Cognitive deficits associated with an aging population have been the focus of clinical research interest as an increasing number of people survive into older age. These research interests have determined that there is a need to accurately detect the onset of cognitive changes that show the beginning of a dementia syndrome and to differentiate among disorders with distinct etiologies and sites of pathology. Impairment in executive functions has been recognized as one cognitive feature in which changes and deficits have been reported in various types of neurodegenerative disorders. Mild cognitive impairment is often viewed as a transitional stage between normal aging and Alzheimer’s disease (AD), frontotemporal lobe dementia (FTD), and Lewy body dementia (LBD). Neuropsychological evaluations can assist in detecting the onset of cognitive executive functioning changes and decline in the early stages of dementia disorders. The purpose of this study was to determine if there is a change in executive functioning profiles in subjects who initially have no dementia but later receive a diagnosis of neurodegenerative disorders of Alzheimer’s, frontotemporal lobe, and Lewy body dementias. Possible early executive functioning indicators might be found that could then be used to identify at-risk individuals before a formal diagnosis is made. Strategic interventions could then be provided to lessen the effects of these disorders. Early intervention allows more time for individuals to gain access to strategies and plan for changes that may occur throughout the process of these disorders. It also provides information for further study. The aim of this study was to test the hypothesis that once a subject has been diagnosed with dementia a detectable change has occurred in executive functioning measures. Participants were 34 persons between the ages of 61-89 who had been given a series of neuropsychological tests of executive functioning. Individuals who met criteria for AD, LBD, and FTD disorders were included in this sample, and their scores from baseline evaluation to initial diagnosis of AD, LBD, and FTD were analyzed to determine changes in executive functioning measures. The executive functioning tests included verbal associative fluency retrieval of animal and vegetable exemplars, Trail Making Part B, and Digit Span Backward from the Wechsler Memory Scale-Revised (WMR-R). Analysis included changes in executive functioning measures when the diagnosis of AD, LBD, or FTD was made after a change from the initial diagnosis of no dementia. The results of this study are that patients performed similarly across different measures, with the exception of the Trails B subtest, which indicated a significant difference. This subtest difference emerged between the initial evaluation and the first diagnosis of AD, LBD, or FTD.

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The current fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013) differentiates individuals with conduct disorder according to the presence vs. absence of “limited prosocial emotions,” known in the literature as callous-unemotional (CU) traits. Research suggests that CU traits confer risk for more stable, severe antisocial behavior over the lifetime. However, other trait dispositions may play an important role in understanding the temperamental and neural characteristics underlying this heterogeneous disorder. The current study sought to extend existing knowledge of biobehavioral traits’ contributions to antisocial behavior by examining the relations of adolescent callousness and disinhibition to concurrent neural response and clinical symptoms (e.g., conduct disorder and ADHD). These questions were addressed using existing data from the IMAGEN project, a large (N ~ 2200), longitudinal European adolescent sample with questionnaire, clinical-interview, and neuroimaging data. First, a reliable self-report callousness scale was created from administered questionnaire items and validated in relation to empathy and drug use variables. Second, selective associations were found between callousness and decreased neural activation in empathy-relevant areas while viewing ambiguous and angry facial expressions, over and above the effects of disinhibition. Finally, callousness and disinhibition were independently related to conduct disorder symptoms in the best-fitting negative binomial regression model; disinhibition alone was related to ADHD symptoms and, to a lesser extent, symptoms of distress disorders. The current study advances understanding of the development of antisocial behavior in relation to dispositional traits, in line with recent calls for a multidimensional conceptualization of childhood antisocial tendencies beyond CU traits alone. Results support trait-related revisions to current diagnostic nosology to guide provision of effective treatment. / A Thesis submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Master of Science. / Summer Semester 2018. / June 26, 2018. / Adolescence, Antisocial behavior, Conduct disorder, fMRI, Personality / Includes bibliographical references. / Christopher J. Patrick, Professor Directing Thesis; Pamela K. Keel, Committee Member; Colleen M. Ganley, Committee Member.

