Midbrain dopamine (DA) neurons and the cortico-basal ganglia circuits they innervate are critically involved in normal motor behavior and learning, in motivation and reward, and in numerous neuropsychiatric disorders, including drug addictions and Parkinson's disease (PD). Despite the importance of DA, much about its mechanism of action remains to be discovered, in part because of the complexity both of the behaviors and of the circuits studied in many animals. Songbirds can provide a useful small animal model for providing insights into DA function, because their speech-like learned behavior, the song, is subserved by a discrete set of brain regions that include a specialized basal ganglia-cortical circuit, complete with midbrain DA inputs. This 'anterior forebrain pathway' (AFP) is critical for vocal learning and adult vocal plasticity, and like mammalian basal ganglia circuits, is modulated by context. In particular, prior work from this lab has revealed that social context potently modulates this sensorimotor circuit: males singing to females ('directed singing') show a marked decrease in the rate and variability of AFP neuronal firing and consequently in the variability of song, compared to birds singing alone ('undirected' song). This proposal hypothesizes that this social modulation of neural and song variability is a result of DA action, and that it represents a tractable example of DA's general function in gating and selecting inputs and increasing signal-to-noise in the brain in response to important external cues. This will be tested in three general ways. First, in vivo microdialysis will be used to ask whether DA is released into the AFP of male finches in response to the 'directed' social context. Then DA signaling will be disrupted in the AFP in vivo, either acutely, by infusing DA antagonists, or chronically, with a neurotoxin used in models of PD, to test whether this alters 1) the normal neurophysiological differences between directed and undirected firing in the AFP, and 2) song production. The prediction is that decreases in DA will transform the stereotyped activity and behavior in the social setting first towards the more variable undirected activity and song, and then beyond, towards abnormalities reminiscent of DA diseases. Experiments in this simple system with its highly quantifiable activity and motor output should shed general light on the function of DA in the modulation of behavior and behavioral variability, with implications both for intact animals and learning as well as for neuropsychiatric diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH078824-03
Application #
7491458
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Simmons, Janine M
Project Start
2006-09-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$262,534
Indirect Cost
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Stepanek, Laurie; Doupe, Allison J (2010) Activity in a cortical-basal ganglia circuit for song is required for social context-dependent vocal variability. J Neurophysiol 104:2474-86
Woolley, Sarah C; Doupe, Allison J (2008) Social context-induced song variation affects female behavior and gene expression. PLoS Biol 6:e62