Thesis (Ph. D.)--University of Wisconsin--Madison, 1956. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 120-124).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1960. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1966. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

The hippocampal to medial prefrontal cortex (HPC-mPFC) pathway has a role in mnemonic processing. A key function of the hippocampus (HPC) is to organize contextual memories by how they were experienced, and the prefrontal cortex (PFC) retrieves contextual memories by sorting and suppressing irrelevant memories for the task at hand. Studies have highlighted the HPC-mPFC connection in rodents, however, there is a relative paucity of primate studies. The present study addressed this issue by investigating the connection from the HPC to anterior cingulate cortex (ACC; areas 24a, 25 and 32) of the mPFC in rhesus monkeys (Macaca mulatta). The distribution of hippocampal axons and terminals (boutons) was largest in area 25. Bouton diameter was largest in the deep layers of area 25, suggesting an efficient transmission system from the HPC. The robust projections from the HPC terminated most densely in the superficial layers of area 25. The HPC pathway also innervated some inhibitory neurons, labeled for the calcium binding proteins calbindin or calretinin in the superficial layers of the ACC, whereas axons innervated parvalbumin inhibitory neurons in the deep layers of the ACC. The findings suggest that area 25 may be a fundamental pathway from the HPC for memory processing and can be a focal point in therapeutic interventions in neurological and psychiatric diseases.

Selective inhibition of 5-hydroxytryptamine by parachlorophenylalanine (PCPA) is able to restore sexual receptivity in female rhesus monkeys made unreceptive by bilateral adrenalectomy. PCPA in the doses used reduces the levels of 5-hydroxyindoleacetic acid (5HIAA) in the cerebrospinal fluid to 40 per cent of the normal oestradioltreated condition. Both the increased sexual receptivity and the lowered 5HIAA levels "in the CSF are in turn reversed by 5-hydroxytryptophal (5HTP), the irrmediate precursor of 5HT and the substance whose synthesis is inhibited by PCPA. 5HTP on its own reduces sexual receptivity and increases 5HIAA levels in the CSF of ovariectomised, oestradiol-treated (but otherwise intact) female rhesus monkeys. A substance other than an adrenal androgen has therefore been shown to restore sexual receptivity in adrenalectomised female monkeys . Testosterone propionate and oestradiol benzoate both lower the turnover rates of 5HT in the brains of ovariectomised female monkeys, as measured by the 2 hour probenecid test. Taken together, these findings suggest that adrenal androgens could act on specific sites in the female monkey brain via 5HT-containing neural systems, to control (or at least influence) sexual receptivity. All the results of administering oestradiol to ovariectomised monkeys in these experiments are consistent with the established roles of this hormone in female sexual attractiveness and in the gonadotrophin- controlling systems of the hypothalamo-hypophyseal axis. In contrast to these findings on 5HT and sexual receptivity in female monkeys, no clear role for 5HT- containing neural systems could be demonstrated in the grooming, aggressive or social behaviours of female monkeys. No clear role for 5HT could be demonstrated in the refractory period following ejaculation in male monkeys , or when testosterone replacement is given to castrated male monkeys.

