Spatial navigation in humans correlates with activity of cells in hippocampus that respond when we traverse specific locations in our environment. Hippocampal pyramidal cells in rodents called "place cells" may contribute to episodic memory by encoding location in physical space. Place cells display plasticity by "remapping" or altering their firing rates and patterns of activity in response to changes in spatial environment. Impaired remapping may underlie age-related deficits in spatial memory tasks. Using in vivo high-density electrophysiology to record place cell activity in awake, behaving rats, we tested the hypothesis that CA3 neuron hyperactivity in aged animals could be normalized by pharmacotherapy. Results show that acute, systemic administration of low dose levetiracetam and sodium valproate ameliorates deficits in the aged hippocampal network by reducing firing rates, decreasing place field area, and increasing the spatial selectivity of CA3 place cells. We then tested the hypothesis that place cell activity, field area, and spatial selectivity may be an indicator for therapeutic enhancement of spatial memory in young adult rats. The results demonstrate that α5IA enhances hippocampal-dependent spatial memory as measured by the location novelty recognition task in rats, consistent with the previously established action of α5IA as an enhancer of spatial memory in the water maze test. Electrophysiological recordings on the same animals carried out in parallel demonstrate that α5IA increases place cell firing rates, reduces field area, and increases spatial selectivity. Together, these results suggest that reducing place field area and enhancing spatial selectivity correlate with the age-independent therapeutic improvement of spatial memory. The increase in place cell firing rates by α5IA likely results from its known action as a negative allosteric modulator of α5-subunit-containing receptors (α), which are located extrasynaptically at the base of dendritic spines on CA1 and CA3 pyramidal cells. Thus, to potentially target extrasynaptic tonic inhibition in the hippocampus, we synthesized and validated two α specific miRNAs as a platform for future attempts to improve spatial memory in young adult and aging animals via molecular genetics.

Episodic memory is an imperfect record of events arranged in time and space. When dealing with the storage of memories, the brain is faced with a predicament: it must retain an acceptably faithful facsimile of transpired events while simultaneously permitting inevitable modifications to accommodate learning new information. In this thesis, I first review contemporary theories of how memories can be stored in a neural substrate within the hippocampus, particularly in regards to how they can be arranged in time. Next, using in vivo calcium imaging, I detail how hippocampal “time cell” sequences could support encoding of behavioral events along multiple temporal dimensions. In this study, I trained mice to run in place on a treadmill, thereby measuring single-cell activity in CA1 as a function of time. Neurons in CA1 formed sequences, each cell firing one after another as if forming a scaffold upon which memories can be laid. These sequences were relatively well-preserved over a period of four days, satisfying the first requirement that information must be stored for a memory to persist. Additionally, these sequences also changed over time, which may be revealing a mechanism for how memories can change over time to assimilate new information. In the next experiment, I describe a collaborative project where we used immunohistochemistry, optogenetics, and calcium imaging to investigate the long-term dynamics of a fear memory. After mice initially associated a context with an aversive stimulus, they were placed in the same context over two days where they gradually relearned that the context was harmless. This produced molecular and neurophysiological signatures consistent with memory modification. However, after re-triggering fear, mice reverted to fearful expression with commensurate neural correlates. Using optogenetics, these behaviors could also be reliably suppressed. Finally, I conclude by synthesizing these findings with hippocampal literature on sequence formation and consolidation by proposing a holistic view of how these features can support episodic memory.

