The dynamics of biological neural networks are of great interest to neuroscientists and are frequently studied using conductance-based compartmental neuron models. For speed and ease of use, neuron models are often reduced in morphological complexity. This reduction may affect input processing and prevent the accurate reproduction of neural dynamics. However, such effects are not yet well understood. Therefore, for my first aim I analyzed the processing capabilities of 'branched' or 'unbranched' reduced models by collapsing the dendritic tree of a morphologically realistic 'full' globus pallidus neuron model while maintaining all other model parameters. Branched models maintained the original detailed branching structure of the full model while the unbranched models did not. I found that full model responses to somatic inputs were generally preserved by both types of reduced model but that branched reduced models were better able to maintain responses to dendritic inputs. However, inputs that caused dendritic sodium spikes, for instance, could not be accurately reproduced by any reduced model. Based on my analyses, I provide recommendations on how to construct reduced models and indicate suitable applications for different levels of reduction. In particular, I recommend that unbranched reduced models be used for fast searches of parameter space given somatic input output data. The intrinsic electrical properties of neurons depend on the modifiable behavior of their ion channels. Obtaining a quality match between recorded voltage traces and the output of a conductance based compartmental neuron model depends on accurate estimates of the kinetic parameters of the channels in the biological neuron. Indeed, mismatches in channel kinetics may be detectable as failures to match somatic neural recordings when tuning model conductance densities. In my first aim, I showed that this is a task for which unbranched reduced models are ideally suited. Therefore, for my second aim I optimized unbranched reduced model parameters to match three experimentally characterized globus pallidus neurons by performing two stages of automated searches. In the first stage, I set conductance densities free and found that even the best matches to experimental data exhibited unavoidable problems. I hypothesized that these mismatches were due to limitations in channel model kinetics. To test this hypothesis, I performed a second stage of searches with free channel kinetics and observed decreases in the mismatches from the first stage. Additionally, some kinetic parameters consistently shifted to new values in multiple cells, suggesting the possibility for tailored improvements to channel models. Given my results and the potential for cell specific modulation of channel kinetics, I recommend that experimental kinetic data be considered as a starting point rather than as a gold standard for the development of neuron models.

The work we present in this thesis is a series of studies of how heterogeneities in coupling affect the synchronization of coupled neural oscillators. We begin by examining how heterogeneity in coupling strength affects the equilibrium phase difference of a pair of coupled, spiking neurons when compared to the case of identical coupling. This study is performed using pairs of Hodgkin-Huxley and Wang-Buzsaki neurons. We find that heterogeneity in coupling strength breaks the symmetry of the bifurcation diagrams of equilibrium phase difference versus the synaptic rate constant for weakly coupled pairs of neurons. We observe important qualitative changes such as the loss of the ubiquitous in-phase and anti-phase solutions found when the coupling is identical and regions of parameter space where no phase locked solution exists. Another type of heterogeneity can be found by having different types of coupling between oscillators. Synaptic coupling between neurons can either be exciting or inhibiting. We examine the synchronization dynamics when a pair of neurons is coupled with one excitatory and one inhibitory synapse. We also use coupled pairs of Hodgkin-Huxley neurons and Wang-Buzsaki neurons for this work. We then explore the existance of 1:n coupled states for a coupled pair of theta neurons. We do this in order to reproduce an observed effect called quantal slowing. Quantal slowing is the phenomena where jumping between different $1:n$ coupled states is observed instead of gradual changes in period as a parameter in the system is varied. All of these topics fall under the general heading of coupled, non-linear oscillators and specifically weakly coupled, neural oscillators. The audience for this thesis is most likely going to be a mixed crowd as the research reported herein is interdisciplinary. Choosing the content for the introduction proved far more challenging than expected. It might be impossible to write a maximally useful introductory portion of a thesis when it could be read by a physicist, mathematician, engineer or biologist. Undoubtedly readers will find some portion of this introduction elementary. At the risk of boring some or all of my readers we decided it was best to proceed so that enough of the mathematical (biological) background is explained in the introduction so that a biologist (mathematician) is able to appreciate the motivations for the research and the results presented. We begin with a introduction in nonlinear dynamics explaining the mathematical tools we use to characterize the excitability of individual neurons, as well as oscillations and synchrony in neural networks. The next part of the introductory material is an overview of the biology of neurons. We then describe the neuron models used in this work and finally describe the techniques we employ to study coupled neurons.

