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The medial temporal hippocampal system exhibits high plasticity and is influenced by behavioral and socioenvironmental factors. Animal models have demonstrated the neuroplasticity of this system through environmental enrichment, exercise, and chronic stress. Human studies have replicated these findings, highlighting the positive impact of exercise and cardiorespiratory fitness, as well as the detrimental effect of chronic stress on brain structure. However, limited research has explored the differences between young and older adults in extrahippocampal regions of the medial temporal lobes. Additionally, the impact of psychosocial stressors such as perceived discrimination and moderating factors like sense of control on this brain system remains understudied. Furthermore, there is a lack of investigation into the neurobiological consequences of perceived discrimination as a significant psychosocial stressor on neurocognitive health. The goals of this dissertation project were to investigate the role of cardiorespiratory fitness and perceived discrimination on medial temporal hippocampal system neurocognitive integrity in humans. I had two hypotheses. First, higher cardiorespiratory fitness would correlate with higher extrahippocampal cortical thickness in young and older adults. Second, a greater number of experiences of perceived discrimination would correlate with reduced amygdala and anterior hippocampus volume in older adults. Two experiments were conducted to assess the impact of behavioral and socioenvironmental factors on medial temporal hippocampal system structure. In the first experiment, cross-sectional data were collected from two randomized clinical controlled trials (n = 100; 56 young adults and 44 older adults). In the second experiment data were collected from two pilot studies (n = 36). Finally, we discuss how the built and social environment, artificially created or modified areas where individuals live, work, or engage in recreational activities, can facilitate or impede behaviors that benefit brain health such as physical activity to increase cardiorespiratory fitness or social engagement. Experiment 1 used structural MRI and assessed cardiorespiratory fitness in sedentary young and older adults. The primary objective was to examine the relationship between cardiorespiratory fitness and entorhinal, parahippocampal, and perirhinal cortical thickness. The results indicated a positive association between cardiorespiratory fitness and cortical thickness in these regions, specifically in the left hemisphere of young adults. However, this relationship was not observed in older adults. Experiment 2 focused on the association between participants' perceived social discrimination experiences and amygdala and anterior hippocampus volume. Additionally, the moderating role of locus of control, a measure of self-efficacy, was examined. The findings revealed that higher levels of perceived social discrimination were associated with reduced amygdala and anterior hippocampus volume. Moreover, higher levels of locus of control attenuated the relationship between perceived social discrimination and these brain regions. The third project integrated the aforementioned ideas within the context of the built and social environment. The discussion centered around how systemic barriers within the environment can either support or hinder engagement in health-promoting behaviors like cardiorespiratory fitness. The importance of considering the built and social environment in clinical interventions was highlighted, with a focus on improving translation of research findings to benefit research participants. Factors such as safety, access to green spaces, and social connectedness were explored, particularly in relation to universal design and its potential to enhance healthy aging and accessibility while addressing systemic racism and structural barriers. These chapters provide evidence to inform policymakers, clinicians, and neuroscientists about the broader implications of clinical research in communities. By considering the impact of clinical interventions on the built and social environment, this work aims to promote health and well-being beyond laboratory settings.

