Thesis (Ph. D. in Psychology)--Vanderbilt University, May 2006. / Title from title screen. Includes bibliographical references.

Following unilateral stroke there is significant loss of function in the body side contralateral to the damage and a robust degenerative-regenerative cascade of events in both hemispheres. It is natural to compensate for loss of function by relying more on the less-affected body side to accomplish everyday living tasks (e.g. brushing teeth, drinking coffee). This is accompanied by a “learned disuse” of the impaired side thought to occur due to repeated experience with its ineptness. However, as investigated in these studies, it may also be due to brain changes instigated by experience with the intact body side. The central hypothesis of these dissertation studies is that experience with the intact forelimb, after unilateral sensorimotor cortex (SMC) damage, disrupts functional recovery with the impaired forelimb and interferes with peri-lesion neural plasticity. Following unilateral ischemic lesions, rats were trained on a skilled reaching task with their intact (less-affected) forelimb or received control procedures. The impaired forelimb was then trained and tested on the same skilled reaching task. Intact forelimb experience worsened performance with the impaired forelimb even when initiated at a more delayed time point following lesions. Intact forelimb training also reduced peri-lesion expression of FosB/ΔFosB, a marker of neuronal activation, and caudal forelimb motor map areas compared to animals without intact forelimb training. It was further established that it is focused training of the intact forelimb and not experience with this limb per se, as animals trained with both forelimbs in an alternating fashion did not exhibit this effect. Transections of the corpus callosum blocked the maladaptive effect of intact forelimb experience on impaired forelimb recovery, suggesting a disruptive influence of the intact hemisphere onto the lesion hemisphere that is mediated by experience. Together these dissertation studies provide insight into how experience with the less-affected, intact body side, can influence peri-lesion neural plasticity and recovery of function with the impaired forelimb. The findings from these studies suggest that compensatory use of the less-affected (intact) body side following unilateral brain damage is not advantageous if the ultimate goal is to improve function in the impaired body side. / text

A blockade of GABAergic inhibition increases the receptive field(RF) size of most somatosensory cortex (SI) and some ventrobasal thalamus (VB) neurons. The results suggest RF size of cuneate neurons may be modulated through GABAa and GABAb receptors, independent of firing frequency.

The p38 mitogen-activated protein kinase [p38(MAPK)] mediates responses to extracellular stressors. An increase in the phosphorylated form of p38(MAPK) [p-p38(MAPK)] has been associated with early events in Alzheimer disease (AD). Although most often associated with processes including apoptosis, inflammation and oxidative stress, p-p38(MAPK) also mediates beneficial physiological functions, such as cell growth, survival and phagocytosis of cellular pathogens. Amyloid plaques [β-amyloid aggregates] are a hallmark of AD-related pathology. As p38(MAPK) has been detected in the vicinity of senile plaques, we combined immunohistochemistry and stereological sampling to quantify the distribution of plaques and p-p38(MAPK)-immunoreactive (IR) cells in the sensorimotor cortex of 3-, 6- and 10-month-old TgCRND8 mice. This animal model expresses an aggressive nature of the AD-related human amyloid-β protein precursor (APP). It was confirmed by the appearance of both dense-core (thioflavin-S-positive) and diffuse plaques, even in the youngest mice. p-p38(MAPK)-IR cells were associated with both dense-core and diffuse plaques, but the expected age-dependent increase in the density of plaque-associated p-p38(MAPK)-IR cells was restricted to dense-core plaques. Furthermore, the density of dense-core plaque-associated p-p38(MAPK)-IR cells was inversely correlated with the size of the core within the given plaque, which supports a role for these microglia in restricting core growth. p-p38(MAPK)-IR cells were also observed throughout wildtype and TgCRND8 mouse cortical parenchyma, but the density of these non-plaque-associated cells remained constant, regardless of age or genotype. We conclude that the constitutive presence of p-p38(MAPK)-IR microglia in aging mouse brain is indicative of a longitudinal role for this kinase in normal brain physiology. Additionally, the majority of p-p38(MAPK)-IR cells were predominantly co-immunoreactive for the Macrophage-1 (CD11b/CD18) microglial marker, regardless of whether they were associated with plaques or localized to the parenchyma. We suggest that the facts that a pool of p-p38(MAPK)-IR microglia appears to restrict b-amyloid plaque core development and the non-pathological role of p-p38(MAPK) in parenchyma, needs to be considered when anticipating targeted p38(MAPK) therapeutics in the context of clinical AD.

