At the adult frog neuromuscular junctions (Rana pipien and Rana catesbiana), F-actin microfilaments are enriched in the nonrelease domains of nerve terminals, outside the vesicle-rich release sites. The development of this defined F-actin cytoskeleton may be critical for nerve terminal function as microfilaments may play a role in synaptic vesicle release and recycling and/or synaptic maintenance. I used cutaneous pectoris muscles of adult frogs (Rana pipiens) and bullfrog larvae (Rana catesbiana) stained with markers of synaptic and cytoskeletal components to ask how elements of the neuronal cytoskeleton, microfilaments, microtubules, and neurofilaments, are organized at the frog neuromuscular junction and how they organize during development of presynaptic motor nerve terminals. The presynaptic actin cytoskeleton stained by β-actin antibody extended the length of the nerve terminal in a series of interconnected rings that surrounded clusters of synaptic vesicles. At developing neuromuscular junctions β-actin stain is initially concentrated at growth cones and intermittently along the lateral surfaces of the nerve terminal. The assembly of the β-actin cytoskeleton appeared secondary to clustering of synaptic vesicles. I compared the stability of the presynaptic actin cytoskeleton of developing and adult neuromuscular junctions after treatment with latrunculin A. The β-actin cytoskeleton was noticeably less stable at larval neuromuscular junctions than at adult synapses. These data support a role for the actin cytoskeleton in presynaptic maturation and stability. I tested whether the perisynaptic Schwann cells (PSCs) have a role in maintaining the actin cytoskeleton of the nerve terminal using complement-mediated cell lysis to selectively ablate PSCs in vivo. At various time points after ablation, I examined the actin organization at denuded motor nerve terminals. I report here that the stability and long-term maintenance of the nerve terminal actin cytoskeleton is dependent at least in part on the presence of PSCs. Following ablation of PSCs, a significant decrease in the intensity of presynaptic actin stain was observed and remained altered for several weeks. After PSC ablation, terminals also displayed reduced staining for synaptic vesicles.

Temporal Lobe Epilepsy (TLE) is the most common form of epilepsy in adults, and patients with TLE often suffer from seizures refractory to antiepileptic drugs. A deeper understanding of the pathophysiology of TLE is critical for improving treatment. In this dissertation we assess how TLE affects neuron in the rat presubiculum (PrS), a less-studied parahippocampal brain region believed to drive activity in structures implicated in TLE, specifically the medial entorhinal area (MEA). We conducted an electrophysiological assessment and created a classification schema to characterize neurons in superficial layers of PrS in control rats in order to expand upon limited knowledge available PrS neuron physiology. The PrS is comprised of seven electrophysiologically distinct cell types, suggesting greater functional heterogeneity than previously envisaged. By correlating morphology of recorded neurons with physiology, we determined that morphologically similar neurons may have very different physiological properties. PrS cell types include classes of projection neurons capable of coupling activity of spatially distributed structures. The extent to which physiology of PrS neurons is altered by TLE was assessed in chronically epileptic rats. Three of the previously identified PrS cell-types were encountered in epileptic rats. Regular-spiking cells, the most common cell-type in PrS, known to include MEA-targeting projection neurons, were the only PrS cell-type that became hyperexcitable in TLE. These cells displayed altered excitatory and inhibitory synaptic drive that likely contributes to cell hyperexcitability. Excitatory and inhibitory drive in superficial MEA neurons was measured while PrS activity was altered using either electrical stimulation or focal application of compounds to compare PrS contributions to MEA excitability between control and epileptic animals. Synaptic inputs from PrS to MEA neurons are conserved, and PrS stimulation is sufficient to trigger epileptiform activity in MEA neurons under epileptic conditions. PrS influence on excitatory and inhibitory synaptic drive in MEA is layer specific. Our data suggest that contribution to stellate cell inhibitory drive from PrS is reduced, and PrS may be decoupled from pyramidal neurons in epileptic rats. The work presented in this dissertation greatly advances our basic physiological knowledge of neurons in the PrS, and for the first time assesses how TLE impacts physiology of PrS neuron and their ability to drive activity in the MEA. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester, 2015. / July 8, 2015. / electrophysiology, hyperexcitability, parahippocampal, presubiculum, temporal lobe epilepsy / Includes bibliographical references. / Sanjay S. Kumar, Professor Directing Dissertation; Barbara Licht, University Representative; Richard Hyson, Committee Member; Frank Johnson, Committee Member; Mohamed Kabbaj, Committee Member.

