<p>The mammalian neocortex is highly dynamic, demonstrating incredible variability in size and complexity across species. This phenotypic diversity, however, evolved from an extinct common ancestor. By illuminating organization of this mammalian ancestor, we can better understand the common features and the constraints of the mammalian neocortex across all species. Brain organization is not preserved in fossilized tissue. Therefore, examinating the brain of extant species, such as the short-tailed opossum, and comparing it to the brains of other mammals, provides the best available data for understanding the brain organization of early mammals. We investigated both corticocortical and thalamocortical connections of parietal cortical areas as well as the visual acuity in the short-tailed opossum (Monodelphis domestica). This species was chosen because it is thought to share many features with early mammaliforms (including body morphology, ecological niche, and gross brain morphology). We also discuss the neocortical organization of the somatosensory and motor systems across small-brained mammals. This provides a more comprehensive understanding of similar features of organization, inherited from the common ancestor (homologous) as well as features of organization that are unique to this particular species. For studies of cortical connections of parietal cortex in Monodelphis domestica, injections of anatomical tracers were placed in four different cortical areas and both injection sites and retrogradely labeled cells were related to myeloarchitectonic boundaries of cortical fields. Using these techniques, we identified rostral and caudal somatosensory fields (SR and SC, respectively) on either side of primary somatosensory cortex (S1), as well as a multimodal region caudal to SC (termed MM). Together with the second somatosensory area (S2), these five areas compose an interconnected somatosensory/multisensory network in Monodelphis. Next, we investigated the thalamocortical connections of SR, S1, SC, and MM. In contrast with thalamocortical connections described in previous studies in the closely related Virginia opossum (Didelphis virginiana), Monodelphis domestica does not have strong projections from ventral lateral/ventral anterior nucleus to S1, suggesting a different pattern of motor organization in Monodelphis neocortex, and further complicating the hypothesized organization of the common mammalian ancestor. Finally, we provided the first behavioral measure of visual acuity in any American opossum. We discuss the significance of this finding, both in the context of future research on the visual system of Monodelphis as well as in the context of visual system organization across mammals.

Benzodiazepines (BZs) are widely used in the treatment of anxiety and sleep disorders. However, unwanted side effects, such as sedation, motor impairment, and the potential for physical dependence and tolerance, can hinder their use in the clinic. Elucidating the GABAA receptor subtypes underlying these behavioral effects can facilitate the development of an anxiolytic pharmacotherapy with enhanced clinical utility and reduced unwanted side effects. Subtype selective compounds were used to investigate the underlying receptor mechanisms involved in the observable behavioral effects of BZs. In addition, the receptor mechanisms involved in BZ physical dependence and tolerance were also investigated. In addition to observable behavioral effects and motor impairment (MAP and FRR) of BZs, novel categories of observable sedation (sleep posture, moderate sedation, and deep sedation) have been included. Acutely, sleep posture is likely mediated by α2/3GABAA receptors while α1GABA A receptors may mediate deep sedation associated with BZs. The motor impairing effects observed with the MAP and FRR tasks likely involve an interaction of GABAA receptors containing α1, α2, and α3 subunits. The receptor mechanisms underlying tolerance and physical dependence associated with chronic alprazolam administration were investigated. Tolerance developed rapidly to deep sedation, which is likely mediated by α1GABA A receptors, while sleep posture, which is thought to be mediated by α2/3GABAA receptors, persisted throughout chronic treatment. Motor impairment measured by the MAP and FRR tasks also developed tolerance at a similar rate as deep sedation, further suggesting a role for α1GABA A receptors in these behaviors. Substitution tests were conducted to investigate physical dependence and cross-tolerance. Results suggest physical dependence developed following chronic alprazolam treatment. In addition, α1GABAA receptors likely play a role in physical dependence. Withdrawal effects following substitution tests with zolpidem and NEP-581 precluded the determination of cross-tolerance.

<p>In Post-Traumatic Stress Disorder (PTSD), social and emotional dysfunction has been interpreted as a secondary consequence of the broad impact of amygdala and fear circuitry dysregulation. However, research in social neuroscience has uncovered a number of neural systems involved in attachment and emotional regulation that may be impacted by trauma. One example is the Default Mode Network (DMN), which is implicated in human beings&rsquo; sense of self and ability to connect with others. </p><p> This qualitative study explored the impact of physical and emotional traumata on the structures and functions of the DMN. The goal was to determine if dysregulation of the DMN could account for aspects of the psychological and social dysfunction found in PTSD. This study explored the following two questions: 1. What does the research literature tell us about the role of the DMN? 2. How does trauma impact DMN functioning? </p><p> The DMN has been associated primarily with autobiographical recall, self-referential processing, social cognition, prospection, and moral sensitivity. The DMN appears to support internal reflective capacity, further maintaining and connecting self-functions and social cognition. Trauma results in internetwork rigidity, as well as overall reductions in DMN activity, volume, and connectivity. These objective changes result in a Traumatized Resting State (TRS), characterized by increased Salience Network connectivity and reductions in Central Executive functioning. Studies suggest that a TRS develops in reaction to acute trauma, even before the development of PTSD, and may continue despite the stabilization of other networks. Overall, DMN incoherence significantly disrupts core psychosocial processes. </p>