The p38 mitogen-activated protein kinase [p38(MAPK)] mediates responses to extracellular stressors. An increase in the phosphorylated form of p38(MAPK) [p-p38(MAPK)] has been associated with early events in Alzheimer disease (AD). Although most often associated with processes including apoptosis, inflammation and oxidative stress, p-p38(MAPK) also mediates beneficial physiological functions, such as cell growth, survival and phagocytosis of cellular pathogens. Amyloid plaques [β-amyloid aggregates] are a hallmark of AD-related pathology. As p38(MAPK) has been detected in the vicinity of senile plaques, we combined immunohistochemistry and stereological sampling to quantify the distribution of plaques and p-p38(MAPK)-immunoreactive (IR) cells in the sensorimotor cortex of 3-, 6- and 10-month-old TgCRND8 mice. This animal model expresses an aggressive nature of the AD-related human amyloid-β protein precursor (APP). It was confirmed by the appearance of both dense-core (thioflavin-S-positive) and diffuse plaques, even in the youngest mice. p-p38(MAPK)-IR cells were associated with both dense-core and diffuse plaques, but the expected age-dependent increase in the density of plaque-associated p-p38(MAPK)-IR cells was restricted to dense-core plaques. Furthermore, the density of dense-core plaque-associated p-p38(MAPK)-IR cells was inversely correlated with the size of the core within the given plaque, which supports a role for these microglia in restricting core growth. p-p38(MAPK)-IR cells were also observed throughout wildtype and TgCRND8 mouse cortical parenchyma, but the density of these non-plaque-associated cells remained constant, regardless of age or genotype. We conclude that the constitutive presence of p-p38(MAPK)-IR microglia in aging mouse brain is indicative of a longitudinal role for this kinase in normal brain physiology. Additionally, the majority of p-p38(MAPK)-IR cells were predominantly co-immunoreactive for the Macrophage-1 (CD11b/CD18) microglial marker, regardless of whether they were associated with plaques or localized to the parenchyma. We suggest that the facts that a pool of p-p38(MAPK)-IR microglia appears to restrict b-amyloid plaque core development and the non-pathological role of p-p38(MAPK) in parenchyma, needs to be considered when anticipating targeted p38(MAPK) therapeutics in the context of clinical AD.

Thesis (Ph. D.)--University of Oregon, 2002. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 195-205). Also available for download via the World Wide Web; free to University of Oregon users.

Thesis (Ph. D. in Neuroscience)--Vanderbilt University, Aug. 2006. / Title from title screen. Includes bibliographical references.

Electrophysiology has produced a wealth of information concerning characteristic patterns of neural activity underlying movement control in non-human primates. Such patterns differentiate functional classes of neurons and illuminate neural computations underlying different stages of motor planning and execution. The scarcity of high-resolution electrophysiological recordings in humans has hindered such descriptions of brain activity during uniquely human acts such as speech production. The goal of this dissertation was to identify and quantitatively characterize canonical temporal profiles of neural activity measured using surface and depth electrocorticography electrodes while pre-surgical epilepsy patients read aloud monosyllabic utterances. An unsupervised iterative clustering procedure was combined with a novel Kalman filter-based trend analysis to identify characteristic activity time courses that occurred across multiple subjects. A nonlinear distance measure was used to emphasize similarity at key portions of the activity profiles, including signal peaks. Eight canonical activity patterns were identified. These activity profiles fell broadly into two classes: symmetric profiles in which activity rises and falls at approximately the same rate, and ramp profiles in which activity rises relatively quickly and falls off gradually. Distinct characteristic time courses were found during four different task stages: early processing of the orthographic stimulus, phonological-to-motor processing, motor execution, and auditory processing of self-produced speech, with activity offset ramps in earlier stages approximately matching activity onset rates in later stages. The addition of an anatomical constraint to the distance measure to encourage clusters to form within local brain regions did not significantly change results. The anatomically constrained results showed a further subdivision of the eight canonical activity patterns, with the subdivisions primarily stemming from sub-clusters that are anatomically distinct across different brain regions, but maintained the base activity pattern of their parent cluster from the analysis without the anatomically constrained distance measure. The analysis tools developed herein provide a powerful means for identifying and quantitatively characterizing the neural computations underlying human speech production and may apply to other cognitive and behavioral domains.

