About

Miriam Bocarsly, PhD, is a Principal Investigator at Rutgers University, associated with Rutgers Biomedical and Health Sciences, Rutgers Brain Health Institute, and Rutgers New Jersey Medical School. The page lists her among the research staff and indicates her role as a leader in her research group. No additional details about her research focus, background, or key contributions are provided on the page.

Research topics

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

Selected publications

• D2 autoreceptors gate vulnerability to cocaine use disorder

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-11

  articleOpen access

  SUMMARY A defining feature of substance use disorder is that repeated drug use does not always lead to addiction, motivating the search for biomarkers of vulnerability 1 . Reduced striatal dopamine D2/3 receptor availability is a robust PET correlate of problematic stimulant use 2–5 , but the signal may reflect high endogenous dopamine level, and it conflates presynaptic D2 autoreceptors on dopamine axons with postsynaptic D2/3 heteroreceptors on striatal projection neurons. We dissociated these contributions using cell type–specific Drd2 haploinsufficiency in dopamine neurons (autoD2KD), D2-expressing medium spiny neurons (MSN-D2KD), or both. Autoreceptor haploinsufficiency (autoD2KD) weakened presynaptic control of dopamine release, enhanced phasic gain, and prolonged cocaine-evoked dopamine elevations. This was accompanied by a hyper-exploratory trait and altered cocaine adaptation. Specifically, autoD2KD mice showed greater cocaine-seeking behavior, despite intact responses to sucrose reward and punishment. Although all genotypes showed graded reductions in striatal D2/3 binding, D1-like compensations diverged, resulting in different D1:D2/3 ratio in the striatum. The clinical implication is that striatal D1 density and D1:D2/3 balance may emerge as critical biomarkers for distinguishing cell-type-specific D2 reductions relevant to addiction vulnerability.

  PublisherOA PDFDOI

• 477. Alterations in Striatal Dopaminergic Functioning in High-Risk Schizophrenia Mouse Model

  Biological Psychiatry · 2025-04-09

  articleSenior author
  PublisherDOI

• Brain insulin signaling restores deficits in striatal dopamine release in overweight male mice with preexisting low D2-receptor expression

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-30

  preprintOpen access1st author

  Obesity is characterized by insulin resistance, motivational impairments, and, in some cases, reduced availability of dopamine D2 receptors in the brain. However, whether the low D2 receptor levels represent a predisposing factor or a consequence of obesity, and how these processes are mechanistically linked, remains unclear. Here, we directly tested this causal relationship by selectively reducing D2 receptor density in striatal neurons. Male, but not female, mice with a low density of striatal D2 receptors consumed more food, gained more weight, and developed metabolic features of peripheral insulin resistance despite being maintained on standard chow. Motivational deficits preceded weight gain, manifesting as delayed circadian locomotor onset, reduced physical activity, and diminished effort to obtain food. In the brain, male mice with low D2 receptor density showed reduced dopamine release capacity and age-dependent alterations in brain insulin sensitivity. Prior to weight gain, brain insulin responses were blunted compared to those of controls, in which insulin potentiates dopamine release and enhances striatal acetylcholine signaling. Once overweight, however, these mice exhibited brain insulin hypersensitivity, with insulin strongly restoring dopamine release capacity. Together, these findings demonstrate that low striatal D2 receptor density predisposes male mice to an obesity-like phenotype through early dopaminergic dysfunction that precedes weight gain and is later compensated by insulin hypersensitivity in the brain.

  PublisherOA PDFDOI

• Local Regulation of Striatal Dopamine Release Shifts from Predominantly Cholinergic in Mice to GABAergic in Macaques

  Journal of Neuroscience · 2025-01-21 · 4 citations

  articleOpen access

  Dopamine critically regulates neuronal excitability and promotes synaptic plasticity in the striatum, thereby shaping network connectivity and influencing behavior. These functions establish dopamine as a key neuromodulator, whose release properties have been well studied in rodents but remain understudied in nonhuman primates. This study aims to close this gap by investigating the properties of dopamine release in macaque striatum and comparing/contrasting them to better-characterized mouse striatum, using ex vivo brain slices from male and female animals. Using combined electrochemical techniques and photometry with fluorescent dopamine sensors, we found that evoked dopamine signals have smaller amplitudes in macaques compared with those in mice. Interestingly, cholinergic-dependent dopamine release, which accounts for two-thirds of evoked dopamine release in mouse slices, is significantly reduced in macaques, providing a potential mechanistic underpinning for the observed species difference. In macaques, only nicotinic receptors with alpha-6 subunits contribute to evoked dopamine release, whereas in mice, both alpha-6 and non-alpha6-containing receptors are involved. We also identified robust potentiation of dopamine release in both species when GABA A and GABA B receptors were blocked. This potentiation was stronger in macaques, with an average increase of 50%, compared with 15% in mice. Together, these results suggest that dopamine release in macaque is under stronger GABA-mediated inhibition and that weaker cholinergic-mediated dopamine release may account for the smaller amplitude of evoked dopamine signals in macaque slices.

