Birdsong is a motivated behavior used for courtship and territorial defense. Juvenile male Bengalese finches learn song from their fathers, and over time produce an increasingly accurate copy of their tutor's song. Since it is thought that the ventral tegmental area (VTA) is important in learning and crucial for the production of motivated behavior, we sought to examine the role of the VTA during singing. To probe the function of the VTA we recorded multi-unit activity in adult male Bengalese finches. We observed that neural activity in VTA consistently increased prior to the initiation and termination of song bouts, suggesting that increased activity in this region might mediate behavioral switching. To further test this idea, we coupled VTA recordings with a behavioral manipulation known to cause abrupt terminations of song. We delivered disruptive auditory stimuli during specific notes of ongoing song, which caused song terminations on a subset of trials (Sakata, 2006). Neural activity in the VTA transiently increased at a short latency (10-20ms) in response to the stimulus both during and outside of song. These data indicate that the VTA in singing birds has rapid access to information about salient perturbations of sensory experience, and extend findings indicating that the VTA responds to salient stimuli (Horvitz, 1997). Moreover, we consistently found that neural responses were significantly greater in magnitude on trials in which feedback elicited song termination versus trials in which the bird continued to sing, and the probability of song termination increased as the level of VTA neural activity increased. Because song termination was associated with neural responses of higher magnitude, we stimulated in VTA during song to test the idea that activity in this region might be causally related to song termination. Song terminations were produced at significantly lower current intensities in VTA than in surrounding regions. One interpretation of these data is that the VTA monitors the environment for salient stimuli and is able to effect a cessation of ongoing motor behavior when environmental conditions favor behavioral switching. This supports the interesting possibility that VTA participates in action selection, and might function in contexts unrelated to reward.

Chronic impairment of upper limb motor function is a common and debilitating consequence of stroke with limited treatment options. While past research has identified neuroplastic changes that are crucial for recovery, most studies focused on changes that are not directly related to movement and in single brain areas. A better understanding of how neural dynamics during movement, across multiple motor areas, are altered throughout recovery is necessary to develop targeted neuromodulatory treatments.

In both chapters 2 and 3, spiking and local field potential (LFP) activity were measured from motor areas of rodents undergoing upper limb rehabilitation after a motor cortical stroke. Chapter 2 studied the movement-related neural dynamics in the perilesional cortex (PLC), the primary site of plasticity post-stroke. Movement-related low frequency oscillations (LFOs), present in both spiking and LFP, in PLC was diminished after stroke and was associated with motor recovery. The amplitude of LFOs was also reduced in a human stroke patient compared to intact subjects. Epidural direct current stimulation applied during movement increased the amplitude of LFOs and improved motor function in rodents, even in the chronic phase post-stroke. These findings demonstrate that LFOs can be a stable and translatable biomarker for tracking of post-stroke motor function and a target for neuromodulation. Chapter 3 investigated the role of the dorsolateral striatum (DLS), a motor area one synapse downstream of cortex and crucial for both motor execution and learning, and the interaction between PLC and DLS during recovery. With recovery, neural activity in both PLC and DLS became more movement modulated, more reliable and contained more information about motor behavior. PLC and DLS reorganized simultaneously throughout rehabilitation and their spiking activity also became more coordinated. These results show that motor recovery involve concerted reorganization of neural activity patterns in both cortical and subcortical motor areas.

Overall, this thesis showed that synchronous and reliable neural patterns during movement, coordinated across motor areas, are important for motor recovery. Neuromodulatory methods, such as electrical stimulation, that increase the reliability and coordination of neural activity could be promising treatments to enhance motor function post-stroke.

Song production in birds requires planning on two different time-frames: the immediate muscle program for the vocal effectors (vocal and respiratory musculature), as well as the more temporally extended control of sequencing the shorter vocal elements (syllables) into longer vocalizations. The songs of the Bengalese finch exhibit variability in both dimensions: syllables are produced with a small amount of variability from rendition to rendition, and the syllables themselves can be used in a variety of sequences. The following research examines three question in regards to variability in Bengalese finch song.

1. Does a syllable's sequence affect its phonology?

2. Are changes in phonology are a result of differences in brain activity?

3. Is there a correlation between changes in brain activity and changes in phonology?

In analyzing the songs of Bengalese finches, we find that syllable structure is altered by sequence in two different ways: syllable production is modified by the immediate history of the system, as well as long time-scale patterns in the sequencing of syllables. These sequence effects upon syllable production are not the result of purely peripheral influences, however. There are multiple ways in which changes to central neural activity correlate with changes in syllable phonology. Changes in the activity of the robust nucleus of the arcopallium (RA) neurons were correlated with mean changes in syllable production, as well as with changes to syllable production around the mean. The correlation between mean changes in RA activity and syllable structure implies that the RA motor program is phonological in nature. We also find that RA activity correlates specifically with changes in syllable features such as pitch, amplitude and entropy. In taking these results together, a more complete model of syllable control by RA can be constructed. The data suggest that general patterns in RA activity relate to the identity of individual syllables, and that changes in syllable structure are made by increasing or decreasing that activity of specific pools of RA neurons. The results of this research are the first demonstration of phonological encoding by RA neurons.

Birdsong is an ideal behavior for testing the neural mechanisms that underlie motor learning, as the dedicated neural circuits that control song production and learning are well-elucidated and amenable to experimental manipulation. Here I investigate how the anterior forebrain pathway (AFP), an avian cortical-basal ganglia circuit long implicated in vocal plasticity, contributes to two hierarchically distinct forms of adaptive song modification in adult songbirds. First, I tested how the AFP contributes to adaptive modifications of the acoustic structure of individual song syllables, both in the context of reinforcement-driven learning and a self-driven recovery process. I found that, in both contexts, transiently interfering with the AFP's output to the primary motor pathway reversed the expression of newly learned changes to syllable acoustic structure, but that over multiple days, the expression of learning consolidated to become AFP-independent. This finding supports an emerging view that cortical-basal ganglia circuits can direct the initial expression of learning via top-down influences on primary motor circuits. Second, I tested how adult Bengalese finches control the stochastic sequence transitions that occur between syllables. I found that the probabilities of transitions are ordinarily stable, yet birds have a previously unrecognized capacity to adaptively modify these probabilities in response to differential reinforcement. Despite this capacity for modification, when reinforcement was terminated, birds gradually restored transition probabilities to their baseline values, indicating that these values are set points that the nervous system has the impetus to restore. These findings suggest that the statistics of sequence variation in a motor skill can reflect an end point of learning that is actively maintained via continual self-monitoring. Finally, I tested the extent to which the adaptive modification of syllable acoustic structure and syllable sequencing rely on the same basal ganglia circuitry. I found that lesions of LMAN, the AFP's cortical outflow nucleus, prevented the adaptive modification of syllable structure but did not affect birds' capacity to adaptively modify syllable sequencing. Therefore, although similar principles of differential reinforcement can be used to drive changes to syllable structure and syllable sequencing, an avian basal ganglia circuit contributes differently to these hierarchically distinct forms of learning.

The neuromodulator acetylcholine has a well-establi¬shed role in enhancing sensory perception in states of heightened arousal, but whether acetylcholine acts centrally to exert an analogous influence on behavioral outputs is largely unknown. Here we use the quantifiable nature of birdsong to investigate how cholinergic tone modulates the cortical song premotor nucleus HVC, and influences vocal output. We found that dialysis of the cholinergic agonist carbachol into HVC enhanced the vigor of vocal output by increasing the pitch, tempo, amplitude and stereotypy of song. These effects did not require input from basal-ganglia circuitry, indicating direct cholinergic modulation of song premotor circuitry. Moreover, blockade of muscarinic acetylcholine receptors in HVC attenuated natural increases in vigor observed when song is directed at females in a courtship context. Neural recordings revealed that both dialysis of carbachol and courtship song were associated with higher firing rates in HVC, with conspicuous enhancement of low-frequency activity locked to the underlying rhythm of song. Further, neural activity in HVC predicted behavioral variability on a trial-by-trial basis, consistent with the possibility that natural variation in cholinergic tone influences acoustic output. Our findings establish that acetylcholine exerts a potent influence on forebrain premotor circuitry that acts to invigorate motor output, and indicates that such modulation contributes to the natural invigoration of song during courtship.