The extent to which cortical maps may reorganize in adult humans is a significant and topical debate in visual neuroscience. Though there are conflicting findings, evidence from humans and animals indicates that the topography of the visual cortex may change after retinal deafferentation. Remarkably, this reorganization seems to be possible in adults, whose brains are less amenable to plastic change. If adult visual reorganization is legitimate, an understanding of its causes and consequences could be profound considering the millions suffering from age-related visual disorders. This dissertation explores whether visual training may yield a reorganization of sensory maps in the adult visual cortex. It describes research in which patients, diagnosed with age-related macular degeneration (AMD), underwent visual rehabilitation therapy. Functional brain scans and behavioral tests were conducted pre and post training. These interventions generated valuable knowledge regarding whether "reorganized" activity is a true rewiring of feed forward cortical processes or an artifact of attentional feedback. The rehabilitation training produced demonstrable differences in activation patterns along the primary visual cortex (V1), but sparse improvement in the behavioral tests. In contrast, there was significant improvement in fixation tests which assessed oculomotor control. These results suggest that the nature of reorganized activity has more to do with attentional mechanisms than feed forward reorganization. Future investigations could benefit from examining the brain sites that govern visual attention in the frontal and parietal cortices. These areas may have more to do with visual adaptation in AMD patients than V1.

Thesis (M.A.)--The University of North Carolina at Greensboro, 2008. / Directed by Thomas Kwapil; submitted to the Dept. of Psychology. Title from PDF t.p. (viewed Jan. 28, 2010). Includes bibliographical references (p. ).

Diffusion tensor imaging (DTI) is a noninvasive MRI technique used to assess white matter (WM) integrity, fiber orientation, and structural connectivity (SC) using water diffusion properties. DTI techniques are rapidly evolving and are now having a dramatic effect on depression research. Major depressive disorder (MDD) is highly prevalent and a leading cause of worldwide disability. Despite decades of research, the neurobiology of MDD remains poorly understood. MDD is increasingly viewed as a disorder of neural circuitry in which a network of brain regions involved in mood regulation is dysfunctional. In an effort to better understand the neurobiology of MDD and develop more effective treatments, much research has focused on delineating the structure of this mood regulation network. Although many studies have focused on the structural connectivity of the mood regulation network, findings using DTI are highly variable, likely due to many technical and analytical limitations. Further, structural connectivity pattern analyses have not been adequately utilized in specific clinical contexts where they would likely have high relevance, e.g., the use of white matter deep brain stimulation (DBS) as an investigational treatment for depression. In this dissertation, we performed a comprehensive analysis of structural WM integrity in a large sample of depressed patients and demonstrated that disruption of WM does not play a major role in the neurobiology of MDD. Using graph theory analysis to assess organization of neural network, we elucidated the importance of the WM network in MDD. As an extension of this WM network analysis, we identified the necessary and sufficient WM tracts (circuit) that mediate the response of subcallosal cingulate cortex DBS treatment for depression; this work showed that such analyses may be useful in prospective target selection. Collectively, these findings contribute to better understanding of depression as a neural network disorder and possibly will improve efficacy of SCC DBS.

Long-term adrenalectomy (ADX) results in a specific loss of dentate gyrus granule cells in the hippocampus of adult rats, occurring over a period of weeks to months. This loss of granule cells results in cognitive deficits in a number of tasks that depend on intact hippocampal function. The gradual nature of ADX-induced cell death and the ensuing deficits in cognition are similar to those experienced by patient populations suffering from a variety of pathological conditions. Here we present an animal model by which we use ADX to produce a loss of granule cells within the hippocampus of rats. We also provide experimental evidence for a treatment strategy by which the lost granule cells may be replaced, with the goal of functional recovery in mind. / xii, 191 leaves : ill. (chiefly col.) ; 28 cm