Chemical signals are an important mode of communication and behavior regulation in many mammalian species. Non-volatile signals are sent by one animal and received by a second animal, typically of the same species. They are detected by the vomeronasal organ, which transmits information through the accessory olfactory bulb to the medial amygdala. Within the medial amygdala, non-volatile odors are categorized based on the behavioral relevance to the receiver. Non-relevant biological odors activate only the anterior medial amygdala, whereas relevant biological odors activate both the anterior and posterior medial amygdala. The main intercalated nucleus, which lies adjacent to the medial amygdala, contains inhibitory GABA-ergic neurons, is activated by non-relevant odors, and may be responsible for suppressing posterior medial amygdala response to those odors. Intercalated cell groups are known to be inhibited by dopamine meaning the main intercalated nucleus may be involved in categorization through the effects of dopamine at the D1 receptor. The experiments presented here investigate the roles of the main intercalated nucleus, dopamine, and learning on medial amygdala activity in mice. Within the main intercalated nucleus different doses of the dopamine agonist (SKF-38393) lead to different activation depending on which odor was presented, however this activation was not correlated with medial amygdala activity. Instead, the dopamine agonist increased medial amygdala activity in a dose dependent, but not odor dependent, manner. Classical conditioning to change an odor's significance from non-relevant to relevant did not affect medial amygdala activity, although dopamine did blunt the effect of odor learning within the basolateral amygdala. Finally, both the dopamine agonist and antagonist (SCH-23390) disrupted the expected pattern of investigation of a novel non-relevant odor after habituation to a relevant odor. These results suggest that dopamine may be involved in main intercalated nucleus activity and investigation of non-relevant odors, but the role of both dopamine and the intercalated nucleus in medial amygdala activation remains unclear. / A Thesis submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Master of Science. / Summer Semester 2015. / May 18, 2015. / Amygdala, Chemosignal, Dopamine, Mouse / Includes bibliographical references. / Michael Meredith, Professor Directing Thesis; Thomas Houpt, Committee Member; Elaine Hull, Committee Member.

abstract: Hysterectomy is the second most common gynecological surgery performed in women. Half of these surgeries involve removal of the uterus alone, and half involve concomitant removal of the ovaries. While the field has retained the notion that the nonpregnant uterus is dormant, more recent findings suggest that hysterectomy is associated with cognitive detriment. Of note, the clinical literature suggests that an earlier age at hysterectomy, with or without concomitant ovarian removal, increases dementia risk, implicating age at surgery as a variable of interest. While preclinical work in a rodent model of hysterectomy has demonstrated spatial working memory impairments, the role of age at surgery has yet to be addressed. The current experiment utilized a rodent model of hysterectomy to investigate the importance of age at surgery in post- surgical cognitive outcomes and to evaluate relative protein expression related to brain activity, FosB and ∆FosB, in regions critical to spatial learning processes. Young adult and middle-aged female rats underwent sham surgery, hysterectomy, or hysterectomy with ovariectomy, and were tested on a behavioral battery that evaluated spatial working and reference memory. Following the behavioral battery, animals were sacrificed and brain tissues from the Dorsal Hippocampus and Entorhinal Cortex were processed via Western Blot for relative FosB and ∆FosB expression. Behavioral analyses demonstrated that animals receiving hysterectomy, regardless of age or ovarian status, were generally impaired in learning a complex spatial working memory task. However, rats that received hysterectomy in middle-age uniquely demonstrated persistent working memory impairment, particularly with a high working memory demand. Subsequent neurobiological analyses revealed young rats that underwent hysterectomy had reduced relative FosB expression in the Entorhinal Cortex compared to sham controls, where no significant effects were observed for rats that received surgery in middle-age. Finally, unique relationships between neurobiological and behavioral outcomes were observed largely for sham rats, suggesting that such surgical manipulations might modulate these relationships. Taken together, these findings suggest that age at surgery plays an important role in learning and memory outcomes following hysterectomy, and demonstrate the need for further research into the role of the uterus in communications between the reproductive tract and brain. / Dissertation/Thesis / Masters Thesis Psychology 2020

