About

Vadim Bolshakov is a Professor of Psychiatry at McLean Hospital, affiliated with the Harvard Medical School. His research focuses on cellular and molecular mechanisms of learned and innate behaviors, with a particular emphasis on understanding fear-related behavioral responses at the neural network level. His laboratory combines electrophysiological, cell biological, and optogenetic techniques to relate long-term synaptic modifications in fear circuits induced by fear conditioning to memories of aversive experiences. Bolshakov's work has illuminated how specific afferent input activity is encoded and preserved during fear learning, identifying mechanisms of pathway specificity that maintain functional independence of convergent inputs and contribute to the directionality of information flow in fear conditioning circuits. His research also demonstrates that synaptic modifications and fear memory formation are regulated by neural circuitry-specific gene expression, providing cellular evidence for plasticity in conditioned stimulus pathways as a mechanism of fear memory formation. More recently, his lab has explored how anxiety-related behaviors are mediated through interactions between brain regions such as the amygdala and BNST, uncovering network-level mechanisms that control anxiogenesis by modulating the activity of BNST neurons to downstream regions.

Research topics

• Neuroscience
• Medicine
• Biology
• Internal medicine
• Endocrinology
• Psychiatry
• Clinical psychology
• Psychology

Selected publications

• APP family in inhibitory neurons controls inhibitory recruitment and short-term plasticity in the hippocampus

  Molecular Brain · 2026-03-29

  articleOpen access

  Abstract Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer’s disease. We previously reported that APP and its family members, amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2), regulate intrinsic neuronal excitability and synaptic plasticity in excitatory principal neurons, though APP family is dispensable for neuronal survival. However, the physiological role of APP family in inhibitory interneurons remains poorly understood. Here, we use our previously characterized floxed APP , APLP1 , APLP2 and GAD2-Cre alleles to generate inhibitory neuron-specific conditional triple knockout (IN- APP/APLP1/APLP2 cTKO) mice. Our electrophysiological analysis of acute hippocampal slices revealed that IN- APP/APLP1/APLP2 cTKO CA1 pyramidal neurons exhibit increased amplitudes of evoked GABA A receptor-mediated inhibitory postsynaptic currents (IPSCs), while basal spontaneous IPSC frequency and amplitude remain unchanged. At Schaffer collateral (SC)–CA1 synapses, short-train frequency facilitation is enhanced in slices from IN- APP/APLP1/APLP2 cTKO mice, whereas paired-pulse facilitation (PPF) and long-term potentiation (LTP) are normal. Consistent with a cell-autonomous interneuron defect, basal excitatory transmission, measured by spontaneous and miniature excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons, is unaltered. These data show that APP family in inhibitory interneurons regulates activity-dependent inhibitory output without overtly perturbing baseline glutamatergic transmission and thus, indirectly shapes short-term facilitation at SC–CA1 synapses. Together with our earlier findings in excitatory neuron-specific APP/APLP1/APLP2 cTKO mice showing intrinsic hyperexcitability, enhanced short-term facilitation, and impaired LTP, these results suggest that the APP family modulates inhibitory and excitatory functions at SC–CA1 synapses through complementary mechanisms in principal neurons and interneurons.

  PublisherDOI

• Dissecting the functional role of basolateral amygdala CRF neurons in stress and alcohol drinking

  Alcohol · 2026-04-07

  article
  PublisherDOI

• Sex-specific behavioral and thalamo-accumbal circuit adaptations after oxycodone abstinence

