Component 1 of the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium is focused on the enduring effects of adolescent intermittent ethanol (AIE) on learning and hippocampal function in adulthood, issues that are of keen scientific and social interest. The collaborative studies of the NADIA consortium have identified a large number of enduring behavioral and neural effects of AIE, and have begun to identify possible mechanisms underlying them. During the proposed funding period we will directly pursue those mechanisms that are most promising and work to identify translational treatments to prevent or reverse the long-term neural and behavioral effects of AIE. This Component has observed AIE-induced impairment of spatial memory, which is accompanied by changes in hippocampal structure and function that suggest hyperexcitability and aberrant synaptogenesis within hippocampal circuits. For example, we have observed an apparent lowering of the threshold for the induction of long-term potentiation (LTP), decreased tonic inhibition, up-regulation of GluN2A and GluN2B receptor subtypes, and up-regulation of thrombospondins that are known to promote excitatory synaptogenesis, after AIE. Importantly, we have preliminary data indicating an enduring decrease in the numbers of mature neurons in area CA1 after AIE. Together, these findings strongly support our hypothesis that AIE produces hyperexcitability and aberrant plasticity in the hippocampus, resulting in neuronal loss caused by altered synaptogenesis and excitatory drive.
Specific Aims 1 &2 will address this hypothesis in detail by assessing the receptor mechanisms underlying the effects of AIE on hippocampal excitatory function and synaptic plasticity, the propensity of hippocampal circuits toward aberrant saturation of synaptic plasticity, and AIE-induced neuronal loss. We and other NADIA Components have also observed an AIE-induced reduction in the density of ChAT positive neurons in the medial septum and vertical limb of the diagonal band of Broca (also known as areas Ch1-2). Cholinergic neurons in this region project diffusely to the hippocampal formation and regulate both memory-related synaptic plasticity and neurogenesis. Their reduction after (and perhaps during) AIE is likely to have profound long-term consequences for hippocampal function. Therefore, we also hypothesize that reduced cholinergic input from Ch1-2 during or after AIE compromises memory-related hippocampal function, and that treatment with agents that enhance cholinergic function will prevent or reverse those effects.
Specific Aim 3 will determine the point at which cholinergic cell loss in Ch1-2 is initiated during AIE, how the loss o that input to the hippocampal formation alters memory, and memory- related synaptic plasticity in the hippocampal formation, and whether those effects of AIE can be prevented or reversed by agents that promote cholinergic function. These two hypotheses are linked together, addressing related forms of hippocampal dysregulation - one intrinsic and one extrinsic - and our Specific Aims target timely questions that emerge directly from them and are of mechanistic and translational significance. Importantly, each of the Specific Aims in this Component includes direct collaboration with at least one other NADIA Component. This markedly increases our capacity to orient the proposed experiments mechanistically and allows us to be nimble in our pursuit of new directions as they emerge.
Adolescence is a critical period for cognitive, emotional, and social maturation that is accompanied by the pruning of synapses, the refinement of neural circuitry, and marked changes in behavioral functioning. These processes all contribute to the normal maturation of cognitive processes crucial for successful adult function, including planning, inhibitory control, and memory. Although it has become clear that adolescents and young adults respond differently than adults to the acute effects of alcohol, the enduring consequences of repeated alcohol exposure during adolescence have only recently begun to be addressed in detail. During the past five years we have identified several long- lasting effects of adolescent alcohol exposure on brain mechanisms of learning and memory. The proposed project is designed to identify the mechanisms underlying the most important of those effects as well as possible treatments for the prevention or reversal of those effects.
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