Dissecting the Action Learning Process with Dopaminergic Reinforcement

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Principal Investigator: Jonathan  Tang
Organization: SEATTLE CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $241,524
Funding agency: National Institute of Neurological Disorders and Stroke

Understanding the process by which animals learn to perform specific actions from rewarding experiences is
important for identifying the neural and behavioral patterns that indicate system dysregulation; such knowledge
can help lead to the development of diagnostics and therapy for conditions where action learning is impaired.
Dopaminergic neurons and their targets have been implicated as major contributors to action learning. Though
it is well known that stimulation of dopaminergic neurons can reinforce behavior, it is less clear how stimulated
dopaminergic activities guide the animal to behaviorally search the world for the action that produces reward.
The goal of this proposal is to characterize the role of dopaminergic activity in shaping behavior that hones in
on a specific action or action sequences for reward. A key to this proposal is the combination of optogenetics
and objective, unsupervised behavioral clustering to develop a closed loop reinforcement system in which
reward in the form of dopaminergic stimulation is delivered to the VTA of animals as they learn to perform
specific actions or action sequences. The K99 phase of the application will involve characterization of the
behavioral patterns underlying single action and action sequence learning, followed by imaging of the
dorsolateral striatum (known to represent the action space) in freely moving mice to understand the neural
correlates of the action learning process. Functional circuit dissection will also be performed to elucidate which
specific VTA projection pathways mediate action learning. Following mastering of these techniques, the
applicant will enter the R00 phase and continue studying the role of specific VTA projection pathways on the
action learning process. Chemogenetics in combination with closed loop reinforcement will be performed to
dissect the pathways necessary for action learning. Neuronal activity imaging will then be performed on
dopaminergic targets found to be important for action learning. The training plan, under the joint mentorship of
Dr. Rui Costa and Dr. Stefano Fusi at Columbia University, will provide a complete set of neuroscience tools
and the necessary career development resources for the applicant to obtain a faculty position and start an
independent research program to explore the role of VTA dopaminergic neurons on the action learning
process.

Terms: <Address><Affect><Amentia><Animals><Area><Behavior><Behavioral><Behavioral Mechanisms><Behavioral Paradigm><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Signaling><Computing Methodologies><Corpus Striatum><Corpus striatum structure><Cues><DA Neuron><Data><Dementia><Dissection><Dopamine neuron><Dopaminergic Cell><Dorsal><Encephalon><Environment><Faculty><Genetic><Goals><History><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><Image><Impairment><Instrumental Learning><Intracellular Communication and Signaling><Joints><Knowledge><Label><Lead><Learning><Life><Mammalia><Mammals><Mechanisms of Behavior and Behavior Change><Mediating><Mentors><Mentorship><Methods><Mice><Mice Mammals><Modeling><Monitor><Motor><Movement><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic><Neurologic Disorders><Neurological><Neurological Disorders><Neurons><Neurosciences><Operant Conditioning><Paralysis Agitans><Parkinson><Parkinson Disease><Pathway interactions><Pattern><Pb element><Performance><Phase><Population><Position><Positioning Attribute><Primary Parkinsonism><Process><Psychological reinforcement><Recording of previous events><Reinforcement><Research><Resolution><Resource Development><Rewards><Role><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Striate Body><Striatum><Substantia Nigra><Substantia nigra structure><System><Technical Expertise><Techniques><Testing><Training><Universities><Ventral Striatum><Ventral Tegmental Area><Viral><Work><behavior influence><behavior mechanism><behavior response><behavior study><behavioral influence><behavioral response><behavioral study><biological signal transduction><body movement><career development><computational methodology><computational methods><computer based method><computer methods><computing method><diagnostic approach><diagnostic development><diagnostic strategy><dopaminergic neuron><experience><experiment><experimental research><experimental study><experiments><genetic approach><genetic strategy><heavy metal Pb><heavy metal lead><histories><imaging><instrumental conditioning><learning activity><learning method><learning strategies><learning strategy><neural><neural correlate><neural mechanism><neurological disease><neuromechanism><neuronal><optogenetics><pars compacta><pathway><programs><reinforced behavior><resolutions><response><sequence learning><social role><striatal><technical skills><tool><treatment strategy><ventral tegmentum>