This thesis presents the development and application of methods to assess cognitive markers of emotion and psychological wellbeing in a species of nonhuman primate, the rhesus macaque (Macaca mulatta). In humans, vulnerability to emotional disorders such as anxiety and depression is characterized by particular cognitive profiles, known as cognitive biases. For example, anxious people automatically attend to threat-relevant information, interpret ambiguous information negatively, and have negative expectations of future events. In this thesis, I first describe two treatments that were used prior to cognitive testing to induce positive and negative shifts in inferred affective state in the monkeys (enrichment and a health-check, respectively) and discuss the impact of these treatments on the monkeys’ behaviour and physiology (Chapters 2 and 3). In the first cognitive study (Chapter 4), I present a method that uses eye-gaze to assess the extent to which threatening (versus non-threatening) stimuli capture visual spatial attention when two stimuli are presented at different locations. In the second study (Chapter 5), I present a simple operant touch-screen task to assess the extent to which a threatening distractor stimulus captures attention and impairs performance on an ongoing task when presented at the same location as the taskrelevant stimulus. In the third study (Chapter 6), I present a Go/NoGo touchscreen task to assess judgements about the reward value of ambiguous stimuli. In all of these studies, the two treatments led to different cognitive profiles in the monkeys. Monkeys showed a) automatic capture of attention by threatening stimuli, which was followed by avoidance following the health-check, but not Post-enrichment; b) impaired task performance when a threatening distractor stimulus was presented Post-health-check, and improved performance on these trials Post-enrichment; and c) a more negative judgement about the reward value of ambiguous stimuli Post-health-check versus Post-enrichment. I discuss these cognitive biases in light of available data from humans, and recent work with nonhuman animals. These data indicate that furthering our understanding of primate and other animal psychological wellbeing, may be achieved through the development of measures of cognitive bias, such as those presented here.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / While memory function in primates depends on the integrity of the medial temporal lobe, the contribution of the hippocampal formation (HF) independent of the overlying ventromedial temporal cortices, particularly the entorhinal (ENT) and parahippocampal (PHG) cortices, remains unclear. To address this issue we have prepared groups of rhesus monkeys with ibotenic acid lesions of the HF or aspiration lesions of the ENT or PHG cortices. We then administered behavioral tasks to assess the effects of these lesions relative to normal controls. To test recognition memory, the Delayed Non-Matching to Sample (DNMS) task and the Delayed Recognition Span Task (DRST) were administered. On DNMS, all groups were impaired on both acquisition and 2 and 10 minute delays. The DRST, administered in Spatial, Color and Object conditions, yielded slightly different results. On the Spatial condition, all groups were impaired on both unique and repeated trials of the task. On the Color condition, all groups were impaired on unique trials while only the HF group was impaired on repeated trials. On the Object condition, ENT and PHG groups were only impaired on unique trials, while the HF group was unimpaired. To assess associative memory, two choice reversals were administered in Spatial (SR) and Object (OR) modalities. On the SR task, The HF group was impaired on acquisition and the first of three reversal phases. The ENT group was impaired on all three reversals, and the PHG group was impaired on only the last. On the OR task, HF animals were impaired on all reversals, while ENT animals were impaired on the initial reversal and PHG animals on the last two. These results indicate that damage to the HF alone causes impairments in recognition, spatial processing and object reversal learning. They also indicate that ENT and PHG regions make unique contributions to memory processes as seen in additional impairments on DRST and the inability to perform spatial reversals. Thus impairments previously attributed to hippocampal damage in studies where the ENT and PHG cortices were removed in conjunction with the HF need to be reevaluated in view of additional contributions provided by these cortical regions. / 2031-01-01

Behaving in a complex world requires flexible mapping between sensory inputs and motor outputs. One must be able to make decisions about what actions to take based on a wide variety of inputs. This presents a routing problem: brain areas involved in decision making must receive information encoded by different sensory neurons in different situations. In this thesis I investigate this routing problem using two variations of the random dot motion task which require flexible routing. In the first, a single random dot motion task appears in different locations on different trials. Recording from the lateral intraparietal area (LIP) revealed several neural features which varied with stimulus location. A second task made it possible to disentangle routing from other signals, by separating the time of routing from the onset of motion and decision making. In this second task, a visual cue indicated the location at which relevant motion would appear. After the cue was extinguished, two random dot motion patches appeared. An informative patch appeared at the cued location, and an uninformative patch appeared at another location. Comparison of these two tasks revealed three location dependent signals at motion onset: a visual signal related to surround suppression, a second suppressive signal that may set the amount of evidence required for decision making, and a 12-20 hertz oscillation in firing rate. This oscillation appears to be a signature of flexible information routing. It appears at motion onset when the motion stimulus varies in location unpredictably; it appears at cue onset when a spatial cue indicates the location information must be routed from; and it does not appear when stimulus location is fixed and flexible routing is not required. Future work on this project will eventually require tools which are not well developed for use in rhesus macaques. The final chapter describes two projects which attempt to address this problem, one through the use of optogenetics in monkeys and the other by adapting an established monkey behavioral task for use in mice.

