Exercise is emerging as a promising low-cost intervention to mitigate age-related memory decline and promote successful aging. Aerobic exercise training enhances cardiorespiratory fitness (CRF) and improves integrity of the medial temporal lobe (MTL) memory system. The hippocampus, a brain region located within the MTL, is critically involved in episodic and spatial memory formation, including spatial navigation, and demonstrates subfield-specific plasticity in response to aerobic exercise among both animals and young adult humans. Yet it remains unclear whether hippocampal subfield-specific exercise training and CRF effects also extend to older adults. Another modulator of structural and functional integrity of the MTL is chronic stress. Importantly, chronic stress was shown to predominantly impact brain regions such as the hippocampus and associated cognitive functions, including episodic memory, that are highly vulnerable to the effects of chronic stress and decline with age. Allostatic load (AL), or the integrative biological dysregulation of multiple biological systems resulting from chronic stress, is associated with poorer cognition, and reduced structural brain integrity. Black Americans were shown to have high burden of AL compared to non-Hispanic White Americans, and this was associated with reports of greater perceived discrimination, a salient psychosocial stressor, among the former group. Although race is a sociocultural construct, Black-White disparities exist in cognitive task performance, and risk of Alzheimer’s disease (AD) and dementia, with Black Americans displaying significantly worse cognitive task performance scores, and a greater likelihood to be diagnosed with AD and dementia compared to non-Hispanic White Americans. Thus, greater AL and discriminatory experiences in Black compared to non-Hispanic White older adults may underlie the racial disparity in neurocognitive aging. The goal of this dissertation was to examine the opposing impact of chronic stress and exercise on neurocognitive aging. This was accomplished by 1) investigating aerobic exercise intervention effects on hippocampal subfield volume and fMRI activity during spatial navigation, a complex cognitive function that declines with age and that is, in part, supported by the MTL (Project 1), 2) examining the effect of AL as a cumulative, physiological stress measure on neurocognitive aging (Project 2), and 3) examining the effect of chronic psychosocial stress through the lens of social discrimination on the functional connectivity of the MTL subsystem of the default mode network, a resting state network that has been linked to episodic memory (Project 3). The secondary aim of this dissertation was to look at the effect of AL (Project 2) and social discrimination (Project 3) on racial neurocognitive disparities in cognitively intact older Black and non-Hispanic White adults. In the first project, data from two randomized controlled clinical trials of aerobic exercise intervention targeting healthy, initially sedentary adults aged 55-85 years were used to examine the effect of exercise training and exercise-related CRF on the hippocampal integrity on the subfield level. Both randomized controlled trials randomly assigned participants to either: aerobic exercise group or active control group and underwent baseline and end-of-study fitness testing, cognitive testing, and high resolution structural and functional MRI. The first objective of this project aimed to test whether aerobic exercise training increases CRF level, which, in turn, increases anterior hippocampal subfield volume and/or attenuates volumetric decline among older adults undergoing aerobic exercise training compared to those in the active control group. Partially supporting our prediction, results displayed that following the period of the 12-week exercise intervention, the active control group but not the aerobic exercise group showed a right dentate gyrus (DG) head volumetric decline that was trending toward statistical significance. Additionally, a positive significant association between changes in CRF and left subiculum (SUB) head volume following the exercise intervention among women was found. The second objective sought to examine whether aerobic exercise intervention modulates the activation in the hippocampus in a subfield-specific manner during virtual reality navigation task performance, particularly modulating activation in the SUB subfield. Consistent with our structural results an increase in CRF was associated with a decrease fMRI activity in the left SUB. Whole-brain analysis during virtual reality navigation task performance showed that an increase in CRF was associated with a decrease in fMRI activity in the cuneus and right middle frontal gyrus, both brain regions that repeatedly display activation during virtual navigation. In the second project, existing data from the Framingham Heart Study (FHS) was used. Cognitively intact men and women, who identified as either Black or African American from the first multiracial Omni group 1 cohort (OMNI1), or White non-Hispanic from the second-generation cohort (Gen2), and were native English speakers, were included in the study. AL was calculated using the values for 10 biomarkers available in the FHS database for the two cohorts studied that are biomarkers for immune, metabolic, and cardiovascular system function. The objective of this project sought to test the prediction that AL correlates with cognitive function and brain structures, particularly hippocampal volume. We additionally sought to examine the secondary prediction that AL mediates the relationship between race and cognitive task performance and structural brain integrity, in age- sex- and education matched racial groups of cognitively intact older adults after controlling for quality of education, cardiovascular-related comorbidities and depression in the FHS cohorts. Results demonstrated that there was no significant correlation between AL and cognitive and brain volumetric measures, however there were significant Black-White disparities in cognitive task performance in verbal and visual learning and memory, abstract reasoning and attention span. These Black-White cognitive task performance disparities existed even after controlling for quality of education, and cardiovascular-related comorbidities. Although there was no significant racial disparity in the mean score of AL index, our physiological stress measure, AL partially explained the observed Black-White disparity in cognitive task performance in verbal learning and memory. Importantly the observed AL effect was not driven by the cardio-metabolic component biomarkers that are part of the AL index, known to overlap with cardiovascular risk factors, but rather, the AL index drove this effect as a whole. There were no racial disparities in brain volumetric measures after controlling for cardiovascular-related comorbidities. Furthermore, there were no sex differences in the effect of AL in any of our neurocognitive outcome measures. In the third project, cognitively intact older Black and White adults (aged 55-80 years) were recruited from the greater Boston area. To measure perceived social discrimination, participants were asked to complete the Experiences of Discrimination questionnaires. Additionally, participants underwent fMRI scanning to examine the functional connectivity of resting-state brain networks. This project sought to test the prediction that greater perceived everyday discrimination would be associated with alteration of resting state functional connectivity, particularly in the MTL subsystem. Results showed that greater perceived everyday discrimination predicted stronger resting-state connectivity between the MTL subsystem, and a cluster located in the right control network, suggesting that perceived discrimination, a psychosocial stressor, may cause functional alteration in brain networks supporting memory and cognitive control in older adults. In conclusion, findings of these studies suggest a neuroprotective effect of exercise, where exercise may attenuate aging-related decline in the structure and function of hippocampal subfields, especially among women, and possibly by targeting the SUB. Furthermore, findings of these studies suggest stress related mechanisms underlying neurocognitive integrity, particularly in the MTL memory system.