  PublisherDOI

• Susceptibility of Glucose Regulation to Social Isolation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-22

  articleOpen access

  Loneliness and social isolation strongly associate with increased incidence of diabetes in humans. However, it remains unclear if lack of meaningful social interactions represents a cause or a symptom of disease. In rodents, social isolation leads to metabolic dysregulation, however the dynamics and contributing factors remain poorly understood. Here we show that single-housing young adult male mice for at least three weeks led to fasting hyperglycemia, an effect that was maintained for the duration of single-housing, but was corrected within a week of reverting mice to co-housing conditions. Single-housing did not affect glucose regulation in females. Gonadectomy experiments revealed that testicular factors induced susceptibility to social isolation, as orchiectomy prevented isolation-induced fasting hyperglycemia in males. We did not find a protective role for ovarian hormones, as ovariectomized females were as resilient as intact females to isolation-induced fasting hyperglycemia. To understand the underlying mechanisms for susceptibility to isolation, we measured plasma levels of glucoregulatory hormones. Isolation did not affect the levels of insulin, epinephrine, and corticosterone. However, glucagon levels were distinctly modulated by social isolation in intact and orchiectomized mice. Social isolation induces increased immediate early gene expression in specific neurons of the ventromedial hypothalamus, a glucoregulatory brain structure that promotes glucagon release. Taken together, our findings show that testicular hormones make males susceptible to isolation-induced disruption of glucose regulation and suggest that brain glucoregulatory neurons play a role.

  PublisherOA PDFDOI

• Preexisting risk-avoidance and enhanced alcohol relief are driven by imbalance of the striatal dopamine receptors in mice

  Nature Communications · 2024-10-22 · 6 citations

  articleOpen access1st authorCorresponding

  Alcohol use disorder (AUD) is frequently comorbid with anxiety disorders, yet whether alcohol abuse precedes or follows the expression of anxiety remains unclear. Rodents offer control over the first drink, an advantage when testing the causal link between anxiety and AUD. Here, we utilized a risk-avoidance task to determine anxiety-like behaviors before and after alcohol exposure. We found that alcohol's anxiolytic efficacy varied among inbred mice and mice with high risk-avoidance showed heightened alcohol relief. While dopamine D1 receptors in the striatum are required for alcohol's relief, their levels alone were not correlated with relief. Rather, the ratio between striatal D1 and D2 receptors was a determinant factor for risk-avoidance and alcohol relief. We show that increasing striatal D1 to D2 receptor ratio was sufficient to promote risk-avoidance and enhance alcohol relief, even at initial exposure. Mice with high D1 to D2 receptor ratio were more prone to continue drinking despite adverse effects, a hallmark of AUD. These findings suggest that an anxiety phenotype may be a predisposing factor for AUD.

  PublisherOA PDFDOI

• Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice

  Proceedings of the National Academy of Sciences · 2024-04-29 · 22 citations

  articleOpen access

  Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1 . Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.

  PublisherDOI

• Presynaptic and Postsynaptic Mesolimbic Dopamine D3 Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice

  Biological Psychiatry · 2024-06-03 · 12 citations

  articleOpen access
  PublisherOA PDFDOI

• Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-11-28 · 3 citations

  preprintOpen access

  Abstract Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1 . Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occurs alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD. Significance Statement We generated mouse models that express mutations in high-confidence genes linked to Tourette disorder (TD). These models show sensorimotor and cognitive behavioral phenotypes resembling TD-like behaviors. Sensorimotor gating deficits and repetitive motor behaviors are attenuated by drugs that act on dopamine. Reward learning and striatal dopamine is enhanced. Brain development is grossly normal, including cortical layering and patterning of major axon tracts. Further, no signs of striatal interneuron loss are detected. Interestingly, behavioral phenotypes in affected females can be more pronounced than in males, despite male sex bias in the diagnosis of TD. These novel mouse models with construct, face, and predictive validity provide a new resource to study neural substrates that cause tics and related behavioral phenotypes in TD.

  PublisherOA PDFDOI

• Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward

  Cell Reports · 2022 · 19 citations

  • Neuroscience
  • Chemistry
  • Internal medicine

  Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.

  PublisherOA PDFDOI

Recent grants

• Striatal dopamine circuitry mediating psychostimulant induced consummatory behavior

  NIH · 2016–2019

Frequent coauthors

• Nicole M. Avena

  70 shared

• Mark S. Gold

  31 shared

• Bartley G. Hoebel

  29 shared

• William A. Carlezon

  McLean Hospital

  25 shared

• Anita J Bechtholt-Gompf

  McLean Hospital

  25 shared

• Bruce M. Cohen

  McLean Hospital

  25 shared

• Marie None

  Harvard University

  25 shared

• Stan Floresco

  University of British Columbia

  25 shared

Labs

• Bocarsly LabPI

Education

• Ph.D., Psychology and Neuroscience

  Princeton University

  2013