Pain normally subserves a vital role in the survival of the organism by prompting the avoidance of situations associated with tissue damage. However, the sensation of pain can become dissociated from its normal physiological role when the pain-sensing nervous system becomes hypersensitive, a condition known as neuropathic pain. Currently available...
Previous research has shown that creative insight problem-solving is distinct from systematic analytical problem-solving. Behaviorally, a positive mood has shown to facilitate insights but without knowing the processes that are fundamental to insight, the mechanisms as to how a positive mood facilitates insights have remained unspecified. Here, we investigate the...
Sleep deprivation (Sd) preferentially impairs predictive and adaptive behaviors that shift responses based on the appropriate context. Behavioral studies implicate the frontal lobes as particularly susceptible to Sd. Aging also impairs frontal functioning, and alters the response to Sd. The interaction between age and Sd is poorly understood, and few...
Spinal cord injury causes devastating and frequently irreversible loss of neurological function. Although injured central nervous system neurons have the intrinsic ability to regenerate, the environment in the damaged spinal cord is non-permissive. The goal of this thesis was to explore the cellular and molecular mechanisms that limit recovery after...
Most organisms use rhythms of sunlight to synchronize their activity to the environment. These rhythms of activity are called circadian rhythms. The rhythms persist with near 24 hour periods when external synchronizing cues are absent. In mammals, the circadian clock is generated at the molecular level by a transcriptional/translational feedback...
The studies in this thesis are directed towards defining the signaling mechanisms that regulate astrogliosis after SCI and towards developing potential therapeutic techniques for modifying this process. The central hypothesis is that alteration of the extracellular milieu after SCI can limit the deleterious effects of glial scar formation and enhance...
Saccades are rapid eye movements that bring visual images into focus by placing them on the fovea. The control of accurate and precise saccades is essential for normal visual perception of the world around us. Disruptions in saccade production are the hallmark of several neurological disorders such as schizophrenia and...
The vertebrate brain, which is made up of a vast array of individual neurons, is responsible for controlling numerous functions and behaviors, including distinguishing between visual cues, learning to navigate in a new environment, or making complex decisions. These neurons form specific networks that receive, process, and integrate chemical and...
Peripheral neuropathic pain is a debilitating affliction for which there is little effective treatment. Patients suffer from symptoms ranging from loss of sensation to hyperalgesia and allodynia. The neuroinflammatory process in chronic pain conditions has become a main focus of study because of the release of proinflammatory cytokines, which can...
Synapses in the central nervous system vary widely in how they transmit and store information. The properties of short-term and long-term plasticity, in particular, seem to be specific for each class of synapse studied. The types of plasticity expressed at a particular synapse determine how it processes, transmits and possibly...
Autism spectrum disorders (ASD) is a highly heterogeneous and pervasive developmental disorder that affects nearly 1 in 150 children. A primary indicator of ASD is behavioral language impairment with respect to social communication, but the neurophysiology behind this impairment is not well understood. Both the perception and production of prosody...
In several neurodegenerative diseases, the microtubule-associated protein tau self-aggregates to form filaments that accumulate in neurons and/or glia, although the relationship between tau aggregation and cell death is a subject of debate. The amino terminus of tau is involved in conformational changes that appear critical for filament formation, hinting at...
The set of experiments described here test the hypothesis that the declarative memory system supported by the medial temporal lobe and habit/procedural memory supported by the basal ganglia are recruited when learning novel category representations. The theory guiding specific hypotheses about these neural systems and their operation in category learning...
Estrogens are traditionally thought to act through a nuclear receptor-mediated mechanism to regulate gene transcription in target tissues. The hippocampus has been shown to be sensitive to estrogen; estrogen regulates GABAergic inhibition and spine density of dorsal CA1 pyramidal cells. However, very few neurons expressing nuclear estrogen receptors (ERs) have...
During movement, the dendrites of spinal motoneurons receive steady excitatory and inhibitory synaptic input from supraspinal sources, interneurons, and sensory afferents. Motoneurons also have dendritic voltage sensitive ion channels. Most notable is a persistent inward current (PIC), which can enhance the amplitude of synaptic input by several fold. PICs are...
The neurotropic alphaherpesviruses infect and spread trans-synaptically within the vertebrate nervous system. Recurrent diseases are often manifested at the periphery of the host organism but occasional dissemination of the virus to the brain results in fatal encephalitis. Interactions between viral and host cellular proteins are integral to the success of...
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...
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...
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...
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...
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...
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...
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,...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...