Project Summary Normal aging is typically associated with pervasive declines in cognitive, motor and sensory function, however, there are substantial individual differences: some older adults experience mild impairments while others experience severe cognitive declines. Understanding the neural bases of individual differences during aging is imperative in designing future interventions to address age-related cognitive impairments. Using behavioural testing, functional MRI, spectroscopy and pharmacological manipulations in human adults, I propose to investigate the scope, cause and consequences of age-related decline in two neural factors that may play a role in these individual differences: (1) neural distinctiveness (how similar/confusable neural activation patterns are in response to different stimulus categories) and (2) brain signal variability (moment-to-moment change in neural activity independent of task). Both these measures have been found to decline with age and both have been associated with individual differences in behavior. During the predoctoral (F99) phase of the training, my research will focus on healthy aging: 1) investigating the scope and cause (specifically role of GABA levels) of age-related decline in neural distinctiveness in sensory regions, 2) the cause of age-related declines in brain signal variability, and 3) the behavioral consequences of age-related declines in these two neural measures. During the postdoctoral (K00) phase, I will extend my previous research to again study neural distinctiveness and brain signal variability, but now in the context of memory and hippocampal dysfunction, and in a clinical population (patients with Mild Cognitive Impairment, MCI). I will use task-based fMRI to measure neural distinctiveness, resting-state fMRI to measure brain signal variability, and MR spectroscopy to measure levels of various neurotransmitters (including glutamine, glutamate, NAA, and GABA), all in the hippocampus, in healthy younger and older adults as well as MCI patients. I will also collect behavioral data from the same participants during the Mnemonic similarity task (MST), a highly sensitive measure of hippocampal dysfunction. I propose to investigate a) age-related changes in neural distinctiveness and resting state variability in the hippocampus, b) the neurochemical basis of these neural changes, and c) the behavioral and pathological consequences of these neural changes. For all the MCI patients, I will also have access to a rich dataset of other biomarkers (e.g., longitudinal measures of CSF and PET-based amyloid and tau) collected at UCI’s Alzheimer’s Disease Research Center (ADRC). I will therefore be able to examine neural distinctiveness and brain signal variability in the context of the Amyloid Tau Neurodegeneration (biomarker profiling) Framework. Together, this research could lead to the development of preclinical markers for AD and open new avenues for early pharmacological interventions to treat ...