About

Ann M. Graybiel joined the MIT faculty in 1973 and was named Walter A. Rosenblith Professor of Neuroscience in the Department of Brain and Cognitive Sciences in 1994. She was appointed Investigator at the McGovern Institute for Brain Research in 2001 and has received numerous honors including the National Medal of Science, the James R. Killian Faculty Achievement Award, the Woman Leader of Parkinson’s Science award, and the Harold S. Diamond Professor title. In 2008, she was named Institute Professor, the highest academic award at MIT, and in 2012, she shared the Kavli Prize in Neuroscience. She is a member of the National Academy of Sciences, the Institute of Medicine, and the American Academy of Arts and Sciences. Her research focuses on the mechanisms of learning and memory within the basal ganglia, particularly how the brain constructs habits and transitions between conscious and non-conscious behaviors. Her laboratory investigates how the basal ganglia and cortico-basal ganglia loops facilitate the acquisition, execution, and breaking of habits, with implications for understanding disorders such as Parkinson’s disease, obsessive-compulsive spectrum disorders, and addiction. Her work involves neural recording techniques in awake, behaving animals, revealing plasticity in the response properties of neurons during learning processes. She also explores the interaction between emotional and motor systems, the molecular basis of learning mechanisms, and genes involved in behavioral exploration and repetitive behaviors, contributing significantly to the understanding of basal ganglia function and its role in neuropsychiatric disorders.

Research topics

• Computer Science
• Psychology
• Biology
• Physics
• Neuroscience

Selected publications

• Functional distinctions between orbitofrontal cortex and anterior cingulate cortex subregions in decision-making and autonomic regulation

  Nature Communications · 2026-02-14 · 1 citations

  articleOpen accessSenior author

  Mood disorders are associated with complex disruptions in brain networks, including those associated with the orbitofrontal cortex (OFC) and pregenual anterior cingulate cortex (pACC). Differential functions of these regions, especially the functions of the far-caudal OFC, are incompletely understood. We trained macaques to perform an approach-avoidance task and recorded cOFC and pACC neuronal activity and autonomic/somatic responses during performance, including during electrical microstimulation (EMS) of the cOFC. The cOFC was sensitive to both positive and negative stimuli, whereas the pACC was significantly more active during aversive outcomes. cOFC EMS increased avoidance, suggesting a causal cOFC function in cost-benefit decision-making. The cOFC activity led pACC activity during the decision period, supporting cOFC network prominence. Autonomic and somatic responses were positively correlated with behavioral patterns, consistent with a coordinated body-brain involvement during emotionally significant decision-making. We suggest that dysfunction of this network could potentially contribute to the etiology of mood disorders. The roles of orbitofrontal and cingulate cortex in emotional decisions remain unclear. Here the authors show distinct timing between caudal orbitofrontal and cingulate signals, that orbitofrontal stimulation increases avoidance, and that physiological responses mirror behavior.

  PublisherDOI

• Habit learning is associated with efficiently controlled network dynamics in naive macaque monkeys

  npj Complexity · 2026-01-22

  articleOpen access

  Primates utilize distributed neural circuits to learn habits in uncertain environments, but the underlying mechanisms remain poorly understood. We propose a formal theory of network energetics explaining how brain states influence sequential behavior. We test our theory on multi-unit recordings from the caudate nucleus and cortical regions of macaques performing a motor habit task. The theory predicts the energy required to transition between brain states represented by trial-specific firing rates across channels, assuming activity spreads through effective connections. We hypothesized that habit formation would correlate with lower control energy. Consistent with this, we observed smaller energy requirements for transitions between similar saccade patterns and those of intermediate complexity, and sessions exploiting fewer patterns. Simulations ruled out confounds from neurons' directional tuning. Finally, virtual lesioning demonstrated the robustness of observed relationships between control energy and behavior. This work paves the way for examining how behavior arises from changing activity in distributed circuitry.