  eLife · 2025-01-13 · 3 citations

  preprintOpen access

  Abstract Opioid use disorder is marked by a progressive change in the motivation to administer the drug even in the presence of negative consequences. After long periods of abstinence, the urge to return to taking the drug intensifies over time, known as incubation of craving. Conditioned responses to drug-related stimuli, can acquire motivational properties and exert control over motivated behaviors leading to relapse. Although, preclinical data suggest that the behavioral expression of opioid use is similar between male and female rodents, we do not have conclusive results on sex differences on craving and relapse across abstinence periods. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and ex vivo electrophysiology, we assessed synaptic strength and glutamate release probability in this pathway, as well as NAcSh medium spiny neurons (MSN) intrinsic excitability, in slices from rats which were subjected to either 1 (acute) or 14 (prolonged) days of forced abstinence after self-administration. Our results revealed no sex differences in oxycodone self-administration or somatic withdrawal symptoms following acute abstinence. However, we found a sex-specific enhancement in cue-induced relapse after prolonged, but not acute, abstinence from oxycodone self-administration, with females exhibiting higher relapse rates. Notably, prolonged abstinence led to similar increases in synaptic strength at PVT-NAcSh inputs compared to saline controls in both sexes, which was not observed after acute abstinence. Thus, prolonged abstinence results in a time-dependent increase in PVT-NAcSh synaptic strength and sex-specific effects on cue-induced relapse rates. These findings suggest that prolonged abstinence leads to significant synaptic changes, contributing to heightened relapse vulnerability, highlighting the need for targeted therapeutic strategies in opioid use disorder.

  PublisherDOI

• Sex-specific behavioral and thalamo-accumbal circuit adaptations after oxycodone abstinence

  eLife · 2025-01-13

  preprintOpen access

  Opioid use disorder is marked by a progressive change in the motivation to administer the drug even in the presence of negative consequences. After long periods of abstinence, the urge to return to taking the drug intensifies over time, known as incubation of craving. Conditioned responses to drug-related stimuli, can acquire motivational properties and exert control over motivated behaviors leading to relapse. Although preclinical data suggest that the behavioral expression of opioid use is similar between male and female rodents, we do not have conclusive results on sex differences in craving and relapse across abstinence periods. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and ex vivo electrophysiology, we assessed synaptic strength and glutamate release probability in this pathway, as well as the intrinsic excitability of NAcSh medium spiny neurons (MSNs), in slices from rats subjected to either 1 (acute) or 14 (prolonged) days of forced abstinence following self-administration. Our results revealed no sex differences in oxycodone self-administration or somatic withdrawal symptoms following acute abstinence. However, we found a sex-specific enhancement in cue-induced relapse after prolonged but not acute abstinence, with females exhibiting higher relapse rates. Prolonged but not acute abstinence led to comparable increases in PVT-NAcSh synaptic strength in both sexes, while inhibitory synaptic transmission in this pathway was not significantly altered at either abstinence time point. Intrinsic excitability of NAcSh MSNs was largely unaltered following oxycodone abstinence in both sexes; however, a trend toward increased spike output was observed in males after prolonged abstinence. Together, these findings suggest that prolonged oxycodone abstinence produces time-dependent and pathway-selective increases in excitatory synaptic strength at PVT-NAcSh inputs, accompanied by sex-specific effects on relapse vulnerability, highlighting the need for targeted therapeutic strategies in opioid use disorder.

  PublisherOA PDFDOI

• Association between social dominance hierarchy and PACAP expression in the extended amygdala, corticosterone, and behavior in C57BL/6 male mice

  Scientific Reports · 2024-04-18 · 3 citations

  articleOpen accessSenior author

  The natural alignment of animals into social dominance hierarchies produces adaptive, and potentially maladaptive, changes in the brain that influence health and behavior. Aggressive and submissive behaviors assumed by animals through dominance interactions engage stress-dependent neural and hormonal systems that have been shown to correspond with social rank. Here, we examined the association between social dominance hierarchy status established within cages of group-housed mice and the expression of the stress peptide PACAP in the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). We also examined the relationship between social dominance rank and blood corticosterone (CORT) levels, body weight, motor coordination (rotorod) and acoustic startle. Male C57BL/6 mice were ranked as either Dominant, Submissive, or Intermediate based on counts of aggressive/submissive encounters assessed at 12 weeks-old following a change in homecage conditions. PACAP expression was significantly higher in the BNST, but not the CeA, of Submissive mice compared to the other groups. CORT levels were lowest in Submissive mice and appeared to reflect a blunted response following events where dominance status is recapitulated. Together, these data reveal changes in specific neural/neuroendocrine systems that are predominant in animals of lowest social dominance rank, and implicate PACAP in brain adaptations that occur through the development of social dominance hierarchies.

