Experimental and computational investigations addressing how various neural functions are achieved in the brain converged in recent years to a unified idea that the neural activity underlying most of the cognitive functions is distributed over large scale networks comprising various cortical and subcortical areas. Modeling approaches represent these areas and their connections using diverse models of neurocomputational units engaged in graph-like or neural field-like structures. Regardless of the manner of network implementation, simulations of large scale networks have encountered significant difficulties mainly due to the time delay introduced by the long range connections. To decrease the computational effort, it is common to assume severe approximations to simplify the descriptions of the neural dynamics associated with the system's units. In this dissertation we propose an alternative framework allowing the prevention of such strong assumptions while efficiently representing th e dynamics of a complex neural network. First, we consider the dynamics of small scale networks of globally coupled non-identical excitatory and inhibitory neurons, which could realistically instantiate a neurocomputational unit. We identify the most significant dynamical features the neural population exhibits in different parametric configuration, including multi-cluster dynamics, multi-scale synchronization and oscillator death. Then, using mode decomposition techniques, we construct analytically low dimensional representations of the network dynamics and show that these reduced systems capture the dynamical features of the entire neural population. The cases of linear and synaptic coupling are discussed in detail. In chapter 5, we extend this approach for spatially extended neural networks. / We consider the dynamical behavior of a neural field-like network, which incorporates many biologically realistic characteristics such as heterogeneous local and global connectivity as well as dispersion in the neural membrane excitability. We show that in this case as well, we can construct a reduced representation, which may capture well the dynamical features of the full system. The method outlined in this dissertation provides a consistent way to represent complex dynamical features of various neural networks in a computationally efficient manner. / by Roxana A. Stefanescu. / Thesis (Ph.D.)--Florida Atlantic University, 2009. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2009. Mode of access: World Wide Web.

<p>The overall aim of this thesis was to explore gene-environmental (G*E) interactions in relation to deviant behaviour among 200 Swedish adolescents, with a focus on criminality, alcohol consumption and depressive symptoms. Those behaviours have been extensively investigated in relation to both psychosocial and biological risk factors. The biological markers used were the monoamine oxidase (MAO-A) and serotonin transporter (5-HTTLPR) gene polymorphisms. </p><p>The main findings indicated a considerable gene-environment interaction in relation to all outcome variables studied. Individuals with the long/short variant of the 5HTTLPR gene, in combination with unfavourable family relations, both consumed more alcohol and had 12-14 times higher risks of being classified as high alcohol consumers.</p><p>The MAO-A gene showed a G*E interaction related to criminality. Among boys, the short allele predicted an increased risk for criminality, whereas among girls, it was the long allele, if they lived in multi-family houses and/or had been maltreated, assaulted or sexually abused. </p><p>A G*E interaction in relation to depressive symptoms among both boys and girls was determined. Girls carrying the short 5HTTLPR allele in combination with psychosocial stress, presented elevated depressive symptoms, whereas among boys, the long 5HTTLPR allele was a source of depressive symptoms. In both sexes, there was a G*E interaction of a psychosocial risk index. Girls were more affected by poor family relations and boys by multi-family housing and separated parents.</p><p>In conclusion, the MAO-A and 5HTTLPR genotypes, in interaction with psychosocial adversity, are related to different deviant behaviours among adolescents. The direct effects of the genotypes needed to be adjusted for the psychosocial factors, whereas the psychosocial factors had direct relation to the outcome measures. There is also an indication of a different pattern in G*E interaction between boys and girls and that different psychosocial factors affect boys and girls differently.</p>

The overall aim of this thesis was to explore gene-environmental (G*E) interactions in relation to deviant behaviour among 200 Swedish adolescents, with a focus on criminality, alcohol consumption and depressive symptoms. Those behaviours have been extensively investigated in relation to both psychosocial and biological risk factors. The biological markers used were the monoamine oxidase (MAO-A) and serotonin transporter (5-HTTLPR) gene polymorphisms. The main findings indicated a considerable gene-environment interaction in relation to all outcome variables studied. Individuals with the long/short variant of the 5HTTLPR gene, in combination with unfavourable family relations, both consumed more alcohol and had 12-14 times higher risks of being classified as high alcohol consumers. The MAO-A gene showed a G*E interaction related to criminality. Among boys, the short allele predicted an increased risk for criminality, whereas among girls, it was the long allele, if they lived in multi-family houses and/or had been maltreated, assaulted or sexually abused. A G*E interaction in relation to depressive symptoms among both boys and girls was determined. Girls carrying the short 5HTTLPR allele in combination with psychosocial stress, presented elevated depressive symptoms, whereas among boys, the long 5HTTLPR allele was a source of depressive symptoms. In both sexes, there was a G*E interaction of a psychosocial risk index. Girls were more affected by poor family relations and boys by multi-family housing and separated parents. In conclusion, the MAO-A and 5HTTLPR genotypes, in interaction with psychosocial adversity, are related to different deviant behaviours among adolescents. The direct effects of the genotypes needed to be adjusted for the psychosocial factors, whereas the psychosocial factors had direct relation to the outcome measures. There is also an indication of a different pattern in G*E interaction between boys and girls and that different psychosocial factors affect boys and girls differently.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 175-193).

