This proposal addresses fundamental roles of nicotinic cholinergic signaling in guiding the development of the nervous system and regulating the function of adult neural networks.
The specific aims are to elucidate mechanisms by which nicotinic signaling, both endogenous and exogenous, determine the pattern of glutamatergic innervation during development and sustain it in the adult. The findings are likely to change how we think about basic processes in the brain and will have clear health-relevance because of the impact of early nicotine exposure.
AIM I will identify specific mechanisms by which nicotinic activity induces dendritic spines and promotes glutamate synaptogenesis. It will also elucidate how distinct nicotinic pathways determine the location of glutamate synapses on spines vs. shafts.
AIM II will define the window of vulnerability and the duration of the effects both in culture systems and in vivo. The experimental approaches include nicotine administration in culture and in vivo, and the use of wildtype, knockout, and virally-manipulated test rodents. Methods of analysis include immunohistochemistry and functional assays on fixed and live tissues. The health consequences of nicotine addiction are huge. Conversely, deficits in endogenous nicotinic cholinergic signaling contribute to a number of pathologies including schizophrenia, epilepsy, autism, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, and dementia. Higher order functions such as learning and memory, attention, and cognition are subject to nicotinic regulation. This proposal examines how nicotine can hijack developmental processes normally controlled by endogenous nicotinic cholinergic signaling. The results will have direct health relevance because they will provide information about the consequences of nicotine exposure, particularly early in development. They will also offer information about the role of endogenous nicotinic signaling. Answers here may, in addition, suggest how nicotinic signaling contributes to neurological disorders, providing incentive and opportunities for preventative therapies. Health Relevance: Tobacco consumption, driven by nicotine addiction, is the leading cause of preventable deaths. The studies proposed here will reveal ways in which nicotinic activity early in development helps shape the nervous system, possibly producing long-lasting network changes likely to alter or limit behavior. The fact that endogneous nicotine signaling has also been implicated in major diseases such as Alzheimer's and Parkinson's provides another opportunity for the results obtained here to suggest specific targets for intervention.
| Halff, Andrew W; Gómez-Varela, David; John, Danielle et al. (2014) A novel mechanism for nicotinic potentiation of glutamatergic synapses. J Neurosci 34:2051-64 |