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. / 2999-01-01

Adult hippocampal neurogenesis—a unique form of plasticity in the dentate gyrus (DG)—is regulated by experience, and when manipulated can have specific effects on behavior. Different methods have been used over the years to study new neurons’ functional role in the hippocampus, many of which focus on ablating neurogenesis. While ablation methods can test the necessity of adult-born granule cells (abGCs) for behavior, these techniques remove all abGCs from the circuit and thus do not allow one to determine which properties of abGCs are required for behavior. Such information is required to understand the mechanism of their action. Thus, new strategies are needed to determine what properties of young abGCs allow them to distinguish themselves from their mature counterparts and uniquely impact behavior. Recent hypotheses have suggested that the enhanced synaptic plasticity exhibited by 4–6-week-old abGCs allows them to uniquely contribute to hippocampal circuit function, and thus behavior. The primary goal of this thesis was to explore the contribution young abGCs’ heightened synaptic plasticity makes to hippocampal function. This was achieved using a transgenic mouse approach that allowed for the conditional deletion of NR2B from abGCs. Overall, iNR2BNes mice generated the same number of new neurons in adulthood as control mice at baseline. These neurons survived and matured with only a slight reduction in dendritic complexity. However, a potentially important electrophysiological property of these neurons—their enhanced synaptic plasticity—had been eliminated. From an electrophysiological standpoint, iNR2BNes mice resemble mice with ablated neurogenesis, while from all other neurogenic standpoints examined they most closely resemble wild-type mice. Consequently, these mice provided a novel model to test the extent to which young abGCs’ enhanced plasticity contributes to hippocampal-dependent behaviors. The results reveal that eliminating NR2B-containing NMDA receptors from abGCs does not alter baseline anxiety or antidepressant (AD)-like behavior. However, iNR2BNes mice differed from controls in measures of cognitive function. These mice were able to learn in the contextual fear conditioning test, but were impaired in the more difficult contextual fear discrimination test. Mice also exhibited a decreased novelty exploration phenotype that impaired their performance in the novel object recognition test. Together, these results indicate that the NR2B-dependent heightened plasticity exhibited by 4–6-week-old abGCs is necessary for responses to novelty and fine contextual discrimination, but does not contribute to baseline anxiety or emotionality. AD treatment increases levels of adult neurogenesis in the hippocampus, and these newborn neurons have been shown to be necessary for some of the behavioral effects of ADs seen in rodents. In addition, the maturation timeline of adult neurogenesis correlates with the onset of behavioral responses to ADs. ADs also enhance a neurogenesis-dependent form of long-term potentiation (LTP) in the DG evoked by medial perforant path stimulation under intact GABAergic tone called ACSF-LTP. Thus, a potential mechanism by which abGCs may contribute to AD behavioral efficacy is by providing extra plastic units to the DG circuit. This theory was tested by once again using the mouse line in which NR2B can be conditionally deleted from abGCs in the DG. Here, we found that deletion of the NR2B subunit significantly attenuated a neurogenesis-dependent behavioral response to fluoxetine in the novelty suppressed feeding test, and additionally blocked fluoxetine’s ability to enhance young abGCs’ maturation and subsequent integration into the hippocampal network. This suggests that eliminating abGCs’ enhanced plasticity decreases their ability to influence DG output resulting in an AD response that is less robust than seen in control mice. Control experiments revealed the specificity of this effect, as NR2B deletion did not impact the effect of fluoxetine in a neurogenesis-independent behavioral assay (tail suspension test) or in an assay that was insensitive to fluoxetine in this strain of mice (elevated plus maze). Our efforts to isolate the contribution of abGCs’ unique physiology from the neurogenic effects of fluoxetine were not entirely successful as the results presented here also revealed slight group differences in neurogenesis between control mice and mice lacking NR2B in young neurons. Yet, this data still supports the idea that fluoxetine increases the ability of abGCs to participate in DG output by increasing the chance that new neurons will be activated during DG stimulation. This may be achieved either by increasing their overall number, increasing their potential to make synaptic connections, or increasing their ability to strengthen their connections. However, due to the close link between activity and maturation that appears to be enhanced with fluoxetine treatment, a different approach with greater temporal resolution is needed to separate the neurogenic effects of fluoxetine from the physiological contribution abGCs make to hippocampal output. With this in mind, a mouse line in which abGCs could be temporally inhibited was also generated. Cellular and behavioral characterization of mice conditionally expressing hM4Di—a mutated muscarinic acetylcholine receptor that is insensitive to endogenous acetylcholine, but can be activated by the biologically inert, highly bioavailable compound, clozapine N-oxide (CNO)—has begun. Results show that acute CNO treatment in mice expressing this designer receptor exclusively activated by a designer drug (DREADD) in DG granule cells can impair encoding of contextual fear memory. Chronically treating these mice had an anxiogenic effect in the open field test, but otherwise anxiety and emotionality in these mice were comparable to controls. Chronic CNO treatment in mice expressing hM4Di in young abGCs effectively decreased these cells’ dendritic complexity, but did not alter proliferation or early survival. Thus, hM4Di DREADDs represent a novel tool that can be used to modulate activity of neurons in a temporally restricted manner, allowing for both acute and chronic manipulations of hippocampal granule cells. The experiments put forth in this thesis will highlight the importance of abGCs enhanced plasticity. The utility as well as potential pitfalls of the mouse models used here to test theories of abGC function will also be explored. Hopefully this analysis will provide an improved framework in which future experiments can be developed with the aim of uncovering novel insights into the hippocampal circuitry that underlies learning and memory and discovering new strategies for the treatment of neurological and psychiatric disorders.

