PROJECT SUMMARY We are facing a growing crisis of a greater number of seniors living with a decline in cognitive function as a common consequence of aging. Once an impairment has reached a level of clinical significance, treatment options are limited. We propose to examine age-related differences in trait and state autonomic control of heart rate and their relation to cognitive performance humans and rats. While cognitive changes may be masked by compensatory efforts, autonomic measures may be more revealing of the underlying age-related changes in the neural substrates and neurochemistry of aging and its clinical course. We will examine these autonomic regulation of heart rate, its relation to and modulation by cognitive performance, as a peripheral proxy of early central alteration of the cholinergic basal forebrain (BF), a progenitor of system-wide neuroanatomical and neurochemical changes related to aging. To understand the underlying neural mechanistic bases of these autonomic indices, we will apply a cross-species approach, including human functional neuroimaging as well as nonhuman neurochemical examinations. Specific Aim 1 will examine whether age-related differences in cognitive control are associated with altered autonomic regulation of the heart. Approach: We will employ a cross-sectional examination of inhibitory cognitive control tasks, which we have shown to depend on the cholinergic BF in rats, in a diverse sample of male and female young, middle-aged, and older adults, examining how cognitive performance relates to autonomic parasympathetic influences on the heart, reflected in vagally- mediated heart rate variability(phasic, beat-to-beat heart rate variability). Specific Aim 2 will examine the specific role of the BF, and its afferent networks, in connecting age-related differences in cognitive control and autonomic regulation of the heart. Approach: We will employ multi-echo fMRI to acquire high SNR signal from BF nuclei and autonomic phasic parasympathetic influences on heart, and their relation to neurocognitive aging, while characterizing and controlling for age-related differences in cerebral blood flow with arterial spin labelling. Specific Aim 3 will test the hypothesized parallel causal contributions of BF cholinergic neurons to central cognitive regulation and peripheral autonomic regulation of the heart. Approach: Using cholinergic immunotoxic lesions, a rat model of cognitive aging will assess the causal role of the BF to cognitive control and parasympathetic autonomic regulation of heart rate (vmHRV) in male and female young, middle-aged, and older rats. Revealing peripheral autonomic aspects of age-related differences in brain integrity and cognitive status would advance our understanding of normative and potentially pathological neurochemical changes in aging. It will further advance the use of a noninvasive, low-cost peripheral biomarker for identifying those who may p...