Cigarette smoking during pregnancy is a major public health concern, resulting in detrimental health effects in the mother and her offspring. The adverse behavioral consequences for children with developmental nicotine exposure include increased risk for attention deficit hyperactivity disorder, working memory deficits, epilepsy, novelty-seeking, and risk-taking behaviors. Interestingly, these behavioral conditions are consistent with altered inhibitory (GABA) neurotransmitter signaling. Therefore, the goal of my dissertation research was to test the hypothesis that early exposure to nicotine alters the development of the GABA system, which can produce functional changes in the brain. In order to test the hypothesis that developmental nicotine exposure produces long-lasting effects in the adult mouse brain, specifically the GABA system, I used a GAD67-GFP knock-in mouse in which GFP is intrinsically expressed under the GAD67 promoter. I first examined GABA neuron numerical densities, non-GABA neuron numerical densities, as well as the GABA-to-non-GABA neuron ratio for male and female offspring that received plain drinking water (WATER) or drinking water containing either 100 µg/ml (Nic100) or 200 µg/ml (Nic200) nicotine during development. I performed these analyses in the prefrontal and medial prefrontal cortices, two brain regions which are important for executive function and regulate behaviors known to be altered in developmental disorders such as attention deficit/hyperactivity disorder. In addition, these frontal cortical brain regions were subdivided into cortical layers (II-III, V, and VI) since each cortical layer is defined based on their cortical connections and hence have different functions. Overall, I found that developmental nicotine exposure does not alter the numerical density of GABA or non-GABA cells in the frontal cortex, however, I saw a significant reduction in the GABA-to-non-GABA ratio in the Nic200 treatment group compared to the WATER and Nic100 groups across both brain regions (prefrontal and medial prefrontal cortices) and across all cortical layers. Next, in order to test the hypothesis that developmental nicotine exposure produces long-lasting effects on behavioral phenotypes, I performed a battery of tests that examined locomotor activity, approach-avoidance behavior, exploratory behavior, spatial working memory, and object-based attention beginning at 90 days of age. Since I found a significant reduction in the GABA-to-non-GABA ratio for the Nic200 treatment group and not for the Nic100 group, I performed behavioral analyses in the WATER and Nic200 treatment groups. For these analyses, I used both male and female offspring as well as GAD67-GFP and wild-type offspring. I found that developmental nicotine exposure increases novelty-induced locomotor activity, increases exploratory behavior, and alters approach-avoidance behavior in favor of the approach behavior. During embryonic development, the majority of the GABA neurons originate in the medial ganglionic eminence of the basal forebrain and migrate tangentially to regions of the dorsal forebrain. At the same time, neurogenesis in the ventricular and subventricular zones is occurring in the dorsal forebrain. Therefore, I wanted to examine the immediate effects of developmental nicotine exposure on GABA neuron migration and neurogenesis in the embryonic brain. To do this, I collected the brains from embryonic day 13 and 15 embryos; two time points during embryonic development in which GABA neurons are migrating through regions of the dorsal forebrain and neurogenesis is occurring in the dorsal forebrain. Using GAD67-GFP embryos, I found that nicotine exposure significantly increases the number of GABA neurons in the prefrontal and medial prefrontal cortices. Similarly, using an in-vitro culture assay, nicotine exposure increased the number of GABA neurons migrating out from a medial ganglionic eminence explant. Taken together these results suggest that nicotine exposure during embryonic development alters GABA neuron migration. In addition, using wild-type embryos, I found that nicotine exposure significantly reduces the cell output in the future prefrontal and medial prefrontal cortices. Overall, developmental nicotine exposure produced dose-dependent decreases in GABA-to-non-GABA neuron ratios in the prefrontal and medial prefrontal cortices without perturbing the intrinsic differences in cortical thickness and laminar distribution of GABA or non-GABA neurons between these regions. A significant increase in exploratory behavior and a shift toward “approach” in the approach-avoidance paradigm were also observed. Thus, developmental nicotine exposure shifts the cortical excitation-inhibition balance toward excitation and produces behavioral changes consistent with novelty-seeking behavior. Lastly, I found that nicotine exposure during embryonic development produces a significant increase in GABA neuron migration and reduces the cell output in the dorsal forebrain. Collectively, these results suggest that developmental nicotine exposure alters embryonic brain development and that continued exposure during the embryonic and early postnatal period produces long-lasting structural and functional changes in the brain. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / 2019 / September 11, 2019. / Acetylcholine, Approach-avoidance behavior, Brain development, Exploratory behavior, GABA, Prenatal nicotine exposure / Includes bibliographical references. / Pradeep G. Bhide, Professor Directing Dissertation; Jonathan H. Dennis, University Representative; Richard S. Nowakowski, Committee Member; Gregg D. Stanwood, Committee Member; Christine Metin, Committee Member.

