Continued neurogenesis represents a remarkable means of cellular and structural neural plasticity in adult brain tissue, and elucidating the fundamental mechanisms that support and guide this phenomenon holds promise towards developing future approaches towards repairing damaged or diseased nervous tissue. Data have shown that numerous extrinsic physiological and pathological processes directly influence adult neurogenesis and synaptic integration of newborn neurons. Notably, increased neural activity enhances adult neurogenesis, synaptogenesis, and circuit remodeling, whereas decreased or altered neural activity compromises newborn neuron survival and integration. To date however, the identities of inputs that convey activity-dependent changes to newborn neurons, and the nature of their signaling in response to activity manipulations are only now beginning to be revealed. In the previous granting period of this award, we have identified previously unknown sources of input, and revealed novel neuromodulatory signaling mechanisms that contribute towards the activity- dependent wiring of newborn neurons in the adult brain. Here we will expand upon these findings to better understand the cellular mechanisms that promote the formation and stabilization of new synapses in adult brain tissue, and further assay how manipulating these pathways affects the formation and/or remodeling of new brain circuits.
We have recently uncovered that cholinergic neurons from the basal forebrain provide GABAergic input to adult-born neurons as they form new connections in adult brain tissue. Interestingly, signaling from the basal forebrain has been implicated in learning, reward, and reinforcement, all of which are physiological states that influence the survival and synaptic integration of adult-born neurons within neural circuits. Using a combination of conditional genetic, optogenetic, in vivo imaging, electrophysiology, and transcriptional profiling approaches, we will set out to determine the role for the cholinergic basal forebrain towards rewiring adult brain tissue.
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