Effects of dietary restriction on age-related neurophysiological adaptations: from behavior to single dopaminergic neurons

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Aging is associated with a decrease in movement and cognition, and understanding the neurophysiological bases of these behavioral deficits will be key to increasing healthspan. Dopamine neurons in the substantia nigra are key central mediators of voluntary movement and reward-related behavior, and the function of these neurons is known to decline with age. Unfortunately, little is currently known about how normal aging affects the specific intrinsic channels and synaptic inputs that are responsible for dopamine neuron excitability and function. Our lab has developed reliable methodology for making electrophysiological recordings of dopamine neurons in brain slices from mice of advanced age, thus a comprehensive investigation into the effects of aging on ion channel physiology in these neurons is now possible. We will combine electrophysiology, behavior, gene expression analysis, and optogenetics to elucidate the effects of aging on ion channel signaling and dopamine-mediated behaviors. Furthermore, we will use dietary restriction (an established healthspan- increasing intervention) to identify the ionic mechanisms that counteract age-related deficits in behavior. Our central hypothesis is that age-related deficits in movement and reward-related behaviors can be attributed to specific ion channel conductances in substantia nigra dopamine neurons, and that these deficits can be attenuated by dietary restriction. Aim 1 is to determine the relationship between age-related deficits in specific ion channel currents and cell firing. We will also relate (in individual mice) our electrophysiological findings in single neurons to previously obtained locomotor behavioral data. Aim 2 is to determine the effects of aging on excitatory inputs from the hypothalamus to dopamine neurons as well as reward-related behavior. For this aim we will employ optogenetics to study identified glutamate inputs in a brain region-specific manner. Aim 3 is to determine the effects of aging on dopamine autoreceptor-mediated neurotransmission. Aim 4 is to determine the effects of dietary restriction in aging mice as an intervention that can counteract age-related decline of ion conductances in dopamine neurons and related behaviors. These studies will provide the first detailed understanding of the relationship between aging, dopamine neuron activity, and dopamine-mediated behaviors, and determine the protective effects of dietary restriction on these parameters.