Understanding the neural and genetic basis of complex behaviors is a major outstanding question in neurobiology. The fruit fly, Drosophila melanogaster, displays innate, complex reproductive behaviors. These behaviors are regulated by transcription factors encoded by fruitless (fru) and doublesex (dsx). Both fru and dsx are sex-specifically spliced downstream of the sex determination hierarchy, resulting in production of male-specific isoforms of Fru and Dsx and a female-specific isoform of Dsx. These transcription factors direct sex differences in behavior by regulating expression of downstream genes. fru is a complex locus and only transcripts from the P1 promoter (fru P1) are sex-specifically spliced to generate male-specific isoforms (FruM). To gain insight into gene expression differences in fru P1-expressing neurons between males and females, we used Translating Ribosome Affinity Purification (TRAP). The results of this study and other studies led us to examine a family of proteins with known functions in synaptic connectivity encoded by defective proboscis extension response (dpr) and Dpr Interacting Protein (DIP) genes. We examined the co-expression of dprs/DIPs with fru P1 neurons. We found the majority of dprs/DIPs are co-expressed with fru P1-expressing neurons in both males and females, but with distinct patterns. When we activate and silence subsets of fru P1 neurons that overlap with dpr/DIP- expressing neurons, particular courtship phenotypes are observed, allowing us to assign functions to subpopulations of neurons. Overall, this work contributes to our understanding of how FruM is specifying and maintaining the neural circuitry for male courtship behavior, with a focus on the regulation and function of the dprs and DIPs. We also focus on the regulation of female reproductive behaviors, by examining interactions between the germline and female head tissues. We examined gene expression changes in head tissues of females with and without a germline, as virgins and at one- and three- day(s) post-mating, as well as in females that had been mated to males lacking a germline. A set of female post-mating behaviors was also characterized. Additionally, we performed a genome-wide association study which led to the identification of polymorphisms that contribute to natural variation of female re-mating behavior. Together, these studies provide insight into the molecular-genetic control of female reproduction. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / 2019 / October 14, 2019. / Includes bibliographical references. / Michelle N. Arbeitman, Professor Directing Dissertation; Kimberly A. Hughes, University Representative; Timothy L. Megraw, Committee Member; Jamila I. Horabin, Committee Member.