This dissertation presents a computational multiscale framework for predicting behavioral tendencies related to human addiction. The research encompasses three main contributions. The first contribution presents a formal, heuristic, and exploratory framework to conduct interdisciplinary investigations about the neuropsychological, cognitive, behavioral, and recovery constituents of addiction. The second contribution proposes a computational framework to account for real-life recoveries that are not dependent on pharmaceutical, clinical, and counseling support. This exploration relies upon a combination of current biological beliefs together with unorthodox rehabilitation practices, such as meditation, and proposes a conjecture regarding possible cognitive mechanisms involved in the recovery process. Further elaboration of this investigation leads on to the third contribution, which introduces a computational hypothesis for exploring the allostatic theory of addiction. A person engaging in drug consumption is likely to encounter mood deterioration and eventually to suffer the loss of a reasonable functional state (e.g., experience depression). The allostatic theory describes how the consumption of abusive substances modifies the brain's reward system by means of two mechanisms which aim to viably maintain the functional state of an addict. The first mechanism is initiated in the reward system itself, whereas the second might originate in the endocrine system or elsewhere. The proposed computational hypothesis indicates that the first mechanism can explain the functional stabilization of the addict, whereas the second mechanism is a candidate for a source of possible recovery. The formal arguments presented in this dissertation are illustrated by simulations which delineate archetypal patterns of human behavior toward drug consumption: escalation of use and influence of conventional and alternative rehabilitation treatments. Results obtained from this computational framework encourage an integrative approach to drug rehabilitation therapies which combine conventional therapies with alternative practices to achieve higher rates of consumption cessation and lower rates of relapse.

Human brain is a complex dynamical system, whose complexity could be highly functional and characterize cognitive abilities or mental disorders. The APOE ɛ4 allele is a well-known genetic risk factor for the development of Alzheimer's Disease and cognitive decline in later human life. However, there are no robust conclusions about the APOE genotype-phenotype association among young healthy adults. The main goal of this study is to investigate the bridges between brain signal complexity, APOE genotype and cognitive performance among young adults under the framework of individual difference. Before going deeper to the main topic, the first study assessed the reliability of Residue Iteration decomposition (RIDE), a method for analysis brain signals that was applied in the main parts of my thesis. Using a dataset independent from the main topic, I demonstrated that as compared with conventional analysis method, the RIDE-reconstructed event-related-potentials (ERPs), including the N400 component reflecting the evaluation of semantic incongruities during social communication, could more sensitively characterize people across a spectrum of autistic level. The second study investigated how individual differences in APOE genotypes are associated with 1) brain signal complexity measured with Multiscale Entropy (MSE) and 2) cognitive ability in specific domain, especially, working memory capacity. Using Structural Equation Modelling (SEM) we showed that APOE ε4 is associated with higher entropy at scale 1-4 and lower entropy at scale 5 and above, especially at frontal scalp regions and in an eyes open condition; in addition, we showed a stronger drop in MSE from closed to open eyes condition among ε4 carriers than non-carriers. The ε4 association with cognitive performance was complex, but basically ε4 seems to be associated with worse cognitive performance among lower educated people, whereas no such association appeared among the higher educated. The third study connected MSE with a different cognitive domain - face and object cognition abilities We showed that 1) increased MSE at all scales is associated with better cognitive performance from the view of both diffusion process during perceptual decision making and task performance accuracy. However, the association was only consistent for a closed eyes condition. 2) Increased MSE at higher scales (7 or 8) was associated with tighter coupling between RIDE-extracted single trial stimulus evaluation speed at the neural level and reaction time at the behavior level. To summarize, the results of my doctoral study connected brain signal complexity, APOE genotype and cognitive behavior among young healthy adults, providing a deeper understanding of brain-behavior relationships and - potentially - for early AD diagnosis when cognitive decline is not yet evident.

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