Les circuits neuronaux peuvent générer une panoplie de rythmes. Nous pouvons séparer les mécanismes de création de ces rythmes en deux grands types. Le premier consiste de circuits contrôlés par des cellules « pacemakers », ayant une activité rythmique intrinsèque, comme dans le ganglion stomatogastique des crustacés. Le deuxième consiste de circuits multi-neuronaux connectés par un réseau synaptique qui permet une activité rythmique sans la présence de neurones pacemakers, tel que démontré pour les circuits de la nage chez plusieurs vertébrés. Malgré nos connaissances des mécanismes de rhythmogénèse chez les vertébrés adultes, les mécanismes de la création et la maturation de ces circuits locomoteurs chez les embryons restent encore inconnus. Nous avons étudié cette question à l’aide du poisson-zébré où les embryons débutent leur activité motrice par des contractions spontanées alternantes à 17 heures post-fertilisation (hpf). Des études ont démontré que cette activité spontanée n’est pas sensible aux antagonistes de la transmission synaptique chimique et ne requiert pas le rhombencéphale. Après 28 hpf, les embryons commencent à nager et se propulser en réponse au toucher. Des études antérieures on démontré que l’apparition de la nage nécessite le rhombencéphale et la transmission synaptique chimique. Cette thèse explore la possibilité que ces changements comportementaux représentent la progression d’un circuit contrôle par un pacemaker à un circuit ou le rythme provient d’un circuit distribué. En mesurant le groupement des contractions de l’activité spontanée, plutôt que la fréquence moyenne, nous avons découvert une nouvelle forme d’activité spontanée qui débute à 22 hpf. Cette activité consiste de deux contractions alternantes à succession très rapide. Contrairement à l’activité spontanée présente dès 17 hpf cette nouvelle forme d’activité requiert le rhombencéphale et la transmission synaptique chimique, comme démontré pour la nage qui apparait à 28 hpf. Cette forme de comportement intermédiaire représente potentiellement une étape transitoire lors de la maturation des circuits moteurs. / Neuronal circuits are capable of generating diverse forms of rhythmic activity. Mechanisms underlying rhythmogenesis can be separated into two main groups. First, pacemaker central pattern generators (CPGs) are composed of neurons that have intrinsic oscillatory properties, such as the lobster stomatogastric ganglion. Second, CPGs driven by network-based dynamics rely on synapse-mediated cell properties, such as locomotion in aquatic vertebrates. Despite an existing wealth of knowledge obtained through studying frog and lamprey swimming CPGs, the means by which a locomotor CPG develops remains elusive. Here, we propose to address this question using the zebrafish embryo, for its rapid development, optical transparency and stereotyped behaviour. Motor activity in zebrafish embryos begins with spontaneous activity around 17 hours post-fertilization (hpf). Studies have shown that this activity is not sensitive to antagonists of chemical neurotransmission, and does not require the hindbrain. By 28 hpf, they become able to swim, and generate low-amplitude alternating contractions at a rate of 30 Hz. This study explores the developmental window between the onset of motility and the onset of a mature locomotor output, such as swimming, with the objective of uncovering key steps in motor network maturation. By measuring the grouping of contractions rather than overall frequency of spontaneous activity, we uncovered a novel form of spontaneous activity, starting around 22 hpf. This activity consists of two alternating contractions in rapid succession. In contrast to early spontaneous activity, this motor activity requires glutamatergic neurotransmission and input from the hindbrain, as previously shown for swimming at 28 hpf. This intermediate behavior may reveal an important step in the maturation of the motor network.