Axons are injured after stroke, spinal cord injury, or neurodegenerative disease such as ALS. Most axons do not regenerate. A recent report suggests that not all neurons are poor regenerators, but rather a small subset can regenerate robustly. What intrinsic property of these regenerating neurons allows them to regenerate, but not their neighbors, remains a mystery. This subtype-specific regeneration has also been observed in Drosophila larvae sensory neurons. We exploited this powerful genetic system to unravel the intrinsic mechanism of subtype-specific neuron regeneration. We found that neuron bursting activity after axotomy correlates with regeneration ability. Furthermore, neuron bursting activity is necessary for regeneration of a regenerative neuron subtype, and sufficient for regeneration of a non-regenerative neuron subtype. This optogenetically-induced regeneration is dependent on a bursting pattern, not simply overall activity increase. We conclude that neuron bursting activity is an intrinsic mechanism of subtype-specific regeneration. We then discovered through a reverse genetic screen that an L-type voltage gated calcium channel (VGCC) promotes neuron bursting and subsequent regeneration. This VGCC has high expression in the regenerative neuron and weak expression in the non-regenerative neuron. This suggests that VGCC expression level is the molecular mechanism of subtype-specific neuron regeneration. Together, our findings identify a cellular and molecular intrinsic mechanism of subtype-specific regeneration, which is why some neurons are able to regenerate while the majority of neurons do not. Perhaps VGCC activation or neuron activity pattern modulation could be used therapeutically for patients with nerve injury.

Microglia are the resident macrophage in the central nervous system (CNS) that actively survey their environment and participate in shaping neuronal circuits. Among the transcription factors necessary for microglia development, interferon regulatory factor 8 (IRF8) is a known risk gene for multiple sclerosis and lupus and it has recently been shown to be downregulated in schizophrenia. These studies suggest that lack of microglial IRF8 can subsequently impact neuronal function in disease, but the mechanisms underlying these effects remain unknown. While most studies have focused on IRF8-dependent regulation of immune cell function, little is known about how it impacts neural circuits. To interrogate the impact of disrupted microglial IRF8 signaling on brain circuits, I first show by RNAseq that several genes known to regulate neuronal function are dysregulated basally in Irf8-/- brains. I then found that these molecular changes are reflected in heightened neural excitability and a profound increase in susceptibility to chemically-induced lethal seizures in Irf8-/- mice. Importantly, I also show that developmental synaptic pruning, a key function for microglia, proceeds normally in Irf8-/-mice. Finally, I identified that these IRF8-dependent effects on circuits are due to elevated TNF-α in the CNS as genetic or acute pharmacological blockade of TNF-α in the Irf8-/- CNS rescued the seizure phenotype. These results provide important insights into the consequences of IRF8 signaling and TNF-α on neural circuits. The next steps are to use cell-specific genetic approaches to manipulate this signaling, which I have further developed over the course of this project.

Activity plays diverse roles in shaping neuronal development and function. These roles range from aiding in synaptic refinement to triggering cell death during traumatic brain injury. Though the importance of activity-dependent mechanisms is widely recognized, the genetic underpinnings of these processes have not been fully described. In this thesis, I use the motor circuit of Caenorhabditis elegans as a model system to explore the functional and morphological consequences of modulating neuronal activity. First, I used a gain-of-function ionotropic receptor to hyperactivate motor neurons and asked how increased excitation affects neuronal function. Through this work, I identified a cell death pathway triggered by excess activation of motor neurons. I also showed that suppression of cell body death failed to block motor axon destabilization, providing evidence that death of the cell body and of motor axons can be genetically separated. Secondly, I removed excitatory drive from a simple neural circuit and asked how loss of excitatory activity alters circuit development and function. I identified excitatory motor neurons as master regulators of inhibitory synaptic connectivity. Additionally, I was able to identify previously undescribed activity-dependent mechanisms for regulating inhibitory synapses in both developing and mature neural circuits. Finally, I show data to implicate the highly conserved genes neurexin and neuroligin in determining inhibitory synapse connectivity. Collectively this work has lent insight into activity-dependent mechanisms in place to regulate neuronal development and function, a core function of neurobiology that is relevant to the study of a wide range of neurological disorders.

Exposure to certain stressors during a sensitive period around puberty can lead to enduring effects on an animal’s response to estradiol. In estradiol-influenced behaviors, such as sexual receptivity, hippocampal-dependent learning and memory, depression-like behavior, and anxiety-like behaviors, exposure to a peripubertal stressor such as shipping stress or an injection of lipopolysaccharide (LPS) can eliminate or even reverse the normal response to estradiol. In addition to regulating these behaviors, estradiol play a role in the regulation of body weight. While some of the previous studies touched on short-term effects on body weight, no systemic long-term study of the effects of a peripubertal stressor on body weight, particularly without interruption by ovariectomy, have been undertaken. This paper introduces a hypothesis that proposes that increased adiposity following exposure to a peripubertal stressor leads to the changes to estrogen-dependent behaviors through altered levels of estrogens and changes to estrogen receptors. The first chapter examines body weight data collected during studies with other aims, and then proposes an experiment to test whether either of two peripubertal stressors results in increased weight gain and body weight. The following chapter proposes further experiments designed to determine the proximate mechanisms leading to weight gain following peripubertal stressors and the role of diet on weight gain. The final chapter proposes experiments to test the effects of adiposity on peripheral levels of testosterone, aromatase, estradiol, and estrone; central levels of estradiol and estrone; and estrogen receptors in the brain.

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