Vocal learning is one of the most distinctive characteristics of the modern human species. Through the intricate interaction between vocal motor and auditory systems during early sensitive periods, humans spontaneously master the ability to speak and decode speech. Because vocal learning is so rare in vertebrates, songbirds (Oscines) are the primary model organisms used in studies of acoustic communication and vocal learning. The acquisition of songs in birds and speech in humans (learning of complex sounds with syntactic structures) exhibit similar developmental trajectories. Research on song learning has focused primarily on vocal production with limited emphasis on the role of auditory perception. While auditory tuning and sensorimotor feedback are indispensable for successful vocal learning and communication, how auditory tuning emerges at different levels of the neural processing hierarchy and how sensorimotor integration occurs in the brain during vocal learning is not fully understood. The neurobiology research described here thus focuses on auditory tuning and sensorimotor integration in vocal learning songbirds using multiple experimental approaches. In the first chapter, I describe peripheral auditory tuning in several songbird species. Using operant conditioning, I trained individual birds to report audible tones and assessed hearing thresholds over the 0.5 to 10 kHz frequency range. I also examined the relationship between song spectral energy and hearing by analyzing song frequency-power spectra and audiograms across species. I found that across songbird species, regardless of age, rearing condition, and sex, hearing range was similar: 0.5 to 8 kHz. Notably, the vocal energy in courtship song matches each species auditory sensitivity, indicating the coevolution of sensory and vocal motor systems. In the second chapter, I describe neuronal tuning in the auditory cortex (AC) of female songbirds. While male songbirds exhibit experience-dependent neuronal tuning in AC, the nature of AC tuning in females that do not sing has not been studied. I used in vivo acute electrophysiological recordings to examine neural responses to tones, ripple stimuli and songs. I compared neuronal firing patterns in female AC between different species groups and rearing conditions. My results suggest that higher-order auditory processing in female songbirds is conserved across species and that early song experience affects some aspects of tuning in the AC of females, suggesting that females exhibit experience-dependent changes in auditory tuning across development. In the final chapter, I examine a potential sensorimotor integration site, the caudal striatum (CSt), and its role in vocal learning. Auditory neurons in CSt suggest that the region may integrate auditory inputs and vocal motor commands to modulate sensorimotor learning. To study the effects of CSt lesions on song learning, I produced excitotoxic lesions in CSt across developmental stages. To label brain regions that project to or receive input from CSt, I injected anterograde or retrograde tracers into CSt. I also characterized the auditory tuning properties of CSt through electrophysiological recording. I found that CSt receives both dopaminergic and auditory projections but is not necessary for successful song learning. Electrophysiological data also show that auditory tuning properties of neurons in CSt are highly similar to neurons in other AC subregions, suggesting that CSt may be a sub-region of AC.

Sensory neocortex contains a significant number of inhibitory neurons that use gamma-aminobutyric acid (GABA) as their neurotransmitter. Functional roles for these neurons have been identified in physiological studies. For example, in primary somatosensory cortex (SI), blockade of GABAa receptors with bicuculline leads to expansion of receptive fields (RFs). The magnitude of RF enlargement varies between SIpopulations of GABAergic neurons were identified by labeling specific calcium binding proteins.