The hippocampus is necessary for normal memory in rodents, birds, monkeys, and people. Damage to the hippocampus can result in the inability to learn new facts, defined by the relationship among stimuli. In rodents, spatial learning involves learning about the relationships among stimuli, and exemplifies the kind of learning the requires the hippocampus. Therefore, understanding the neural mechanisms underlying spatial learning may elucidate basic memory processes. Many hippocampal neurons fire when behaving rats, cats, or monkeys are in circumscribed regions (place fields) of an environment. The neurons, called place cells, fire in relation to distal stimuli, but can persist in signaling location when the stimuli are removed or lights are turned off (memory fields). In this thesis, computational models of spatial information processing simulated many of the defining properties of hippocampal place cells, including memory fields. Furthermore, the models suggested a neurally plausible mechanism of goal directed spatial navigation which involved the encoding of distances in the connections between place cells. To navigate using memory fields, the models required an excitatory, distributed, and plastic association system among place cells. Such properties are well characterized in area CA3 of the hippocampus. In this thesis, a new electrophysiological study provides evidence that a second system in the dentate gyrus has similar properties. Thus, two circuits in the hippocampus meet the requirements of the models. Some predictions of the models were then tested in a single-unit recording experiment in behaving rats. Place fields were more likely to occur in information rich areas of the environment, and removal of single cues altered place fields in a way consistent with the distance encoding mechanism suggested by the models. It was concluded that a distance encoding theory of rat spatial navigation has much descriptive and predictive utility, but most of its predic

Genome-wide association studies (GWAS)s provide an unbiased means of exploring the landscape of complex genetic disease. As such, these studies have identified genetic variants that are robustly associated with a multitude of conditions. I hypothesize that these genetic variants serve as excellent tools for evaluation of the genetic interface between epidemiologically related conditions. Herein, I test the association between SNPs associated with either (i) plasma lipids, (ii) rheumatoid arthritis (RA) or (iii) diabetes mellitus (DM) and late-onset Alzheimer’s disease (AD) to identify shared genetic variants. Regarding the most significantly AD-associated variants, I have also attempted to elucidate their molecular function. Only cholesterol-associated SNPs, as a group, are significantly associated with AD. This association remains after excluding APOE SNPs and suggests that peripheral and or central cholesterol metabolism contribute to AD risk. The general lack of association between RA-associated SNPs and AD is also significant in that these data challenge the hypothesis that genetic variants that increase risk of RA confer protection against AD. Functional studies of variants exhibiting novel associations with AD reveal that the lipid-associated SNP rs3846662 modulates HMGCR exon 13 splicing differentially in different cell types. Although less clear, trends were also observed between the RA-associated rs2837960 and the expression of several BACE2 isoforms, and between the DM-associated rs7804356 and expression of a rare SKAP2 isoform, respectively. In conclusion, the overlap of lipid-, RA- or DM-associated SNPs with AD is modest but in several instances significant. Continued analysis of the interface between GWAS of separate conditions will likely facilitate novel associations missed by conventional GWAS. Furthermore, the identification of functional variants associated with multiple conditions should provide insight into novel mechanisms of disease and may lead to the identification of new therapeutic targets in an era of personalized genomic medicine.

The works presented in this dissertation provide insights into the mechanisms of chemotherapy-induced cognitive impairment (CICI or “ChemoBrain”) and take steps toward outlining a preventive strategy. CICI is now widely recognized as a complication of cancer chemotherapy experienced by a large percentage of cancer survivors. Approximately fifty percent of existing FDA-approved anti-cancer drugs generate reactive oxygen species (ROS). Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, produces the reactive superoxide radical anion (O2-•) in vivo. Dox treatment results in oxidation of plasma proteins, including ApoA-I, leading to TNF-α-mediated oxidative stress in plasma and brain. TNF-α elevation in brain leads to further central nervous system toxicity including mitochondrial dysfunction, neuronal death, and cognitive impairment. Co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma without interfering with the cancer-killing ability of Dox. In studies presented in this dissertation, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline(phosphocholine)/creatine (Cho/Cr) ratios in mouse hippocampus. The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D(PLD) were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox. In the absence of TNF-α, MRS-indexed Cho/Cr ratio, PLD activity, and mitochondrial oxygen consumption are preserved in brain, and markers of oxidative stress are reduced. Together with results from our previous studies, these results provide strong evidence that TNF-α is strongly associated, if not responsible for CICI. We also tested the notion that O2-• is responsible for Dox-induced plasma protein oxidation and TNF-α release. O2-• resulted in increased oxidative damage to proteins when added to plasma and increased levels of TNF-α in macrophage culture, providing strong evidence that O2-• is responsible for these Dox-induced toxicities.