  PublisherOA PDFDOI

• Sex-specific behavioral and thalamo-accumbal circuit adaptations after oxycodone abstinence

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-06 · 3 citations

  preprintOpen access

  Abstract Opioid use disorder is marked by a progressive change in the motivation to administer the drug even in the presence of negative consequences. After long periods of abstinence, the urge to return to taking the drug intensifies over time, known as incubation of craving. Conditioned responses to drug-related stimuli, can acquire motivational properties and exert control over motivated behaviors leading to relapse. Although preclinical data suggest that the behavioral expression of opioid use is similar between male and female rodents, we do not have conclusive results on sex differences in craving and relapse across abstinence periods. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and ex vivo electrophysiology, we assessed synaptic strength and glutamate release probability in this pathway, as well as the intrinsic excitability of NAcSh medium spiny neurons (MSNs), in slices from rats subjected to either 1 (acute) or 14 (prolonged) days of forced abstinence following self-administration. Our results revealed no sex differences in oxycodone self-administration or somatic withdrawal symptoms following acute abstinence. However, we found a sex-specific enhancement in cue-induced relapse after prolonged but not acute abstinence, with females exhibiting higher relapse rates. Prolonged but not acute abstinence led to comparable increases in PVT-NAcSh synaptic strength in both sexes, while inhibitory synaptic transmission in this pathway was not significantly altered at either abstinence time point. Intrinsic excitability of NAcSh MSNs was largely unaltered following oxycodone abstinence in both sexes; however, a trend toward increased spike output was observed in males after prolonged abstinence. Together, these findings suggest that prolonged oxycodone abstinence produces time-dependent and pathway-selective increases in excitatory synaptic strength at PVT-NAcSh inputs, accompanied by sex-specific effects on relapse vulnerability, highlighting the need for targeted therapeutic strategies in opioid use disorder.

  PublisherOA PDFDOI

• An increased copy number of glycine decarboxylase (GLDC) associated with psychosis reduces extracellular glycine and impairs NMDA receptor function

  Molecular Psychiatry · 2024-08-30 · 11 citations

  articleOpen access
  PublisherOA PDFDOI

• Intra-amygdala circuits of sleep disruption-induced anxiety in female mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-19 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Combining mouse genetics, electrophysiology, and behavioral training and testing, we explored how sleep disruption may affect the function of anxiety-controlling circuits, focusing on projections from the basolateral nucleus of the amygdala (BLA) to CRF-positive cells in the lateral division of the central amygdala (CeL). We found in Crh-IRES-Cre::Ai14(tdTomato) reporter female mice that 6 hours of sleep disruption during their non-active (light) cycle may be anxiogenic. Notably, the AMPAR/NMDAR EPSC amplitude ratio at the BLA inputs to CRF-CeL cells (CRF CeL ), assessed with whole-cell recordings in ex vivo experiments, was enhanced in slices from sleep-disrupted mice, whereas paired-pulse ratio (PPR) of the EPSCs induced by two closely spaced presynaptic stimuli remained unchanged. These findings indicate that sleep disruption-associated synaptic enhancements in glutamatergic projections from the BLA to CRF-CeL neurons may be postsynaptically expressed. We found also that the excitation/inhibition (E/I) ratio in the BLA to CRF CeL inputs was increased in sleep-disrupted mice, suggesting that the functional efficiency of excitation in BLA inputs to CRF CeL cells has increased following sleep disruption, thus resulting in their enhanced activation. The latter could be translated into enhanced anxiogenesis as activation of CRF cells in the CeL was shown to promote anxiety-like behaviors.