The increasing incidence of Alzheimer’s disease (AD) combined with recent evidence suggesting that its neuropathologies begin years prior to symptomatic onset has produced an immense focus on ways to attenuate the related structural and cognitive decline of certain brain regions. One low cost intervention is aerobic exercise. Rodent models have demonstrated aerobic exercise induces adult hippocampal neurogenesis, the birth of new neurons, in the dentate gyrus (DG) subregion of the hippocampus (HC) as well as increased performance on a spatial memory task. Further, human studies have demonstrated the association between increased cardiorespiratory fitness (CRF) and increased HC volume, and its translation to increased episodic memory performance. The goal of this study was to assess the relationship between CRF, as measured by VO2max, and brain region of interest (ROI) volumes notably including the left HC, left DG/Cornu Ammonis 3 (CA), and right entorhinal cortex (ErC). A secondary goal was to assess the relationship between CRF and cognitive performance on the Rey Auditory Verbal Learning Test. Baseline data was collected from 31 healthy older adults as a part of two larger clinical trials on aerobic exercise and HC function. Data included a CRF assessment as measured by VO2max, and structural MRI data including a high-resolution whole-brain T1-weighted image, and a T2-weighted image with higher-in-plane resolution. Automatic Segmentation of Hippocampal Subfields (ASHS) was the neuroimaging software utilized to segment the HC and medial temporal lobe cortices into its appropriate subfields. Multiple linear regressions ran in IBM SPSS 25 to determine if CRF predicted ROI volumes yielded no significant results when controlling for age, sex, intracranial volume, education, and scanner location. Multiple one-way between-subject ANOVAs conducted to compare ROI volumes in high-fit versus low-fit individuals revealed marginal significance for the left HC, but no other ROI. Multiple one-way between-subject ANOVAs conducted to compare cognitive performance in high-fit versus low-fit individuals also revealed no significant results. Considering the marginal significance achieved by the one-way between-subjects ANOVA for CRF and left HC, a larger sample size is needed to potentially achieve significant statistical significance. Given these remaining null results, further investigation is suggested using additional neuroimaging analyses that split the DG/CA3 into its anterior and posterior sections, as well as examining different aspects of the RAVLT or utilizing more sensitive episodic memory tests.

Depression is a devastating disease that is the leading cause of disability worldwide. One reason for its massive disease burden is that classical antidepressants require several weeks of administration to take effect, and they are only effective in roughly half of patients. Ketamine, previously known as primarily a veterinary anesthetic, rapidly alleviates treatment-resistant depressive symptoms at sub-anesthetic doses. Indeed, a single intravenous (i.v.) infusion of ketamine elicits an antidepressant effect within 2 hours and can last up to 2 weeks. Furthermore, this therapeutic effect of ketamine can be prolonged with repeated intermittent treatments. However, there are still many unanswered questions regarding ketamine’s safety, especially with respects to the long-term effects of prolonged, repeated exposure. Since ketamine is also a popular club drug with addictive properties, it is critical to characterize the safety and abuse liability of this drug. Additionally, women have twice the prevalence rates of depression as compared to men, and they progress more rapidly through the phases of drug addiction than men. Despite these known sex differences, females have been heretofore underrepresented in clinical and pre-clinical research. We sought to determine if intermittent self-administration of ketamine in rats can trigger drug-seeking behavior, at a dose that is close to the therapeutic human dose, and if the stage of the four-day estrous cycle can influence this behavior, as antidepressant-like effects of ketamine in females depends on estrous cycle stage (Dossat 2016). To that end, rats were trained to self-administer ketamine (0.1 mg/kg/infusion) in an operant chamber once every fourth day for males, while females’ self-administration sessions coincided with either diestrus 1 (when estradiol and progesterone are low), or proestrus (when these hormones are high). Ketamine intake in diestrus-trained females rapidly declined, while proestrus-trained females and males were stable across the acquisition phase of the experiment. After extinction training, proestrus-trained females and males (but not diestrus-trained females) displayed reinstated ketamine-seeking behavior when re-exposed to discrete cues that were previously paired to ketamine availability. Interestingly, a ketamine priming injection in the absence of cues did not reinstate ketamine-seeking behavior as is consistently seen with a priming injection of cocaine, a drug with very high abuse potential. Together, this indicates not only that ketamine-paired cues are more salient precipitators of relapse than the pharmacological effects of ketamine on its own, but also that the stage of estrous cycle associated with high levels of gonadal hormones supports female’s ketamine intake and subsequent ketamine relapse. To address comorbid depression and ketamine addiction, we assessed ketamine addictive-like behaviors in males and females previously exposed to unpredictable chronic mild stress (CMS), a procedure shown to induce a depressive-like phenotype in rodents. They were treated with four intermittent therapeutic i.v. ketamine infusions, designed to mimic infusion protocols used in clinics. They were then given access to self-administer 0.5 mg/kg/infusion ketamine and tested for their motivation to obtain ketamine using progressive ratio schedule (PR) and persistence of incubated ketamine craving after a period of forced abstinence, which is a major factor in the precipitation of relapse. CMS decreased sucrose intake in both sexes, but ketamine had no effect on anhedonia like-behaviors. Ketamine treatment reduced anxiety-induced neophagia, measured by the novelty-suppressed feeding test, suggesting that i.v. ketamine’s antidepressant-like effects may be symptom- and species-specific. While prior ketamine exposure and CMS had no effect on subsequent ketamine addiction-like behavior in males, females that underwent CMS displayed more addiction-like behavior than non-stressed females, suggesting that chronic stress can increase the risk for ketamine abuse in females. Additionally, ketamine pre-exposed females displayed lower ketamine intake, with no alterations in motivated responding or craving. Finally, dendritic spine density and morphology was assessed in the nucleus accumbens (NAc), the central processor for rewarding stimuli that is affected by both depression and addiction. Females with prior ketamine exposure regardless of stress condition had an increase in spine density that was primarily driven by the formation of immature thin spines; there were no changes in males. Together this suggests that although ketamine pre-treatment may alter NAc plasticity in a sex-dependent manner, it does not potentiate ketamine addiction-like behavior. Taken together, this work demonstrates that although ketamine and drug-paired cues have strong reinforcing effects, prior exposure to therapeutic ketamine infusions do not increase the risk of abuse. Estrous cycle stage and prior exposure to chronic stress influences the reinforcing properties of ketamine in females, suggesting an influence of ovarian hormones. The fact that ketamine-seeking behavior was dependent on the drug-paired cues rather than the acute pharmacological effects of ketamine, and that prior therapeutic ketamine did not increase the subsequent development of addiction-like behavior, suggests that there may be little overlap in ketamine’s antidepressant effects and addictive effects. It is possible that ketamine, if administered under the appropriate conditions, may have limited abuse potential, but research is necessary to determine if these sex-specific effects in rats translate to humans. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2017. / November 8, 2017. / addiction, dendritic spines, depression, ketamine, self-administration, sex differences / Includes bibliographical references. / Mohamed Kabbaj, Professor Directing Dissertation; Laura Keller, University Representative; Pradeep Bhide, Committee Member; Jamila Horabin, Committee Member; Jian Feng, Committee Member.

It is found here that the state of a network of coupled ordinary differential equations is partially localizable through a pair of contractive ideal subspaces, chosen from dual complete lattices related to the synchrony and synchronization of cells within the network. The first lattice is comprised of polydiagonal subspaces, corresponding to synchronous activity patterns that arise from functional equivalences of cell receptive fields. This lattice is dual to a transdiagonal subspace lattice ordering subspaces transverse to these network-compatible synchronies. Combinatorial consideration of contracting polydiagonal and transdiagonal subspace pairs yields a rich array of dynamical possibilities for structured networks. After proving that contraction commutes with the lattice ordering, it is shown that subpopulations of cells are left at fixed potentials when pairs of contracting subspaces span the cells' local coordinates - a phenomenon named glyph formation here. Treatment of mappings between paired states then leads to a theory of network-compatible sequence generation. The theory's utility is illustrated with examples ranging from the construction of a minimal circuit for encoding a simple phoneme to a model of the primary visual cortex including high-dimensional environmental inputs, laminar speficicity, spiking discontinuities, and time delays. In this model, glyph formation and dissolution provide one account for an unexplained anomaly in electroencephalographic recordings under periodic flicker, where stimulus frequencies differing by as little as 1 Hz generate responses varying by an order of magnitude in alpha-band spectral power. Further links between coupled-cell systems and neural dynamics are drawn through a review of synchronization in the brain and its relationship to aggregate observables, focusing again on electroencephalography. Given previous theoretical work relating the geometry of visual hallucinations to symmetries in visual cortex, periodic perturbation of the visual system along a putative symmetry axis is hypothesized to lead to a greater concentration of harmonic spectral energy than asymmetric perturbations; preliminary experimental evidence affirms this hypothesis. To conclude, connections drawn between dynamics, sensation, and behavior are distilled to seven hypotheses, and the potential medical uses of the theory are illustrated with a lattice depiction of ketamine xylazine anaesthesia and a reinterpretation of hemifield neglect.