The objective of this study was to determine the relationship between descending motor pathway reorganization and abnormal coordination, defined as a reduced set of muscle coactivation patterns between shoulder and elbow muscles in hemiparetic chronic stroke subjects, using transcranial magnetic stimulation (TMS). Specifically, we wanted to 1) determine the relationship...
The polymerization of the microtubule-associated protein, tau, into insoluble filaments is common to Alzheimer's disease (AD) and in a variety of dementias. The conformational change required for tau to transition from soluble monomers to filamentous AD pathology involves the extreme N-terminus of tau coming into contact with other regions of...
Following dopaminergic denervation in Parkinson's Disease, firing patterns in several basal ganglia neuron populations are pathologically altered. In the globus pallidus (GP), this manifests as a loss of autonomous, rhythmic, high-frequency pacemaking and an appearance of correlated, oscillatory bursting. This oscillatory bursting is best disrupted through high-frequency stimulation of affected...
Neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) and tauopathies occurs when tau protein adopts secondary structure and self-aggregates within neurons. Accompanying NFT maturation are post-translational modifications to tau; hyperphosphorylation, truncation and conformational changes occur in a highly sequential manner. In contrast, granulovacuolar degeneration bodies (GVDs) are a second type...
Stem cells show great promise as cellular replacement and drug delivery therapies for a number of neurological disorders. This dissertation examines embryonic and adult types of stem cells, their plasticity, and mechanisms governing their development (Chapters 1-5). Our studies illustrate that leukemia inhibitory factor (LIF) signaling and bone morphogenetic protein...
The goal of this study was to investigate the properties of the retinal ganglion cell receptive field at low light levels. There has been considerable interest in whether the surround of a ganglion cell receptive field disappears and the center expands in size under scotopic conditions. The previous data from...
The goal of this dissertation was to examine the influence of motivational incentives on visual spatial attention in patients with probable Alzheimer's Disease (PRAD), patients with mild cognitive impairment (MCI) and healthy age-matched control subjects (EC). Specifically, I compared the ability of monetary incentives to influence behavioral and neural performance...
Information processing in the striatum is crucial for voluntary movement control and associative learning and in the normal condition is subject to balanced dopaminergic and cholinergic modulation. However, in Parkinson's disease (PD) striatal dopamine (DA) level falls because of degeneration of DA neurons in the substantia nigra pars compacta and...
Primary Progressive Aphasia (PPA) is an aphasic dementia syndrome caused by neurodegenerative disease in which linguistic abilities are selectively disrupted in the relative absence of other cognitive deficits in early stages. The studies presented in this thesis were designed to examine the integrity of word and object processing by contrasting...
A comprehensive understanding of human memory requires both cognitive and neural descriptions of memory processes along with a conception of how memory processing drives behavioral responses and subjective experiences. Noninvasive neuroimaging techniques have greatly extended our understanding of the functional characteristics of human memory, and how neural events give rise...
Alzheimer's disease (AD) is a progressive amnestic dementia typified by the pathological self-association of the microtubule-associated tau protein into neurofibrillary tangles (NFTs). Important to NFT formation are numerous modifications of tau, including phosphorylation, truncation, and conformational changes. In addition, AD-associated inflammation promotes the formation of peroxynitrite (ONOO-), a potent nitrating...
Primary progressive aphasia (PPA) is a debilitating neurodegenerative syndrome that principally impairs the cognitive domain of language. Patients demonstrate deficits in a variety of language faculties including object naming (anomia), word finding, single word and sentence reading, speech comprehension, repetition, syntactic processing, and paraphasia. PPA has been associated with selective...
Gonadotropin releasing hormone (GnRH) neurons comprise the final pathway through which the central nervous system exerts its control over the hypothalamic-pituitary-gonadal (HPG) axis. GnRH is released in a pulsatile manner, and conveyed to the anterior pituitary gland to stimulate synthesis and secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating...
Development of the central nervous system requires the coordinated interplay of intrinsic and extrinsic factors. I examined the actions of an extrinsic factor, TWEAK, and an intrinsic factor, Iroquois1 (Irx1) on neural progenitor cell behavior. Embryonic day 12 (E12) and post-natal day 1 (PN1) neural progenitor cells both express Fn14,...
The nervous system develops through the highly regulated process of proliferation and differentiation of neural stem cells. Two major regulatory pathways that maintain neural stem cells in a proliferative state or promote their differentiation are the Notch and BMP signaling pathways, respectively. In this dissertation, we demonstrate that HeyL, a...
A comprehensive understanding of how image processing occurs in the primary visual cortex (V1) requires learning what aspects of neuronal responses are driven by strong feed-forward input from the lateral geniculate nucleus (LGN), and what aspects arise due to the densely recurrent network operating within the cortex itself. From an...
After nearly 100 years of research, the function of sleep is unknown, prompting the desire to examine its regulation in a simpler model organism. In 2000, <em>Drosophila</em> was described as a novel model system to investigate sleep. These early studies defined features of normal sleep in <em>Drosophila</em>, and presented evidence...
The growth cone is a highly specialized motile structure with a distinctive and dynamically variable morphology. Current understanding of actin-based protrusive motility has been formulated in terms of the dendritic nucleation/array treadmilling model for lamellipodial protrusion and the convergent-elongation model for filopodial protrusion, that were based upon results obtained primarily...
Many ion channels are localized in specific subcellular domain of the neurons, and the proper localization is critical for the function of ion channels. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (h channels) are asymmetrically distributed in the CA1 pyramidal neurons, enriched in the distal apical dendrites. H current, generated by h...
Humans determine the horizontal position of sound sources based on two cues: interaural time differences (ITDs) and interaural level differences (ILDs). Consistent with other evidence that these two cues are processed by separate neural mechanisms, Wright and Fitzgerald (2001) observed markedly different learning patterns in listeners who were trained on...