Regulation of motor variability is critical for successful behavior. Motor variability must be minimal for optimum motor performance, however high levels of variability are a necessary ingredient for motor learning. One key function of the Basal Ganglia (BG) is the regulation of neural variability and ultimately variability in motor performance. Pathology of the BG is implicated in numerous disorders including Huntington's disease (HD) and Parkinson's disease (PD). As these disease states are characterized by abnormal correlations of BG activity, an emerging hypothesis is that pathological correlations drive dysfunction in the regulation of neural variability, which ultimately leads to behavioral symptoms. However, a direct link between levels of correlated activity in the BG and the regulation of neural variability and resulting behavior has not been demonstrated. Moreover, the neural mechanisms responsible for the regulation of variability generation in the BG have not been well defined. Songbirds possess unique features that allow for rigorous dissection of neural mechanisms underlying the generation and regulation of motor variability. They possess a motor behavior, song, with highly quantifiable variability. Additionally, in songbirds levels of variability have been convincingly linked to learning. Further, songbirds modulate the level of song variability with social context allowing for a powerful assay to assess neural mechanisms involved in variability regulation. Moreover, neural sources of variability generation have been proposed. Indeed, recent work has suggested correlations in the firing rate of spiny neurons (SNs) in the BG may be critical mediators of variability generation. Multiple lines of evidence have advanced the activity of midbrain dopaminergic cells that project to the BG (MBBG cells) as well as dopamine as critical to driving context dependent changes in song variability. Thus, the songbird provides a platform to test a unified model of variability regulation where midbrain dopaminergic cell activity drives changes in the activity of SNs to ultimately determine levels of motor variability. This study will contribute to understanding the links between MBBG cell activity, correlations in SNs, neural variability, and motor variability through the following aims Aim 1. To investigate the neuronal population dynamics of spiny neurons during singing.
Aim 2. To determine the effect of modulating MBBG cells on motor variability.
Aim 3. To determine the effect of modulating MBBG cells on SN spatiotemporal activity dynamics. Methods:
Aim 1 employs a viral strategy to specifically infect SNs with the fluorescent calcium activity reporter, GCaMP6f. Population calcium imaging is then employed in vivo in freely behaving songbirds to record activity from populations of identified SNs in the BG. Correlations in population wide neuronal activity between individual SNs will be quantified and analyzed to determine the relationship between SN correlations and variability in song.
Aim 2 uses optogenetic methods to bidirectionally modulate MBBG cells with an excitatory channelrhodopsin and an inhibitory halorhodopsin to determine the effect of MBBG cell activity on song variability.
Aim 3 combines the imaging approach of Aim 1 with optogenetic manipulation in Aim 2 to directly test the effect of this MBBG cell activity on SN correlations. Objectives: The results of Aim 1 will test the link between correlations in the activity of BG SNs and variability in motor performance. These results will define the natural BG spatiotemporal dynamics during singing to test the hypothesis that the level of correlated activity in SNs is modulated with social context.
Aim 2 will extend ths work using causal experiments to test how midbrain dopaminergic cell modulation influences motor variability.
Aim 3 will determine the effect of this modulation on SN correlations. These experiments directly and independently characterize the links between MBBG cell activity, SN correlations, and motor variability to test the hypothesis that MBBG cells drive changes in the level of correlated activity in SNs, ultimately determining variability in motor performance.

Public Health Relevance

Basal ganglia circuits are a critical locus for many neurological and psychiatric disorders. However, the fundamental mechanisms through which basal ganglia dysfunction drives disease remain unclear. Understanding the mechanisms and regulation of neural variability in the basal ganglia and linking this regulation to correlations known to be disrupted in disease has the potential to inform both fundamental disease mechanisms and elucidate future therapeutic approaches

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Neurological Sciences Training Initial Review Group (NST)
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Chen, Daofen
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Duke University
Schools of Medicine
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Hisey, Erin; Kearney, Matthew Gene; Mooney, Richard (2018) A common neural circuit mechanism for internally guided and externally reinforced forms of motor learning. Nat Neurosci 21:589-597
Roberts, Todd F; Hisey, Erin; Tanaka, Masashi et al. (2017) Identification of a motor-to-auditory pathway important for vocal learning. Nat Neurosci 20:978-986