Theoretical models of information storage in the brain have suggested that neurons may undergo an experience-dependent tuning or sharpening of their representations in order to maximize the amount of information that can be stored. Changes in the tuning profiles of neurons have been demonstrated to occur when animals must learn perceptual discriminations, however, whether similar changes occur in the absence of behavioral demands is unclear. To address these questions, the activity of simultaneously recorded medial temporal lobe (MTL) neurons was studied in relation to a passive visual recognition memory task. The structure of this task was such that it allowed for a comparison between novelty related responses as well as tuning properties of individual neurons. A total of 565 well isolated single neurons were recorded. The first contribution of this dissertation is the finding of a dissociation between different medial temporal lobe regions such that neurons in temporal area F (TF), but not perirhinal cortex (PRC) or the hippocampus, show an experience-dependent change in their stimulus selectivity. This finding indicates that tuning of stimulus representations may be an effective mechanism for maximizing information storage in some brain regions. The absence of stimulus tuning in higher level association regions (i.e. TF and PRC) suggests that tuning in these regions may be disadvantageous due to the need to construct unified representations across sensory modalities. A complimentary question to the question of network storage capacity is how networks avoid saturation in the connections between neurons. The second contribution of this dissertation is the finding that there exists a decrease in the magnitude of the short time scale correlations between pairs of neurons; suggesting that networks reduce the number of connections between neurons as a stimulus becomes familiar. Gamma oscillations have been proposed to be the mechanism by which groups of neurons coordinate their activity. However, network coordination has only been indirectly measured. The final contribution of this dissertation is the finding that the magnitude of gamma oscillations is strongly correlated with enhanced magnitude of correlations between neurons.