by Wong Ho Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 107-129). / Abstract --- p.i / List of Abbreviations --- p.ii / Contents --- p.iii / Chapter Chapter 1. --- Introduction / Chapter 1.1 --- Introduction of aging in central nervous system --- p.1 / Chapter 1.2 --- Introduction of hippocampus / Structure of the hippocampus --- p.4 / Function of hippocampus --- p.6 / Chapter 1.3 --- A literature review of aging in hippocampus / Cell loss in aging --- p.8 / Ultrastructural changes in aging --- p.9 / Changes in neurotransmitter system --- p.10 / Neuroglial change --- p.11 / Change in potentiation --- p.13 / Chapter 1.4 --- A literature survey of Nitric Oxide Synthase (NOS) / General introduction of Nitric Oxide Synthase --- p.15 / Introduction of nNOS --- p.15 / Introduction of iNOS --- p.16 / Introduction of eNOS --- p.17 / Similarities and differences among isoforms --- p.18 / Role of NO/NOS in neurotransmission --- p.19 / Role of NO in neurotoxicity --- p.23 / Chapter 1.5 --- Aim of study --- p.25 / Chapter Chapter 2. --- Change of nNOS in aging / Chapter 2.1 --- Purpose and approach --- p.27 / Chapter 2.2 --- Basic principle of the techniques / Basic principle of immunohistochemistry --- p.28 / Basic principle of RT-PCR --- p.28 / Chapter 2.3 --- Experimental procedure / nNOS immunohistochemistry --- p.32 / RT-PCR of nNOS --- p.34 / Chapter 2.4 --- Result / nNOS immunohistochemistry --- p.38 / RT-PCR of nNOS --- p.44 / Chapter Chapter 3. --- Expression of iNOS in aging / Chapter 3.1 --- Purpose and approach --- p.50 / Chapter 3.2 --- Experimental procedure / iNOS immunohistochemistry --- p.50 / RT-PCR analysis of iNOS --- p.51 / Chapter 3.3 --- Result / iNOS immunohistochemistry --- p.52 / RT-PCR analysis of iNOS --- p.56 / Chapter Chapter 4. --- Verification of the RT-PCR product of iNOS / Chapter 4.1 --- Purpose and approach --- p.58 / Chapter 4.2 --- Basic principle --- p.58 / Chapter 4.3 --- Experimental procedure / Elution of PCR product from PAGE gel --- p.60 / Restriction digestion of the eluted PCR product --- p.61 / Chapter 4.4 --- Result --- p.62 / Chapter Chapter 5. --- Identification of the iNOS-positive cells / Chapter 5.1 --- Purpose and approach --- p.64 / Chapter 5.2 --- Experimental procedure --- p.64 / Chapter 5.3 --- Result --- p.65 / Chapter Chapter 6. --- Quantitation of astrocyte in aging hippocampus / Chapter 6.1 --- Purpose and approach --- p.67 / Chapter 6.2 --- Experimental procedure --- p.68 / Chapter 6.3 --- Result --- p.69 / Chapter Chapter 7. --- Detection of apoptosis in aging / Chapter 7.1 --- Introduction of apoptosis --- p.74 / Chapter 7.2 --- Purpose and approach --- p.75 / Chapter 7.3 --- Basic principle --- p.76 / Chapter 7.4 --- Experimental procedure / TUNEL method --- p.77 / DNA gel electrophoresis --- p.78 / Chapter 7.5 --- Result / TUNEL method --- p.80 / DNA gel electrophoresis --- p.82 / Chapter Chapter 8. --- Discussion / Chapter 8.1 --- Pattern of neuronal NOS in aging / Localization of nNOS --- p.84 / Decrease in staining of nNOS in the hippocampus during aging --- p.87 / No change in nNOS mRNA level --- p.88 / nNOS in aging - past and present works --- p.89 / Implication of the result --- p.91 / Chapter 8.2 --- Increased iNOS expression in aging / Neurotoxicity of iNOS --- p.93 / Circumstances of iNOS expression --- p.95 / Discussion of the present study --- p.96 / Chapter 8.3 --- Detection of apoptosis in aging --- p.103 / Chapter Chapter 9. --- Conclusion --- p.106 / Biblography --- p.107 / Appendix --- p.130 / Acknowledgements --- p.134

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 3 uppsatser.