with FPS during acquisition and HR during extinction, and negatively correlated with HRV during extinction. There were no significant PACAP-by-sex interaction effects in FPS, HR, or HRV models. Our results in the total sample are consistent with prior work demonstrating associations between PACAP and psychophysiological arousal. They add to previous evidence that circulating PACAP levels are associated with biological markers of centromedial amygdala-dependent functioning. Future research is needed among larger samples, including longitudinal designs to better determine causal relationships between PACAP levels and fear-related arousal.

  PublisherOA PDFDOI

• Connectometry reveals differing associations of cortisol and PACAP with dorsal cingulum microstructure in posttraumatic stress

  medRxiv · 2025-06-06

  preprintOpen access

  ABSTRACT Posttraumatic stress disorder (PTSD) has been associated with altered arousal regulation and dysfunction of the hypothalamic-pituitary-adrenal axis, including changes in circulating cortisol and pituitary adenylate cyclase-activating polypeptide (PACAP). Both stress-related hormones affect extended amygdala to medial prefrontal cortex (mPFC) circuit functioning, but it is unclear whether they relate to white matter microstructure connecting these regions. We examined this question in 139 trauma-exposed adults (81 female; ages 19-54) who completed the Clinician-Administered PTSD Scale, a blood draw, and diffusion magnetic resonance imaging. White matter integrity was assessed in tracts connecting the extended amygdala to mPFC, including the uncinate fasciculus, frontal parahippocampal cingulum, and bed nucleus of the stria terminalis to mPFC projections. We used both tract-average fractional anisotropy (FA) to assess the global integrity of these white matter tracts and restricted connectometry to identify spatially localized associations along specific tract segments. Neither cortisol nor PACAP levels were associated with tract-average FA in any tract. However, connectometry, using a stringent statistical T-threshold revealed distinct, region-specific associations within the dorsal cingulum: higher cortisol levels were associated with lower FA ( FDR =.002), whereas higher PACAP levels were associated with higher FA ( FDR =.01). These localized FA alterations were not significantly associated with symptom severity. These findings suggest that cortisol and PACAP levels have differing associations with microstructural integrity of the dorsal cingulum, a region implicated in emotional regulation. These results highlight how distinct stress hormone pathways may differentially impact white matter organization in PTSD and demonstrate the utility of connectometry for detecting regionally specific brain-biomarker relationships.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21DA014789

  NIH · $158k · 2004

• Roles of nuleus accumbens CREB and Kappa function in depression

  NIH · $8.7M · 2021–2026

• NIH Grant R03DA030586

  NIH · $156k · 2013

• SPARED Center

  NIH · $27.1M · 2019–2025

• NIH Grant R56MH097860

  NIH · $381k · 2013

Frequent coauthors

• Bruce M. Cohen

  McLean Hospital

  156 shared

• Elena H. Chartoff

  Harvard University

  123 shared

• Eric J. Nestler

  95 shared

• Edward G. Meloni

  Harvard University

  78 shared

• Kerry J. Ressler

  McLean Hospital

  77 shared

• Diego A. Pizzagalli

  Harvard University

  74 shared

• Rachael L. Neve

  Massachusetts General Hospital

  68 shared

• Galen Missig

  McLean Hospital

  65 shared

Labs

• William A. Carlezon LabPI