Convergent evidence suggests that the perirhinal cortex (PRC) is involved in perception, in addition to long-term memory, by representing higher-order object feature conjunctions. Recent functional magnetic resonance imaging (fMRI) investigations have shown greater PRC activity during the processing of objects with a higher versus lower degree of features in common, but notably, these studies have been limited to examining only two levels of feature overlap. To address this, we scanned neurologically healthy participants with fMRI during a 1-back working memory task for objects that possessed a very low, low, medium or high degree of feature overlap. Somewhat consistent with previous findings, trends towards greater PRC activity for high versus medium feature overlap objects, and for semantically identical compared to semantically different objects were observed. However, other aspects of our data, including diminished PRC activity during medium versus low feature overlap objects, are difficult to interpret and require further investigation.

Convergent evidence suggests that the perirhinal cortex (PRC) is involved in perception, in addition to long-term memory, by representing higher-order object feature conjunctions. Recent functional magnetic resonance imaging (fMRI) investigations have shown greater PRC activity during the processing of objects with a higher versus lower degree of features in common, but notably, these studies have been limited to examining only two levels of feature overlap. To address this, we scanned neurologically healthy participants with fMRI during a 1-back working memory task for objects that possessed a very low, low, medium or high degree of feature overlap. Somewhat consistent with previous findings, trends towards greater PRC activity for high versus medium feature overlap objects, and for semantically identical compared to semantically different objects were observed. However, other aspects of our data, including diminished PRC activity during medium versus low feature overlap objects, are difficult to interpret and require further investigation.

<p>Memories are not veridical representations of the environment. Rather, an individual's goals can influence how the surrounding environment is represented in long-term memory. The present dissertation aims to delineate the influence of reward and punishment motivation on human declarative memory encoding and its underlying neural circuitry. Chapter 1 provides a theoretical framework for investigating motivation's influence on declarative memory. This chapter will review the animal and human literatures on declarative memory encoding, reward and punishment motivation, and motivation's influence on learning and memory. Chapter 2 presents a study examining the behavioral effects of reward and punishment motivation on declarative memory encoding. Chapter 3 presents a study examining the neural circuitry underlying punishment-motivated declarative encoding using functional magnetic resonance imaging (fMRI), and compares these findings to previous studies of reward-motivated declarative encoding. Chapter 4 presents a study examining the influence of reward and punishment motivation on neural sensitivity to and declarative memory for unexpected events encountered during goal pursuit using fMRI. Finally, Chapter 5 synthesizes these results and proposes a model of how and why motivational valence has distinct influences on declarative memory encoding. Results indicated that behaviorally, reward motivation resulted in more enriched representations of the environment compared to punishment motivation. Neurally, these motivational states engaged distinct neuromodulatory systems and medial temporal lobe (MTL) targets during encoding. Specifically, results indicated that reward motivation supports interactions between the ventral tegmental area and the hippocampus, whereas, punishment motivation supports interactions between the amygdala and parahippocampal cortex. Together, these findings suggest that reward and punishment engage distinct systems of encoding and result in the storage of qualitatively different representations of the environment into long-term memory.</p> / Dissertation

Time-based prospective memory has been found to be negatively affected by aging, possibly as a result of the declining frontal function that often accompanies aging. In the present study we investigated the role of the frontal lobes in prospective memory. Based upon their scores on a composite measure of frontal function, 32 older adults were characterized as possessing high- or low-frontal function, and were then tested on a time-based laboratory prospective memory task. Overall age effects were also assessed and each of the frontal groups was compared to a group of 32 younger adults. High-frontal functioning participants demonstrated better prospective memory than low-frontal functioning participants, and were not distinguishable from younger adults. The results of this study suggest that it is not aging per se that disrupts prospective memory performance, but it is instead the diminished frontal function seen in a subset of older adults.

