Elucidating the role of neural circuits responsible for learning and expressing action sequences is imperative for identifying their aberrant condition in the neuropathological state, which can then yield insights into improving diagnosis and therapy. The basal ganglia, particularly its main input nucleus the striatum, have been implicated as a major locus of motor sequence learning in behaviors such as vocalization, grooming, or other operant behaviors, such as sequential lever pressing. Though a great deal of research has recently explored the precise role of subtypes of striatal neurons in motor sequence learning, less is known about the inputs to these cells, particularly from subcortical regions such as the thalamus. The goal of this proposal is to dissect the functional role of two major inputs to the basal ganglia that are involved in motor sequence learning; those arising from cortex and thalamus. The K99 phase of the application will characterize the contribution of the three main subtypes of corticostriatal projection neurons in frontal cortex: layer 2/3, layer 5 pyramidal tract type (PT-), and layer 5 intratelencephalic type (IT-). Using recently created BAC-Cre transgenic mice to target these cell types, a host of viral mediating systems neuroscience tools (including diphtheria based Cre-dependent cell ablation, optogenetic excitation/inhibition, GCaMP6f fiber photometry, and optogenetic identification during in vivo electrophysiology) will be used to identify their functional role in learning a custom designed motor sequence task (Aim 1, K99). Following mastery of these methods, the second aim will be to characterize the role of thalamostriatal projections during motor sequence learning. To achieve this aim, novel viral tools that use a dual recombinase approach (Cre- /Flp-) to drive expression will be developed, in combination with new retrograde AAVs for inducing Flp- recombinase in pathway specific neurons in Cre- expressing transgenic mice. This approach will allow precise targeting of different populations of thalamic neurons, to characterize their role in sequence learning (Aim 2, K99).
The final aim will use the same approaches to characterize the role of corticostriatal and thalamostriatal roles in attending to task relevant and task irrelevant sensory information to the striatum in a stimulus guided Go-No Go task (Aim 3, R00), where corticostriatal projections should support ?top-down?, goal directed attention, whereas thalamostriatal projections represent a ?bottom-up?, salience-guided form of attention. The training plan, under the primary mentorship of Dr. Xin Jin at The Salk Institute for Biological Studies, will provide a full set of cutting-edge system neuroscience tools, as well as the necessary professional development, to obtain a faculty position and start a research laboratory as an independent investigator exploring the role of the basal ganglia in motor sequence learning in pathological and non-pathological states.

Public Health Relevance

Motor sequence learning is critical to the appropriate execution of many behaviors in daily life, and is severely affected in a host of neurological conditions including Parkinson?s disease, Huntington?s chorea and dystonia as well as mental illness such as obsessive-compulsive disorder and attention deficit disorder. The basal ganglia have been identified as a primary locus of sequence learning, and the genetic accessibility of mice has recently lead to an explosion of our knowledge of neuronal subtype specific contributions to neural control of action selection, motor learning, and pathology in the diseased state. The goal of the proposed project is to broaden our understanding of basal ganglia function by characterizing the role of its inputs from cortex and thalamus, which will provide valuable insights to a wide range of neuroscientists beyond the basal ganglia field.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Career Transition Award (K99)
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Neurological Sciences Training Initial Review Group (NST)
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Chen, Daofen
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Salk Institute for Biological Studies
La Jolla
United States
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