  PublisherOA PDFDOI

• State-dependent modulation of spiny projection neurons controls levodopa-induced dyskinesia in a mouse model of Parkinson’s disease

  Science Advances · 2025-12-03 · 2 citations

  articleOpen access

  In the later stages of Parkinson's disease, patients often manifest levodopa-induced dyskinesia (LID), compromising their quality of life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this treatment gap, the intrinsic and synaptic changes in striatal spiny projection neurons (SPNs) triggered by the sustained elevation of dopamine (DA) during dyskinesia were characterized using electrophysiological, pharmacological, molecular, and behavioral approaches. Our studies revealed that the intrinsic excitability and functional corticostriatal connectivity of SPNs in dyskinetic mice oscillate between LID on- and off-states in a cell- and state-specific manner. Although triggered by levodopa, these oscillations in SPN properties depended on both dopaminergic and cholinergic signaling. Disrupting M1 muscarinic receptor signaling specifically in indirect pathway SPNs or deleting its downstream signaling partner CalDAG-GEFI blunted the levodopa-induced alterations in functional connectivity, enhanced the motoric benefits of levodopa, and attenuated LID severity.

  PublisherDOI

• Surprises From the Basal Ganglia: Stop and Go Have New Meaning

  Movement Disorders · 2025-08-14 · 8 citations

  articleOpen access1st authorCorresponding

  This perspective highlights new work suggesting the need for revision of the canonical direct-indirect model of the basal ganglia's influence on movement, with fresh evidence that there is a formerly unappreciated pair of direct and indirect pathways that parallel the standard model's canonical direct and indirect pathways, and promising evidence pointing toward improved clinical treatments for Parkinson's disease. As a working hypothesis, it is suggested that the non-canonical direct and indirect pathways, which arise in striosomes, might act as homeostatic circuits that can reign in or amplify the activity of the canonical pathways in the face of their imbalance, including that occurring in hyperkinetic or hypokinetic disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  PublisherOA PDFDOI

• Molecular unbalances between striosome and matrix compartments characterize the pathogenesis of Huntington’s disease model mouse

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-24

  preprintOpen accessSenior authorCorresponding

  Abstract The pathogenesis of Huntington’s disease is still incompletely understood, despite the remarkable advances in identifying the molecular effects of the Htt mutation in this disease. When we focus on movement disorders, clinical studies offer us some hints about this issue. Human studies employing positron emission tomography have identified a reduction in phosphodiesterase 10A (PDE10A) as the earliest event in the brain of patients with Huntington’s disease, which occurs about 25 years before symptom onset. A PDE10A mutation is also known to cause childhood-onset chorea. GNAL encodes the olfactory type G-protein α subunit (Gα olf ), strongly expressed in the striatum, and its mutation causes familial dystonia. PDE10A and Gα olf are both critical regulators of cyclic AMP and are abundant in striatal spiny projection neurons. These findings suggest that maintaining cyclic AMP levels in the striatum might be an essential target for the pathogenesis of movement disorders such as chorea and dystonia. Why and how these changes in the striatum cause movement disorder are still a mystery. Here we suggest that a key might be evaluating these messenger systems in light of the circuit-level compartmental organization of the striatum, in which there is particular vulnerability of the striosome compartment. We developed machine learning algorithms to define with high precision and reproducibility the borders of striosomes in the brains of q175 Huntington’s disease model mice from 3-12 months of age. We demonstrate that multiple molecules including Gα olf , PDE10A, dopamine D1 and D2 receptors, adenosine 2A receptors, and mu-opioid receptors differentially change their expression patterns in striosomes across ages by comparison with their expression patterns in the matrix compartment. An early and pronounced differential vulnerability of striosomes has been demonstrated in studies of post-mortem Huntington’s brains. Our findings here, mapping the molecular distributions across age in a widely studied mouse model of Huntington’s disease, may help to pinpoint the pathogenic mechanisms of Huntington’s disease by demonstrating the differential molecular changes in the striosome compartment.

  PublisherOA PDFDOI

• State-dependent modulation of spiny projection neurons controls levodopa-induced dyskinesia in a mouse model of Parkinson’s disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02 · 4 citations

  preprintOpen access

  In the later stages of Parkinson's disease (PD), patients often manifest levodopa-induced dyskinesia (LID), compromising their quality of life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this treatment gap, the intrinsic and synaptic changes in striatal spiny projection neurons (SPNs) triggered by the sustained elevation of dopamine (DA) during dyskinesia were characterized using electrophysiological, pharmacological, molecular and behavioral approaches. Our studies revealed that the intrinsic excitability and functional corticostriatal connectivity of SPNs in dyskinetic mice oscillate between the on- and off-states of LID in a cell- and state-specific manner. Although triggered by levodopa, these rapid oscillations in SPN properties depended on both dopaminergic and cholinergic signaling. In a mouse PD model, disrupting M1 muscarinic receptor signaling specifically in iSPNs or deleting its downstream signaling partner CalDAG-GEFI blunted the levodopa-induced oscillation in functional connectivity, enhanced the beneficial effects of levodopa and attenuated LID severity.

  PublisherDOI

• Molecular Imbalances Between Striosome and Matrix Compartments Characterize the Pathogenesis and Pathophysiology of Huntington’s Disease Model Mouse

  International Journal of Molecular Sciences · 2025-09-03 · 1 citations

  articleOpen accessSenior authorCorresponding

  The pathogenesis and pathophysiology of Huntington’s disease (HD) are still incompletely understood, despite the remarkable advances in identifying the molecular effects of the Htt mutation in this disease. Clinical positron emission tomography studies suggest that phosphodiesterase 10A (PDE10A) declines earlier than dopamine D1 and D2 receptors in HD, indicating that it might serve as a key molecular marker in understanding disease mechanisms. In movement disorders, mutations in the genes encoding PDE10A and G-protein α subunit (Gαolf), both critical cAMP regulators in striatal spiny projection neurons, have been linked to chorea and dystonia. These observations highlight the potential importance of striatal cyclic AMP (cAMP) signaling in these disorders, but how such dysfunction could come is unknown. Here, we suggest that a key to understanding signaling dysfunction might be to evaluate these messenger systems in light of the circuit-level compartmental organization of the caudoputamen, in which there is particular vulnerability of the striosome compartment in HD. We developed machine learning algorithms to define with high precision and reproducibility the borders of striosomes in the brains of Q175 knock-in (Q175KI) HD mice from 3–12 months of age. We demonstrate that the expression of multiple molecules, including Gαolf, PDE10A, dopamine D1 and D2 receptors, and adenosine A2A receptors, is significantly reduced in the striosomes of Q175KI mice as compared to wildtype controls, across 3, 6, and 12 months of age. By contrast, mu-opioid receptor (MOR1) expression is uniquely upregulated, suggesting a compartment-specific and age-dependent shift in molecular profiles in the Q175KI HD mouse model caudoputamen. These differential changes may serve as a useful platform to determine factors underlying the greater vulnerability of striatal projection neurons in the striosomes than in the matrix in HD.

  PublisherOA PDFDOI

• Habit learning is associated with efficiently controlled network dynamics in naive macaque monkeys.

  PubMed · 2025-11-13

  articleOpen access

  Primates utilize distributed neural circuits to learn habits in uncertain environments, but the underlying mechanisms remain poorly understood. We propose a formal theory of network energetics explaining how brain states influence sequential behavior. We test our theory on multi-unit recordings from the caudate nucleus and cortical regions of macaques performing a motor habit task. The theory predicts the energy required to transition between brain states represented by trial-specific firing rates across channels, assuming activity spreads through effective connections. We hypothesized that habit formation would correlate with lower control energy. Consistent with this, we observed smaller energy requirements for transitions between similar saccade patterns and those of intermediate complexity, and sessions exploiting fewer patterns. Simulations ruled out confounds from neurons' directional tuning. Finally, virtual lesioning demonstrated robustness of observed relationships between control energy and behavior. This work paves the way for examining how behavior arises from changing activity in distributed circuitry.

  PublisherOA PDF

• Nociceptin Orphanin F/Q Pathways are Dysregulated by Stress and Modulate Reward Learning and Motivation Across Species

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-05 · 2 citations

  preprintOpen access

  Abstract Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has anti-depressant/anti-anhedonic effects. The mechanisms underlying these effects remain, however, unclear. Here, we investigated the role of NOPR in depressive phenotypes alongside potentially prohedonic effects of NOPR antagonism across species. In Study 1, we evaluated whether exposure to early-life adversity (ELA) upregulated ventral tegmental area (VTA) and striatal prepronociceptin ( Pnoc ) gene expression in adult mice. In Study 2, we tested whether chronic social defeat altered Pnoc gene expression in reward-related regions. To establish whether direct NOPR modulation is implicated in reward-related behaviors, in Study 3, we assessed whether NOPR antagonism alters reward learning in rats. Finally, in Study 4, we tested whether NOPR antagonism boosts motivation among depressed humans. ELA induced anhedonic behavior and increased Pnoc expression in the VTA; in females (but not males), ELA increased Pnoc expression in the dorsal striatum (Study 1). Furthermore, chronic stress reduced Pnoc -expressing cells in the VTA, dorsal striatum and prefrontal cortex and susceptible rats showed reduced VTA NOPR gene ( Oprl1)- expressing cells (Study 2). In a behavioral assay, a single 30-mg dose of a NOPR antagonist (BTRX-246040) boosted reward learning in rats (Study 3). Finally, in depressed humans, relative to placebo, 8-week treatment with BTRX-246040 increased incentive motivation (Study 4). Collectively, our findings indicate that chronic stressors alter Pnoc and mRNA levels of Pnoc -expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows anti-anhedonic properties.

  PublisherOA PDFDOI

• Dopamine release plateau and outcome signals in dorsal striatum contrast with classic reinforcement learning formulations

  Nature Communications · 2024-10-14 · 9 citations

  articleOpen accessSenior author

  We recorded dopamine release signals in centromedial and centrolateral sectors of the striatum as mice learned consecutive versions of visual cue-outcome conditioning tasks. Dopamine release responses differed for the centromedial and centrolateral sites. In neither sector could these be accounted for by classic reinforcement learning alone as classically applied to the activity of nigral dopamine-containing neurons. Medially, cue responses ranged from initial sharp peaks to modulated plateau responses; outcome (reward) responses during cue conditioning were minimal or, initially, negative. At centrolateral sites, by contrast, strong, transient dopamine release responses occurred at both cue and outcome. Prolonged, plateau release responses to cues emerged in both regions when discriminative behavioral responses became required. At most sites, we found no evidence for a transition from outcome signaling to cue signaling, a hallmark of temporal difference reinforcement learning as applied to midbrain dopaminergic neuronal activity. These findings delineate a reshaping of striatal dopamine release activity during learning and suggest that current views of reward prediction error encoding need review to accommodate distinct learning-related spatial and temporal patterns of striatal dopamine release in the dorsal striatum. Dorsal striatal dopamine release develops plateau responses to reward cues, but lacks outcome release medially and transitions to both outcome and rewarded cue laterally. Here the authors suggest the need for reconsideration of reward prediction error models for striatal dopamine release.

  PublisherOA PDFDOI

Frequent coauthors

• Jill R. Crittenden

  Massachusetts Institute of Technology

  128 shared

• Ken‐ichi Amemori

  121 shared

• Tomoko Yoshida

  Massachusetts Institute of Technology

  75 shared

• Yasuo Kubota

  McGovern Institute for Brain Research

  64 shared

• Satoko Amemori

  Japan Society for the Promotion of Science

  59 shared

• Helen N. Schwerdt

  Research Network (United States)

  56 shared

• Daniel J. Gibson

  Columbia St. Mary's Hospital

  56 shared

• Dan Hu

  The Seventh Affiliated Hospital of Sun Yat-sen University

  55 shared

Education

• Ph.D., Psychology and Brain Science

  Massachusetts Institute of Technology

  1971

• A.B., Biology

  Harvard University

  1964

Awards & honors

• National Medal of Science
• James R. Killian Faculty Achievement Award
• Woman Leader of Parkinson’s Science award from the Parkinson…
• Harold S. Diamond Professor by the National Parkinson Founda…
• Kavli Prize in Neuroscience