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Nicotinic Regulation of Neurogenesis in Adult Hippocampus

Institution: University of California, San Diego
Investigator(s): Nolan Campbell, B.S. Biology
Award Cycle: 2008 (Cycle 17) Grant #: 17DT-0191 Award: $59,910
Subject Area: Nicotine Dependence
Award Type: Dissertation Awards
Abstracts

Initial Award Abstract
Nicotine addiction is a complex behavioral phenomenon, as are the changes in the nervous system imposed by chronic nicotine exposure. Both appear to involve changes in the connections (called “synapses”) between cells (“neurons”) in the brain and the networks these synapses establish. The hippocampus, a central part of the brain, has been a prominent target of nicotinic research because the hippocampus is required for several forms of memory formation and because it receives significant input normally from “nicotinic cholinergic” pathways that can be hijacked by nicotine. The hippocampus also expresses relatively high levels of the two major detector molecules that can be exploited and inappropriately activated by nicotine (called “nicotinic acetylcholine receptors” or nAChRs). Numerous studies have demonstrated that normal endogenous activity in nicotinic cholinergic pathways can act broadly in the mature hippocampus to acutely modify both the major excitatory and the major inhibitory pathways. A remarkable feature of the hippocampus is that it continues to generate new neurons throughout adult life (“adult neurogenesis”). These neurons are important for normal hippocampal function. Diminished neurogenesis in the adult has been implicated in the pathology of a number of diseases, including chronic temporal lobe epilepsy, depression, schizophrenia, and drug addiction. Newborn neurons in the adult hippocampus express the same two major classes of nAChRs and receive nicotinic cholinergic input early on. Our preliminary results suggest that these receptors regulate neuronal survival, alter gene expression, and are likely to constrain the kinds of signaling found in neurons arising from adult neurogenesis. Furthermore, the two classes of nAChRs appear to have distinct functional influences on the events shaping the fate of such neurons.

This proposal advances three specific aims to examine the impact of nicotinic activity on adult neurogenesis. The first aim takes advantage of special labeling agents in the tissues to test the role of nAChRs in controlling the survival, maturation, and ability of newborn neurons in the adult hippocampus to receive synapses. The second aim compares the two nAChR subtypes to see if they have distinct and possibly complementary actions, one of them being an ability to regulate gene expression in the neurons. The final aim tests the effects of chronic nicotine exposure on adult neurogenesis. Evaluative procedures will include (a) counting newborn neurons to assess survival as a function of age, (b) staining for key developmental markers to assess neuronal development, (c) comparing neuronal shapes to distinguish retarded or constrained development, (d) staining for synaptic markers to evaluate the extent of contacts formed on the neurons (and by inference their ability to participate in networks), and (e) measuring electrical events in the neurons to evaluate their communication with other neurons.

Results obtained here will provide new information about the mechanisms by which normal endogenous nicotinic cholinergic signaling shapes adult neurogenesis. The results will also indicate the extent to which repeated nicotine exposure, comparable to that obtained from tobacco consumption, abrogates these processes. Deficits in neurogenesis caused by repetitive exposure to tobacco-derived nicotine are likely to be most severe in aging adults both because of possibly cumulative effects on the neuronal population derived from adult neurogenesis and because this population is likely to become increasingly relied upon by the aging brain. The information yielded from these experiments will offer new insight into fundamental mechanisms supporting nervous system function. Biomedically, the findings have the possibility of identifying targets for remedial intervention following nicotinic perturbation of adult neurogenesis.
Publications

Endogenous signaling through alpha7-containging nicotinic receptors promotes maturation and integration of adult-born neurons in the hippocampus.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Campbell, NR; Fernandes, CC; Halff, AW; Berg, DK; ART
Yr: 2010 Vol: 30 Nbr: Abs: Pg: 8734-8744

Endogenous nicotinic signaling through a7-containing receptors regulates the fate of new born neurons in the adult hippocampus.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Campbell, NC; Berg, DK ABS
Yr: Vol: Nbr: Abs: 360.3 Pg:

Nicotine has opposing effects on the fate of adultborn neurons depending on exposure timing.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Campbell, NC; Berg, DK ABS
Yr: Vol: Nbr: Abs: Pg: