<p> The fine control of learned movement sequences is a crowning achievement of higher vertebrates. Learned sequences critically depend on sensory feedback, and experimental manipulations of sensory feedback can elucidate its role in sequence acquisition and maintenance. Delayed auditory feedback (DAF) affects production of learned vocalizations in humans and songbirds but has been rarely been studied in songbirds. We used a skull-implanted accelerometer to maintain high amplitude (15-21 dB louder than singing) continuous DAF for 4-68 days in 12 young adult zebra finches. Nine birds sang songs showing new transitions (N = 19; one to five new syllable transitions per bird, e.g. A-B-A or A-B-E ...), including stutters (e.g. A-B-C-D-D) intermixed with songs with normal transitions (e.g. A-B-C-D-E). The mean latency of new transitions was short (7.3 days after DAF onset), presumably due to the high-gain and continuous delivery of DAF. </p><p> New transitions to the start of the motif (syllable A) disrupted 10 sites (e.g. the site of syllable B is disrupted by A-B-A), and a disproportionate number of the remaining new transitions occurred at the same site (e.g. A-B-E) instead of the undisrupted sites. Thus, there was statistical evidence that new transitions were concentrated at disrupted sites (&chi;2 = 7.8, p = 0.005). We observed lengthening of some intersyllable gap durations under DAF, and the minority of sites whose sequence was disrupted accounted for a disproportionate share (79%) of this effect. The average gap lengthening at disrupted sites (e.g the gap following B) was due both to an increase in the duration of the preexisting intersyllable gap (e.g. from B to C), and to the long gap duration of the new transition (e.g. B to E). In fact all 19 new transitions had longer gaps than did the preexisting transitions at the same site. </p><p> At a disrupted transition, the timecourse of gap lengthening typically coincided with that of sequence disruption, as gap duration and transition probability covaried over days (r = -0.39, p = 0.0009). </p><p> We also observed clear and frequent alterations of the morphology of 18 syllables following DAF. Morphological distortions were quantified, and we found that syllables at disrupted transitions had a trend towards greater average morphological change under DAF than other syllables. This effect became highly significant when we sampled syllable morphologies on the day of maximal sequence change (t(55) = 3.1, p = 0.003). Therefore sequence and morphological changes affected the same sites around the same time. This relation is highly intriguing because the neural pathways governing sequence generation are widely viewed as separate from those controlling the morphology of individual elements. </p><p> Thus, the distribution of new transitions, the lengthening of intersyllable gaps and distortions of syllable morphology all implicated a relatively small number of sites (or loci) in the song (14/57) to account for the overwhelming majority of effects. This distribution is reminiscient of human stuttering, where certain phonemes (e.g: k-words , or s-words) may be particularly troublesome. </p><p> Crystallization is a developmental stage of birdsong learning characterized by an increase in song tempo and reduced sequence variability. We review a body of evidence suggesting that sensorimotor internal models are learned during this stage to assist vocal sequencing. Our results suggest that DAF causes localized song decrystallization by disrupting these internal models. We propose that human stuttering may result from pathological vocomotor internal models, and that the ability of DAF and related methods to alleviate stuttering in human subjects by as much as 70-90% results from disrupting these internal models. The many parallels between birdsong learning and speech development are discussed and lend plausibility to this hypothesis.</p>

<p>The striatum is part of a neural feedback network that modifies the functioning of the cerebral cortex. The importance of the striatum is underlined by the clinical consequences of striatal dysfunction: disordered signaling in the striatum gives rise to the clinical syndrome of Parkinson's disease, while degeneration of striatal output neurons produces the clinical manifestations of Huntington's disease. The striatum is a complex structure comprised of two major populations of neurons: the spiny projection neurons that carry the striatal output to other nuclei in the basal ganglia; and several subtypes of aspiny cells that project locally within the striatum to modify striatal output. The two major inputs to the striatum are the glutamatergic pathway from the cerebral cortex and the dopaminergic pathway from the substantia nigra. The goal of my research is to explore the nature and functional significance of dopamine-glutamate signaling and its role in the striatum and basal ganglia. My first series of studies in vivo demonstrated that altering dopaminergic tone in the striatum by D2-dopamine receptor blockade or by 6-hydroxy-dopamine lesion of the nigrostriatal dopamine projection in the rat could modify the pathological, neurochemical and behavioural consequences of glutamate-receptor-mediated-stimulation. In order to investigate the details of this interaction, I developed an in vitro tissue culture system. I showed initially that the growth of striatal neurons in serum free culture parallels their in vivo development. I then went on to use this in vitro system to demonstrate the differential effects of selective glutamate receptor agonists on transmitter release from subpopulations of the two major classes of striatal neurons: (i) those in which somatostatin and neuropeptide Y are colocalised with nitric oxide and (ii) the substance P-containing spiny projection neurons. This series of studies demonstrated that substance P release was selectively stimulated through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor while somatostatin and neuropeptide Y release were selectively provoked by stimulation of the kainate receptor. Stimulation of the metabotropic glutamate receptor had little effect on the release of any of the three peptides. My final series of experiments examined the differential effects of selective dopamine receptor stimulation on glutamate-receptor-induced release of substance P, somatostatin and neuropeptide Y. The D1 agonist SKF 38393, and to a significantly lesser extent the D2 agonist quinpirole, attenuated glutamatergic release of substance P from the spiny neurons. In contrast, the D2 agonist quinpirole potentiated the release of neuropeptide Y and somatostatin from aspiny neurons. The D1 agonist SKF 38393 attenuated glutamate receptor stimulated release of neuropeptide Y, without significantly affecting the release of somatostatin from the same cultures. This latter result indicates that dopamine can differentially regulate transmitter release not only from separate populations of striatal neurons but also differentially control release of transmitter that are colocalised within a single population of neurons. To my knowledge these studies are the first to demonstrate this differential regulation in the striatum, and implies that the delicate balance required for both normal cognition and movement may be intimately related to the balance of signaling between the intrinsic (somatostatin-neuropeptide Y-containing) and extrinsic (substance P-containing) neuronal populations in the striatum.</p> / Doctor of Philosophy (PhD)