The basal ganglia lie at the critical interface between movement and motivation. The striatum, the largest structure of these deep-lying structures, is a hub for inputs from the overlying neocortex and is a main distributor of output to other parts of the brain via basal ganglia output nuclei. This system is implicated in a large range of neurological and neuropsychiatric disorders. It is modulated by neuromodulators, including by dopamine from the midbrain, deficient in Parkinson's disease. The dorsal striatum, the focus of this proposal, receives dopamine-containing input from the pars compacta of the substantia nigra (SNc). This nigrostriatal circuit degenerates in Parkinson's disease, and is a major controller of both motor behavior and responses to reinforcement and to motivational control. Our goal in the proposed research is to elucidate the physiology and anatomy of this system, focusing on critical questions related to these control mechanisms. First, our preliminary work suggests that the organization of the striatum into anatomically distinct compartments, the striosomes and surrounding matrix, is crucial in terms of behavior. Striosomes receive selective input from a restricted set of motivation/mood/emotion-related neocortical regions and are a main origin of the striatal projection to the SNc dopamine-containing neurons so important for mood and motor control. This evidence suggests special functions for striosomes, but what these functions are is not clear. Our preliminary and recent work suggests, however, that striosomes may be specialized for cost-benefit decision-making, in which costs and benefits presented in any situation have to be weighed in order for us to act. This kind of decision-making is critical for survival and, moreover, is disturbed in a number of neuropsychiatric conditions. We propose in Aim 1 to use state-of-the-art physiological and imaging methods in novel genetically engineered mice to test the hypothesis that striosomes underlie such decision-making. Second, our preliminary work has shown a remarkable anatomical organization of the striosome-SNc connection, suggesting that striosomes could exert powerful control over dopamine-containing SNc neurons. We propose to examine this system with novel combinations of optogenetic and physiological experiments combined with anatomy (Aim 2). Third, despite mounting evidence that striosome-matrix organization is a fundamentally important organizing property of the striatum, how this organization relates to the clinically critical division of the striatal output pathways into direct and indirect movement-control pathways is not understood.
We aim to fill this gap by using specially engineered mice allowing direct testing of this relationship in physiological, imaging and behavioral experiments. Disturbances in the balance between cost and benefit in decision-making and movement control are critical in a number of neurologic and neuropsychiatric disorders ranging from Parkinson's disease to obsessive-compulsive disorder to psychosis. Thus, the experiments proposed are directly related to the mission of the NIMH to understand, prevent and cure mental illness.
In daily life, decision-making often involves carefully deliberating costs and benefits of different choice options, and neuropsychiatric disorders with disturbances of such ability can severely affect the quality of life. Our research is dedicated to understanding the brain circuits underlying this decision-making process and to finding clues to new therapeutic approaches through this better understanding. With the proposed work, we hope to help people with anxiety, depression and obsessive-compulsive disorders.
| 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 |
| Graybiel, Ann M; Grafton, Scott T (2015) The striatum: where skills and habits meet. Cold Spring Harb Perspect Biol 7:a021691 |
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