The perirhinal cortex (PER), which is critical for associative memory and stimulus discrimination, has been described as a wall of inhibition between the neocortex and hippocampus. With advanced age, rats show deficits on PER-dependent behavioral tasks and fewer PER principal neurons are activated by stimuli, but the role of PER interneurons in these altered circuit properties in old age has not been characterized. In the present study, PER neurons were recorded while rats traversed a circular track bidirectionally in which the track was either empty or contained eight novel objects evenly spaced around the track. Putative interneurons were discriminated from principal cells based on the autocorrelogram, waveform parameters, and firing rate. While object modulation of interneuron firing was observed in both young and aged rats, PER interneurons recorded from old animals had lower firing rates compared with those from young animals. This difference could not be accounted for by differences in running speed, as the firing rates of PER interneurons did not show significant velocity modulation. Finally, in the aged rats, relative to young rats, there was a significant reduction in detected excitatory and inhibitory monosynaptic connections. Together these data suggest that with advanced age there may be reduced afferent drive from excitatory cells onto interneurons that may compromise the wall of inhibition between the hippocampus and cortex. This circuit dysfunction could erode the function of temporal lobe networks and ultimately contribute to cognitive aging.

Temporal context memory is memory for the timing of events. People can make temporal judgments based on strategies such as assessing the relative familiarity of events or inferring temporal order from the semantic associations among events. The purpose of present study is to investigate the brain regions that support temporal context retrieval in the absence of such non-temporal strategies (i.e. pure temporal context memory). We used three word familiar phrases (triplets) as stimuli. In study phase, three words were presented quickly one after another in either familiar or scrambled order. Participants were instructed to read aloud each word and try to remember the order of the words. Then they were tested on their memory for the order of the words in each triplet. We propose that memory for the scrambled triplets reflects primarily temporal retrieval for two reasons. First, participants were prevented from using semantic strategies during encoding. Second, the relative familiarity of the words in each triplet was similar and not diagnostic of the order of the words during encoding. Neuroimaging results indicate that temporal context retrieval, memory for the order of words in scrambled triplets, was associated with the hippocampus, parahippocampal cortex, ventromedial prefrontal cortex, retrosplenial cortex, and posterior cingulate, which are consistent with the retrieval of non-temporal context in episodic memory. The results also suggest that temporal context retrieval could rely on familiarity, which was demonstrated by the higher accuracy and greater activation of PRc in familiar phrases and scrambled triplets presented in studied order in the test phase. / Master of Science

The aim of this thesis is to examine the underlying cognitive and neural processes at play during retrieval of temporal and contextual source information. This was assessed across three experimental chapters. In the first experimental chapter, Chapter 2, the neural loci of context associations were assessed. Rats trained on an odour-context association task were given lesions to either the Lateral Entorhinal Cortex (LEC) or sham lesions. After surgery, performance on the odour-context task was assessed. It was hypothesised that memory for previously learned odour-context associations would be impaired following LEC lesions but not sham lesions. The results supported this hypothesis, demonstrating impaired memory for the previously learned odour-context associations in the LEC lesion group compared to the Sham lesion. In Chapter 3, the underlying retrieval processes used to retrieve time and context in human memory was assessed across three experiments. It was hypothesised that time would be remembered accurately using both recollection and familiarity, while correct context memory should rely on recollection alone. Two out of the three experiments supported this hypothesis, demonstrating that temporal information can be retrieved using familiarity in certain instances. The final experimental Chapter 4 used fMRI to extend Chapter 3 and examine whether neural activity would be greater in regions associated with recollection during memory for context, while activity in familiarity-related regions would be higher during memory for time. Results revealed no support for these predictions with no regions linked to recollection showing greater context-related activity, and no regions previously linked to familiarity exhibiting increased activation as temporal information was retrieved. The results are discussed in relation to established recollection and familiarity frameworks and previous work examining the neural substrates supporting memory for time and context.

PDFには「高橋 由佳子」と記載 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21955号 / 医博第4497号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 古川 壽亮, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM