Aging is associated with a decline in the ability to understand what a person is saying in the presence of other sounds. This study investigated the perceptual organization of speech in young (n=20) and older adults (n=20). Four vowels were arranged into six sequences, defined by either continuous or discontinuous first-formant transitions. Participants first made an objective response (choosing the sequence that best matched the one they just heard from a list), followed by a subjective response (indicating if they heard one or two streams of sound). There were significant interactions between age and sequence-type for both objective and subjective responses, respectively. These results suggest that aging affects the ability to perceptually organize speech-sounds and the ability to perceive sequential streaming of speech. These findings are discussed within the context of further enriching what is known about auditory scene analysis, cognitive aging, and sequential streaming.

To examine whether executive attention is affected by perceptual attention, we manipulated executive load in a single experiment. Moreover, we assessed the influence of normal aging on knowledge-driven and attentional sensory-driven processes. Healthy young and older adult participants viewed visual streams of superimposed face/place images at low and high perceptual loads while making sex judgments on each face component and then completing a low or high executive load working memory task. Younger adults exhibited independent behavioural patterns for the executive and perceptual load manipulations due to intact selective attention mechanisms, whereas older adults exhibited interacting processes. This is evidenced by the performance of older adults on concurrent executive and perceptual tasks, which was associated with working memory capacity; whereas younger adults did not exhibit this dependency. Selective attention processes that are independent in younger populations seem to converge in older populations due to decrements in executive and perceptual attention domains.

Aging is associated with a decline in the ability to understand what a person is saying in the presence of other sounds. This study investigated the perceptual organization of speech in young (n=20) and older adults (n=20). Four vowels were arranged into six sequences, defined by either continuous or discontinuous first-formant transitions. Participants first made an objective response (choosing the sequence that best matched the one they just heard from a list), followed by a subjective response (indicating if they heard one or two streams of sound). There were significant interactions between age and sequence-type for both objective and subjective responses, respectively. These results suggest that aging affects the ability to perceptually organize speech-sounds and the ability to perceive sequential streaming of speech. These findings are discussed within the context of further enriching what is known about auditory scene analysis, cognitive aging, and sequential streaming.

To examine whether executive attention is affected by perceptual attention, we manipulated executive load in a single experiment. Moreover, we assessed the influence of normal aging on knowledge-driven and attentional sensory-driven processes. Healthy young and older adult participants viewed visual streams of superimposed face/place images at low and high perceptual loads while making sex judgments on each face component and then completing a low or high executive load working memory task. Younger adults exhibited independent behavioural patterns for the executive and perceptual load manipulations due to intact selective attention mechanisms, whereas older adults exhibited interacting processes. This is evidenced by the performance of older adults on concurrent executive and perceptual tasks, which was associated with working memory capacity; whereas younger adults did not exhibit this dependency. Selective attention processes that are independent in younger populations seem to converge in older populations due to decrements in executive and perceptual attention domains.

During aging, there is a decrease both in the stability of central nervous system (CNS) myelin once formed and in the efficiency of its repair by oligodendrocytes (OLs). To study CNS remyelination during aging, I used the cuprizone (a copper chelator) mouse model. Inclusion of cuprizone in the diet kills mature OLs and demyelinates axons in the rostral corpus callosum (RCC) of mice, which enabled me to characterize age-related changes (i.e., 2-16 months of age) in glial cell response during the recruitment (i.e., demyelination) and differentiation (i.e., remyelination) phases of myelin repair. I found that the time between 12 and 16 months of age is a critical period during which there is an age-related decrease in the number of OL lineage cells (Olig2Nuc+ve/GFAP-ve cells) in the RCC of both control mice and mice recovering from cuprizone-induced demyelination. My results also show there was an age-related impaired recruitment of progenitor cells to replace lost OLs even though there was no major age-related decrease in the size of the progenitor cell pool (PDGF á R+ve/GFAP-ve, and Olig2Nuc+ve/PDGFáR+ve cells). However, there were cuprizone-induced increased numbers of astrocyte progenitor cells (Olig2Cyto+ve/PDGFáR+ve) in these same mice; thus PDGFáR+ve progenitor cells in mice as old as 16 months of age retain the ability to differentiate into astrocytes, with this fate choice occurring following cytoplasmic translocation of Olig2. These data reveal for the first time age-related differences in the differentiation of PDGFáR+ve progenitor cells into OLs and astrocytes and lead me to suggest that during aging there must be a transcriptional switch mechanism in the progenitor cell fate choice in favour of astrocytes. This may at least partially explain the age-related decrease in efficiency of OL myelination and remyelination.

Aging is a universal biological phenomenon in all living cells. Questions regarding how cells age are beginning to be answered. Thus, great biological interest and practical importance leading to interventions rest on uncovering the molecular mechanism of aging. This would ultimately delay the aging process while maintaining the physical and mental strengths of youth. The conservation of metabolic and signaling pathways between yeast and humans is remarkably high, leading to the expectation that aging mechanisms are also common across evolutionary boundaries. By utilizing the budding yeast, <i>Saccharomyces cerevisiae</i>, one of the best characterized model systems for studying aging, the span in knowledge between yeast and human aging can possibly be bridged. <p>Evidence is accumulating that a genetic program exists for lifespan determination. Model organisms expressing mutations in single specific genes live longer with increased resistance to stress and cancer development. Mutations that accelerate aging in yeast affect the activity of the APC (Anaphase-Promoting Complex). Our finding that the APC is critical for longevity provides us with a potential central mechanism controlling lifespan determination. The APC is required for mitotic progression and genomic stability in presumably all eukaryotes by targeting regulatory proteins, such as cyclin B (Clb2p in yeast) for degradation. The key feature defining the APC as a central mediator of lifespan is the fact that multiple signaling pathways regulate APC activity and many of these pathways influence lifespan. For example, Snf1 and PKA have antagonistic effects on the APC and on lifespan. Thus, it is intriguing to speculate that the APC may link these signaling pathways to downstream targets controlling longevity. <p>Our hypothesis states that the APC targets a protein that reduces lifespan for ubiquitin-dependent degradation. The results from our two-hybrid screen utilizing Apc5p as bait are consistent with this hypothesis, as Fob1p was isolated as an Apc5p binding partner. The FOB1 gene is located on chromosome IV and the well-known molecular function of FOB1 is the creation of a unidirectional block in replication of rDNA. Fob1p binds to the rDNA locus and overall stalls progression of the replication fork, which increases rDNA recombination and the production of toxic extrachromosomal rDNA circles (ERCs). The FOB1 deletion (fob1∆) mutant confers reduced rDNA recombination, and an increased lifespan of more than 50% compared to WT (wild type) cells.<p>In this study, we expanded on the molecular mechanisms controlling lifespan through a genetic approach, and found that Fob1p was targeted by the APC for degradation in order to prolong lifespan. By utilizing the yeast two-hybrid approach, we confirmed the Apc5p-Fob1p interaction, and determined that the C-terminal half of Fob1p was required for the interaction with Apc5p. BLAST search analysis revealed sequence similarity with the Fob1p C-terminus that was shared with many other proteins from yeast to humans. We speculate that this shared domain may serve as an APC interaction domain employed across evolutionary boundaries. A genetic interaction analysis revealed the influence of FOB1 on the APC, and the cell. For example, deletion of FOB1 increased lifespan in apc5CA and apc10∆ mutant cells and partially suppressed the temperature sensitive (ts) growth of apc10∆ cells. On the other hand, increased FOB1 expression reduced the lifespan of WT and cells and was toxic to apc mutants, particularly the more severe apc mutants, apc10∆ and cdc16-1. Interestingly, overexpression of SIR2, which prolongs lifespan and acts antagonistically with Fob1p, was toxic to WT cells, but suppressed apc5CA ts defects, especially when FOB1 was deleted. These observations suggest that accumulation of Fob1p is harmful to yeast cells, especially when the APC is compromised. This notion was borne out when a cell cycle and steady state analysis of Fob1p revealed that Fob1p was an unstable protein, which was stabilized in apc5CA cells. Taken together, the work presented in this thesis supports a model whereby Fob1p is targeted for degradation by the APC in order to prolong lifespan in yeast. In conclusion, the extreme evolutionarily conserved nature of the APC and the Fob1p C-terminal sequence homology observed in human proteins strongly suggests that the mechanism discovered here could be directing human lifespan.

Schizophrenia has long been considered a disorder of impaired brain connectivity, and such disconnectivity might be due to disruption of white matter tracts that connect brain regions. This thesis investigates the oligodendrocyte/myelin/white matter pathway in schizophrenia in vivo, and also considers aging effects, as similar substrates are affected during the healthy aging process. In study one, association of oligodendrocyte/myelin genes is examined with schizophrenia, and in study two association of a myelin gene is examined with basic MRI volumetric phenotypes. Then, in study three, diffusion tensor tractography, a technique that can visualize and measure white matter is applied, and is shown to be reliable in healthy controls and schizophrenia patients using a novel clustering segmentation method. In study four, this method is then used to examine interaction of schizophrenia and aging with respect to white matter, where fronto-temporal disconnectivity is demonstrated in younger chronic schizophrenia patients, but not in elderly community dwelling schizophrenia patients compared to age-matched controls. In study five, relationships among age, white matter tract integrity, and cognitive decline in healthy aging are demonstrated using diffusion tensor tractography and structural equation modeling. Genetics and neuroimaging are then combined using the intermediate phenotype approach in study six to demonstrate a key role for the BDNF gene across adult life in healthy aging. In these individuals, the BDNF val66met variant influenced neural structures and cognitive functions in a pathological aging risk pattern. Finally, in study seven, complex relationships are then demonstrated among oligodendrocyte gene variants, white matter tract integrity and cognitive performance in both healthy controls and schizophrenia patients. The combination of genetics and neuroimaging can parse out heterogeneity of disease phenotypes, and characterize the effects of gene variants on at-risk neural structures and cognitive functions in healthy and disease populations.

During aging, there is a decrease both in the stability of central nervous system (CNS) myelin once formed and in the efficiency of its repair by oligodendrocytes (OLs). To study CNS remyelination during aging, I used the cuprizone (a copper chelator) mouse model. Inclusion of cuprizone in the diet kills mature OLs and demyelinates axons in the rostral corpus callosum (RCC) of mice, which enabled me to characterize age-related changes (i.e., 2-16 months of age) in glial cell response during the recruitment (i.e., demyelination) and differentiation (i.e., remyelination) phases of myelin repair. I found that the time between 12 and 16 months of age is a critical period during which there is an age-related decrease in the number of OL lineage cells (Olig2Nuc+ve/GFAP-ve cells) in the RCC of both control mice and mice recovering from cuprizone-induced demyelination. My results also show there was an age-related impaired recruitment of progenitor cells to replace lost OLs even though there was no major age-related decrease in the size of the progenitor cell pool (PDGF á R+ve/GFAP-ve, and Olig2Nuc+ve/PDGFáR+ve cells). However, there were cuprizone-induced increased numbers of astrocyte progenitor cells (Olig2Cyto+ve/PDGFáR+ve) in these same mice; thus PDGFáR+ve progenitor cells in mice as old as 16 months of age retain the ability to differentiate into astrocytes, with this fate choice occurring following cytoplasmic translocation of Olig2. These data reveal for the first time age-related differences in the differentiation of PDGFáR+ve progenitor cells into OLs and astrocytes and lead me to suggest that during aging there must be a transcriptional switch mechanism in the progenitor cell fate choice in favour of astrocytes. This may at least partially explain the age-related decrease in efficiency of OL myelination and remyelination.

This investigation explored implicit and explicit memory consequences of age differences in susceptibility to distraction when previous distraction occurs as target information in a later memory task. Younger and older adults were presented with either implicit (Study 1) or explicit (Studies 2 and 3) memory tasks that included previously distracting and new words. Study 1 explored whether prior exposure to distraction would transfer to improve memory when previously distracting words were included in list to be studied for a recall task. Older adults recalled more previously distracting than new words whereas younger adults recalled the same amount of previously distracting and new words. This initial study was implicit in its use of previously distracting information in that participants were neither informed nor aware of their prior exposure to words in the recall task. Here, only older adults’ memory was influenced by prior exposure to distraction and their recall actually increased to the level of younger adults with implicit use of distraction to improve performance. Subsequent studies investigated explicit influences of prior exposure to distraction on later memory. In Study 2, both younger and older adults showed reliable memory for previously distracting words in an explicit recognition task. These results suggest that although younger adults encode distraction, they do not transfer this information when previous distraction occurs as target stimuli in an implicit memory task. Study 3 investigated whether participants would transfer previous distraction to improve recall if the task was explicit in its use of previous distraction. When cueing instructions were given before the memory task informing participants of the connection between tasks, older adults once again recalled more previously distracting than new words. In contrast to the results of Study 1, younger adults also recalled more previously distracting than new words. Taken together, the results indicate that younger adults do encode distraction, but they require explicit instructions to transfer their knowledge of distraction to later tasks. In contrast, older adults apply their knowledge of distraction in both implicit and explicit memory tasks. Implications are discussed in terms of inhibitory control theory and age differences in strategies engaged in memory tasks.

Schizophrenia has long been considered a disorder of impaired brain connectivity, and such disconnectivity might be due to disruption of white matter tracts that connect brain regions. This thesis investigates the oligodendrocyte/myelin/white matter pathway in schizophrenia in vivo, and also considers aging effects, as similar substrates are affected during the healthy aging process. In study one, association of oligodendrocyte/myelin genes is examined with schizophrenia, and in study two association of a myelin gene is examined with basic MRI volumetric phenotypes. Then, in study three, diffusion tensor tractography, a technique that can visualize and measure white matter is applied, and is shown to be reliable in healthy controls and schizophrenia patients using a novel clustering segmentation method. In study four, this method is then used to examine interaction of schizophrenia and aging with respect to white matter, where fronto-temporal disconnectivity is demonstrated in younger chronic schizophrenia patients, but not in elderly community dwelling schizophrenia patients compared to age-matched controls. In study five, relationships among age, white matter tract integrity, and cognitive decline in healthy aging are demonstrated using diffusion tensor tractography and structural equation modeling. Genetics and neuroimaging are then combined using the intermediate phenotype approach in study six to demonstrate a key role for the BDNF gene across adult life in healthy aging. In these individuals, the BDNF val66met variant influenced neural structures and cognitive functions in a pathological aging risk pattern. Finally, in study seven, complex relationships are then demonstrated among oligodendrocyte gene variants, white matter tract integrity and cognitive performance in both healthy controls and schizophrenia patients. The combination of genetics and neuroimaging can parse out heterogeneity of disease phenotypes, and characterize the effects of gene variants on at-risk neural structures and cognitive functions in healthy and disease populations.