The basal ganglia are centrally involved in the etiology of neurologic disorders such as Parkinson's disease and in the motor and cognitive functions that are affected in these disorders. The basal ganglia are also implicated in neuropsychiatric disorders, such as obsessive-compulsive disorder, that are closely related to and often co-morbid with anxiety disorders and depression. It is of great importance to the field of mental health to understand how the basal ganglia could contribute to such a range of brain disorders. The basal ganglia are also central to habit formation and to the neural mechanisms underlying addictive behavior. We propose a series of coordinated studies to test specific hypotheses about cognitive and action-directed functions of the basal ganglia in such habitual and repetitive behaviors. We have developed a behavioral model that allows rats to initiate voluntary movements, and to make a """"""""decision"""""""" whether to execute one or another movement pattern in order to receive reward. Our preliminary data indicate large-scale plasticity in striatal neuronal firing patterns during procedural learning. These patterns occur as a shift occurs behaviorally from """"""""exploration"""""""" to """"""""exploitation"""""""" as a result of learning. We now propose to record neuronal activity in the striatum, with multi-electrode chronic recording methods, as rats perform reward-based tasks that will vary in complexity and in task parameters related to reward anticipation in order to analyze specific properties of striatal plasticity. We propose to record both spike activity and local field potential activity and to approach data analysis focusing on three specific hypotheses. Through these studies, we aim to elucidate functional properties of basal ganglia activity during learning and the plasticity of this activity during learning. Together, the proposed studies will help to clarify the function of cortico-basal ganglia loops implicated in neurologic and neuropsychiatric disorders. Understanding how patterns of activity are acquired in these brain circuits is directly relevant to understanding how abnormal patterns of activity could be laid down. Such analyses of neuroplasticity in the basal ganglia are thus relevant to work on a range of human disorders, including Parkinson's disease, Huntington's disease, Tourette syndrome and related OC- spectrum disorders. We thus believe that the proposed work is important for the mission of the NIMH, which is to understand, prevent and cure mental illness. ? ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Osborn, Bettina D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
Other Domestic Higher Education
United States
Zip Code
Delcasso, Sebastien; Denagamage, Sachira; Britton, Zelie et al. (2018) HOPE: Hybrid-Drive Combining Optogenetics, Pharmacology and Electrophysiology. Front Neural Circuits 12:41
Martiros, Nuné; Burgess, Alexandra A; Graybiel, Ann M (2018) Inversely Active Striatal Projection Neurons and Interneurons Selectively Delimit Useful Behavioral Sequences. Curr Biol 28:560-573.e5
Crittenden, Jill R; Lacey, Carolyn J; Weng, Feng-Ju et al. (2017) Striatal Cholinergic Interneurons Modulate Spike-Timing in Striosomes and Matrix by an Amphetamine-Sensitive Mechanism. Front Neuroanat 11:20
Friedman, Alexander; Homma, Daigo; Bloem, Bernard et al. (2017) Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making. Cell 171:1191-1205.e28
Bloem, Bernard; Huda, Rafiq; Sur, Mriganka et al. (2017) Two-photon imaging in mice shows striosomes and matrix have overlapping but differential reinforcement-related responses. Elife 6:
Nakamura, Toru; Nagata, Masatoshi; Yagi, Takeshi et al. (2017) Learning new sequential stepping patterns requires striatal plasticity during the earliest phase of acquisition. Eur J Neurosci 45:901-911
Friedman, Alexander; Slocum, Joshua F; Tyulmankov, Danil et al. (2016) Analysis of complex neural circuits with nonlinear multidimensional hidden state models. Proc Natl Acad Sci U S A 113:6538-43
Kalueff, Allan V; Stewart, Adam Michael; Song, Cai et al. (2016) Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci 17:45-59
Smith, Kyle S; Graybiel, Ann M (2016) Habit formation. Dialogues Clin Neurosci 18:33-43
Friedman, Alexander; Keselman, Michael D; Gibb, Leif G et al. (2015) A multistage mathematical approach to automated clustering of high-dimensional noisy data. Proc Natl Acad Sci U S A 112:4477-82

Showing the most recent 10 out of 35 publications