archives@tulane.edu / Background: Human Immunodeficiency Virus-1 (HIV-1) has killed over 35 million and infects 1.8 million new people each year. Antiretroviral therapy (ART), although effective controlling plasma viremia and transmission, does not purge latent or persistent reservoirs necessary to eliminate infection, and must be maintained for life. It is thus imperative to discover therapeutics that provide both lifetime suppression of viral loads and depletion of viral reservoirs. Methods: To harness the immunosurveillance capacity of highly functional and persistent CMV-specific adaptive response, rhesus PBMCs were stimulated with rhCMV peptide pools (IE1, IE2, and pp65) to expand rhCMV-specific T cells. These cells were then genetically modified with retroviral vectors expressing a CD4 extracellular domain linked to T cell intracellular signaling domains that instruct CTL activity, converting them into HIV-specific effector cells. Vectors combine CD4 targeting with an maC46 fusion inhibitor to protect against viral entry. In a reversal of the critical step in the HIV viral lifecycle whereby virus targets new CD4+ host cells using its Env glycoprotein, these genetic modifications redirect host immune responses to target and kill Env expressing infected cells. We hypothesize that continuous stimulation of CD4-CAR T cells through their rhCMV-specific TCR will maintain activated T effector memory CTL capable of targeting HIV infected cells. Results: We find that autologous rhPBMCs can be expanded ex vivo with rhCMV peptides up to therapeutically relevant numbers for adoptive transfer. This rhCMV-specific T cell expansion enriches cells in a phenotype consistent with T effector memory differentiation. Following genetic modification and adoptive transfer, cells reach peak expansion at seven days post infusion into ART suppressed or unsuppressed SHIV infected Rhesus Macaques. We observe these cells capable of persisting in vivo for at least 2 years following reinfusion. Furthermore, these cells are maintained in vivo in an effector memory phenotype throughout the duration they were analyzed. Despite this, SHIV plasma viral loads remain unchanged. Conclusion: These studies establish use of rhCMV-specific T cells as an effective way to produce persistent genetically modified cells targeting SHIV. Future studies will need to further increase in vivo expansion, protection, and CTL activity as viral loads remain detectable. / 1 / Nathan Michel Johnson

Human and non-human primates (NHP) undergo age-related cognitive decline beginning as early as middle-age, even in the absence of an underlying pathology or disease. Growing evidence indicates that an increase in white mater pathology related to rising chronic levels of inflammation may be key contributors to age related cognitive decline. Curcumin (CUR), the active ingredient in turmeric, is a polyphenol nutraceutical with potent anti-inflammatory and antioxidative effects. Several ongoing research studies are underway to explore this potential anti-aging compound. For the first time in a rhesus monkey model of aging, we studied the effects of CUR supplementation on cognition and inflammation. Baseline MRI, blood, CSF and cognitive data were collected for all monkeys. Monkeys were fed daily doses of 500mg of CUR or a vehicle control over 18-months during which three rounds of a battery of cognitive testing was performed along with regular collection of blood, CSF and MRI. Following completion of this testing and specific to this thesis, monkeys were further tested on object discrimination, object and spatial reversal tasks. No significant differences were observed between groups in object discrimination task performance. CUR treatment improved performance on object reversal testing, with treated monkeys making fewer perseverative type errors. At the completion of behavioral testing, serum samples from two-year post treatment onset and brain tissue were harvested for post-mortem analysis of markers of inflammation. The density and morphology of microglia, the resident immune cells of the brain, were examined using immunohistochemistry on serial coronal sections through frontal cortical gray (A46, A25) and while matter (FWM, CC, and CngB) regions that are implicated in cognitive aging. We demonstrated that CUR treatment did not significantly alter the density of presumably immune-activated microglia expressing the MHC class II marker LN3. However, treatment did affect morphological features of microglia specifically within the while matter. Within the white matter, CUR treatment was associated with a significant increase in microglial ramification, evidenced by greater process length, number of nodes and convex-hull area and volume. Increased microglial ramification suggests greater likelihood of microglial surveillance within the white matter associated with CUR treatment. No significant group differences however were observed in the select serum cytokine levels quantified using multiplex ELISA, or in inflammatory gene expression in brain tissue measured with qRT-PCR. While our findings show the benefit of CUR supplementation on cognitive performance and its effects on microglial morphology, further study is needed to understand the precise changes that CUR supplementation may have on inflammation.