  PublisherOA PDFDOI

• Prefrontal cortex melanocortin 4 receptors (MC4R) mediate food intake behavior in male mice

  Physiology & Behavior · 2023 · 8 citations

  • Neuroscience
  • Biology
  • Endocrinology

  BACKGROUND: Melanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, and also with complex behaviors that orchestrate energy intake and expenditure, but the downstream neuroanatomical and neurochemical targets associated with these behaviors are elusive. In addition to strong expression in the hypothalamus, the MC4R is highly expressed in the medial prefrontal cortex, a region involved in executive function and decision-making. METHODS: Using viral techniques in genetically modified male mice combined with molecular techniques, we identify and define the effects on feeding behavior of a novel population of MC4R expressing neurons in the infralimbic (IL) region of the cortex. RESULTS: Here, we describe a novel population of MC4R-expressing neurons in the IL of the mouse prefrontal cortex that are glutamatergic, receive input from melanocortinergic neurons, and project to multiple regions that coordinate appetitive responses to food-related stimuli. The neurons are stimulated by application of MC4R-specific peptidergic agonist, THIQ. Deletion of MC4R from the IL neurons causes increased food intake and body weight gain and impaired executive function in simple food-related behavior tasks. CONCLUSION: Together, these data suggest that MC4R neurons of the IL play a critical role in the regulation of food intake in male mice.

  PublisherDOI

• Impact of social dominance hierarchy on PACAP expression in the extended amygdala, corticosterone, and behavior in C57BL/6 male mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-05-04 · 2 citations

  preprintOpen accessSenior author

  The natural alignment of animals into social dominance hierarchies produces adaptive, and potentially maladaptive, changes in the brain that influence health and behavior. Aggressive and submissive behaviors assumed by animals through dominance interactions engage stress-dependent neural and hormonal systems that have been shown to correspond with social rank. Here, we examined the impact of social dominance hierarchies established within cages of group-housed laboratory mice on expression of the stress peptide pituitary adenylate cyclase-activating polypeptide (PACAP) in areas of the extended amygdala comprising the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). We also quantified the impact of dominance rank on corticosterone (CORT), body weight, and behavior including rotorod and acoustic startle response. Weight-matched male C57BL/6 mice, group-housed (4/cage) starting at 3 weeks of age, were ranked as either most-dominant (Dominant), least-dominant (Submissive) or in-between rank (Intermediate) based on counts of aggressive and submissive encounters assessed at 12 weeks-old following a change in homecage conditions. We found that PACAP expression was significantly higher in the BNST, but not the CeA, of Submissive mice compared to the other two groups. CORT levels were lowest in Submissive mice and appeared to reflect a blunted response following social dominance interactions. Body weight, motor coordination, and acoustic startle were not significantly different between the groups. Together, these data reveal changes in specific neural/neuroendocrine systems that are predominant in animals of lowest social dominance rank, and implicate PACAP in brain adaptations that occur through the development of social dominance hierarchies.

  PublisherOA PDFDOI

Recent grants

• PACAP-mediated modulation of amygdalar-BNST interactions: implications for control of anxiety states

  NIH · $446k · 2016–2019

• NIH Grant R01NS045625

  NIH · $1.2M · 2009

• TRPC-mediated control of anxiety

  NIH · $2.3M · 2015–2021

• NIH Grant R01NS044185

  NIH · $1.1M · 2008

• NIH Grant R03DA015098

  NIH · $158k · 2005

Frequent coauthors

• Tsvetkov Ea

  Medical University of South Carolina

  73 shared

• Yan Li

  72 shared

• William A. Carlezon

  McLean Hospital

  49 shared

• Edward G. Meloni

  Harvard University

  33 shared

• Kwang‐Soo Kim

  28 shared

• Uwe Rudolph

  McLean Hospital

  26 shared

• Jun-Hyeong Cho

  University of California, Riverside

  24 shared

• Steven A. Siegelbaum

  24 shared

Labs

• Cellular Neurobiology LaboratoryPI