<p> The observation that the hippocampus is required for memory and spatial navigation has led to extensive study of the hippocampal neural circuit. Past research has focused on established patterns of hippocampal neural activity, such as the classic place cell code and the theta network pattern. However, we still have only a preliminary understanding of how the hippocampus performs cognitive functions. This may be the case because there still remain unknown yet fundamental patterns of hippocampal neural activity. </p><p> To investigate this possibility, we recorded neural activity in the hippocampus of rats engaged in a spatial memory task. In this thesis I describe four previously unidentified patterns of hippocampal neural activity: (1) spatially specific neural firing that is more active when animals are at rest, (2) a &sim;200 ms network pattern that is associated with spatial firing at rest, (3) spatially specific, transient neural firing at the time of behavioral transitions between movement and rest, and (4) a high frequency (65-140 Hz) network pattern that entrains neural firing throughout the hippocampus. I postulate that these patterns of activity have essential roles in complex hippocampal functions. </p>

<p> Individuals who are victimized by bullying during adolescence demonstrate an increased incidence of psychiatric disorders both acutely and later in life. Many of these disorders are characterized by deficits in complex cognitive functions that are mediated by the mesocortical dopamine system. The substantial maturation of the mesocortical dopamine system during adolescence may render it particularly vulnerable to insult from psychosocial stressors such as bullying. Using a rodent model of adolescent social defeat to replicate the imbalance of power inherent in teenage bullying, it was previously demonstrated that defeated rats exhibit various behavioral and neurochemical indications of mesocortical dopamine hypofunction in adulthood. The experimental chapters of this dissertation aim to further understand the consequences of victimization stress during adolescence by 1) evaluating the effects of adolescent social defeat on dopamine dependent cognitive processes and 2) investigating the potential mechanisms by which adolescent social defeat results in mesocortical dopamine hypofunction. Adult rats defeated in adolescence and their controls were initially tested on two separate tasks of working memory known to be dependent on mesocortical dopamine activity, the delayed alternating T-maze task and the delayed win-shift task. Results found a direct link between adolescent social defeat and adult working memory deficits, with previously defeated rats demonstrating impaired performance in the maintenance and utilization of information following delays of 90 seconds and 5 minutes on the T-maze and win-shift tasks respectively. In a separate experiment, quantitative autoradiography revealed increased expression of the dopamine transporter (DAT) in the infralimbic region of the medial prefrontal cortex (mPFC) of adult rats defeated in adolescence. Further investigation of mPFC DAT function utilizing <i>in vivo</i> chronoamperometry demonstrated that previously defeated rats exhibit decreased dopamine accumulation in response to pharmacological DAT inhibition, indicating enhanced DAT function that may increase clearance of dopamine in the mPFC. Combined, these results suggest that increased functional expression of DAT in the mPFC following adolescent social defeat leads to enhanced clearance of dopamine, contributing to deficits in mPFC dopamine activity and associated cognitive processes. Having identified a putative mechanism by which adolescent social defeat causes mesocortical dopamine hypofunction, the results of these experiments can assist in directing the clinical application of novel and existing pharmacotherapies to counteract the deleterious effects of adolescent stress.</p>

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.

Abstract not available

<p> The purpose of this study was to examine potential effects of head-injury on individuals&rsquo; performance on the Picture Memory Interference Test (PMIT). This study examined differences in the performance of college-aged students with and without a history of head-injury on the PMIT. Data was drawn from an archival dataset of PMIT completions held at UCLA and analyzed with permission. From the total dataset of 12,227 completions, experimental groups were derived and separated based upon assumed severity of head-injury, based upon self-report data. Following exclusions, the final data sub-set for analysis consisted of 6,897 unique completions of the PMIT. Of these, 412 were assigned to the Mild head-injury group; 61 individuals were assigned to the Moderate-Severe head-injury group. Multiple one-way ANCOVA were conducted to identify difference between group performances. The results of the current study are unclear as to whether or not the PMIT may effectively detect and discriminate college student participants with a history of head-injury from those without, although significant findings were obtained which demonstrated those with a history of mild head-injury obtained higher scores on particular trials of the PMIT. </p>