The activation of nicotinic-type acetylcholine-receptor (nAChR)s on developing neurons and at mature pre, post and peri-synaptic locales can elicit a broad range of cellular, circuit and behavioral responses. Exposure to nicotine can enhance neuronal survival (or increase apoptosis), modifies rates of neurite outgrowth or elicit growth cone collapse. Early exposure to nicotine can awaken previously silent synapses and increase the susceptibility of an individual to later life addictions and psychiatric disorders. Essential to dissecting the myriad possible outcomes of nAChR activation is understanding how endogenous cholinergic pathways act as modulatory controllers of CMS circuits underlying motivated-behaviors, attention, memory and mood. Increasingly sophisticated anatomical, pharmacological and cellular physiological studies of the brain have yielded an ever-mounting armamentarium of molecular probes and technical refinements to decipher cholinergic circuits. It is time to integrate these new approaches into more interdisciplinary analyses of specific cholinoceptive circuits. Our goal is to determine how the activation of particular types of nAChRs contribute to the modulation of cortico-limbic circuits essential to motivated behaviors. Proposed studies include cell biological, synaptic and circuit analyses to examine the effects of perinatal nicotine exposure on the physiology of specific cortico-limbic relays. These studies have translational relevance to understanding the mechanisms that underlie the plasticity of cholinoceptive circuits that collapse in disorders of motivation, memory and mood. This proposal pursues prior NS22061 supported studies of the nAChR subunit determinants of synaptic modulation by taking a more comprehensive cellular, electrophysiological, and behavioral approach to analyze select cortico-limbic circuits involved in motivated behaviors. Our current goal is to dissect the cellular mechanisms by which alpha7-containing (a7*) -nAChRs participate in signaling in brain areas associated with natural reward. In vitro (microslice co-culture and acute brain slice) preparations will be used (1) to extend initial studies on nAChR-modulation of synaptic transmission in select cortico-limbic circuits and (2) to examine the cellular-signaling mechanisms of sustained vs. transient nicotine-induced synaptic modulation at sites of convergent cortical-limbic projection within the ventral striatum. An important, albeit riskier, goal is (3) to determine the effects of perinatal nicotine exposure on the postnatal function of circuits that underlie natural reward. ? ?
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