Cognitive aging has profound effects on the hippocampus, a brain region that is critical for episodic memory formation and spatial navigation. Accurate episodic memory formation requires pattern separation, a neurocomputational process that orthogonalizes similar stimulus input into distinct neural representations and can be examined using behavioral mnemonic discrimination paradigms in humans. Age-related impairment in hippocampally-dependent cognition emphasizes the importance of identifying modulators of hippocampal plasticity. Critically, studies in older adults have demonstrated that greater cardiorespiratory fitness (CRF) is associated with greater volume of the hippocampus, mitigated age-related decline in spatial mnemonic discrimination, and better visuospatial memory. Nonetheless, how CRF modulates the underlying structural and functional neural correlates of mnemonic discrimination and spatial navigation in cognitive aging remains unknown. Therefore, the overall objective of this dissertation was to examine CRF as a modulator of hippocampal memory system structure and function, specifically regarding the hippocampally-dependent processes of mnemonic discrimination and spatial navigation, in cognitively healthy older adults. In a series of three experiments, we tested the central hypothesis that CRF enhances hippocampal plasticity and modulates the underlying neural correlates of mnemonic discrimination and spatial navigation in older adults. Data for these three experiments came from two studies. In the first, young adults (ages 18-35 years) and older adults (ages 55-85 years) underwent high-resolution fMRI to examine hippocampal subfield blood-oxygenation level-dependent (BOLD) signal during mnemonic discrimination. In the second, older adults (ages 60-80 years) underwent whole-brain, high-resolution fMRI to examine whole-brain BOLD signal during spatial navigation. In both studies, participants performed a submaximal treadmill test to estimate CRF and underwent high-resolution structural MRI to measure hippocampal subfield volumes as markers of neuroplasticity in the hippocampus. The primary goal of Experiment 1 was to examine the prediction that CRF is positively associated with mnemonic discrimination task performance and dentate gyrus (DG)/CA3 volume in older adults, given that these hippocampal subfields are thought to support pattern separation. Contrary to our initial prediction, we did not observe a relationship between CRF and mnemonic discrimination task performance or CRF and DG/CA3 volume. Instead, we observed a significant positive relationship between CRF and the volume of another hippocampal subfield, the bilateral subiculum, in older adult women, but not men. The primary goal of Experiment 2 was to examine the prediction that mnemonic discrimination-related BOLD signal in the hippocampal subfields is modulated by aging and CRF in young and older adults. In line with our initial prediction, there was a significant difference between young and older adults in right DG/CA2-3 BOLD signal during mnemonic discrimination task performance. Most importantly, CRF significantly modulated bilateral subiculum BOLD signal in an opposing fashion in young and older adults. The primary goal of Experiment 3 was to extend the current study beyond the function of the hippocampus in isolation and to examine whole-brain activation in association with an ecologically valid task that engages a large network of brain regions including but not limited to the hippocampus. We predicted that CRF modulates BOLD signal activation patterns driven by the employed spatial navigation task, specifically in brain regions in the frontal, parietal, and temporal cortices, and the cerebellum, given that the previously published literature in older adults has suggested that CRF enhances structural integrity in these regions in addition to the hippocampus. Our results demonstrated that CRF is significantly positively associated with BOLD signal in the right cerebellum lobule VIIa Crus I and Crus II, a region that has been implicated in sequence-based navigation. And, consistent with our results from Experiment 2, this relationship was observed in older adult women. Importantly, the findings of these experiments highlight novel targets of fitness-related neuroplasticity in the older adult brain, including the subiculum subfield of the hippocampus and the cerebellum lobule VIIa Crus I and Crus II. Furthermore, these findings underscore the importance of examining sex as a modulating factor of fitness-related neuroplasticity.

Hippocampal neurogenesis is linked to the onset, progression and remission of major mood disorder such as anxiety and depression. Neurogenesis is the process by which new neurons are formed in the brain. Mitochondria mediate cellular adaption and provide energy to support growth of new neurons. Chronic stress and mood disorders have been associated with impairments in mitochondrial function and neuronal growth. Individuals experiencing stress and mood disorders reportedly use cannabis as a means to self-medicate. The impacts of cannabis on stress-related effects on hippocampal neurogenesis and mitochondria are vastly unexplored. To investigate these effects we generated an in vitro model of hippocampal neuron stress by treating HT22 cells with corticosterone, the major effector molecule of stress in rodents. We first characterized the impacts of corticosterone on markers of neurogenesis and mitochondrial function in HT22 hippocampal cells. We found that corticosterone decreased gene markers of neurogenesis, mitochondrial biogenesis, content, dynamics and decreased mitochondrial membrane potential. Corticosterone also decreased levels of antioxidant enzymes but did not alter levels of reactive oxygen species (ROS) or elicit lipid peroxidation. We then investigated with potential impacts of cannabis components, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on corticosterone-induced stress. Individually, THC and CBD decreased markers of neurogenesis, dysregulated mitochondrial dynamics and decreased mitochondrial membrane potential. Interestingly, both THC and CBD increased a marker of mitochondrial biogenesis. Finally, we co-treated HT22 cells with corticosterone and THC or CBD to interrogate the impacts of THC and CBD on corticosterone-induced alterations. Our results indicated THC and CBD had no effect on corticosterone-related reductions in neurogenesis markers or mitochondrial membrane potential. However, THC demonstrated a rescuing effect on a marker of mitochondrial biogenesis and CBD normalized a marker of mitochondrial fission; both of which were decreased with individual corticosterone treatments. This thesis ultimately identifies some of the pathways THC and CBD may impact stress response in relation to neurogenesis and mitochondria. / Thesis / Master of Science (MSc) / Neurogenesis is a process that describes the production of new nerve cells in the brain. It mainly occurs during early life, but persists in a central brain structure responsible for learning and memory, known as the hippocampus, throughout our lives. This active brain structure relies on the function of certain organelles called mitochondria, which are the primary cellular energy producers and promote nerve cell production. Mood disorders, such as anxiety and depression, may result as a consequence of impaired hippocampal neurogenesis. Evidently, people suffering from anxiety and depression turn to cannabis use for management and treatment of their mood disorders. Considering cannabis has been shown to affect neurogenesis and mitochondrial function, our primary objective was to explore its effects on hippocampal neurogenesis by focusing on mitochondrial function, in the context of stress. We demonstrate that components found in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), alter the stress-induced changes in mitochondrial functions related to neurogenesis, suggesting that cannabis may play a role in protecting nerve cells.

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