CHOLINERGIC MODULATION OF HIPPOCAMPAL INTERNEURON SUBTYPES

University Of Montana, Missoula MT

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Acetylcholine (ACh) release from the medial septum-diagonal band of Broca (MS-DBB) to the hippocampus profoundly alters cellular excitability, network synchronization, and behavioral state. Deficits in cholinergic function induce memory impairments, such as in Alzheimer's disease, while excessive cholinergic activity resulting from nerve agent or organophosphate pesticide poisoning can induce seizures and lead to neuronal death. ACh has diverse pre- and postsynaptic targets onto both glutamatergic and GABAergic cell populations. Recent data has emerged indicating that the actions of ACh can be specific, altering the excitability of distinct GABAergic circuits a cell type-specific manner. However, an understanding of cholinergic neurotransmission onto these targets still remains at a nascent stage due to technical difficulties in systematically studying defined interneuron populations, the lack of information on the density and spatial localization of cholinergic afferents received by defined interneuron subtypes, and the inability to activate diffusely distributed populations of septal cholinergic neurons in a selective yet coordinated manner. To overcome these limitations, we will develop new molecular tools that will facilitate the systematic study of defined interneuron subtypes and their capacity to undergo cholinergic neuromodulation. First, we will develop AAV viruses that express GFP, CFP, or RFP in neurochemically restricted interneuron populations. Secondly, combining mouse transgenic and viral technology, we will then examine how cholinergic afferents innervate and activate these defined interneuron subtypes. With the use of CRE/loxP transgenic technology in combination with AAV viruses, we will introduce channelrhodopsin2 into cholinergic neurons to light-evoke acetylcholine release onto neurochemically and morphologically defined target cells. Third, with this newly available data, we will construct computer models of cholinergic neurotransmission that incorporate precise measurements of the density of cholinergic innervation, spatial distributions of cholinergic receptors on target neurons, temporal dynamics of cholinergic receptor activation and their effectors, and mechanisms by which cholinergic neurotransmission is terminated. Finally, we will develop both experimental and computational paradigms to examine the functional consequence of cholinergic receptor activation in each interneuron subtype during cholinergically induced oscillatory activity. Together, these innovative approaches will allow us to obtain a greater understanding of how ACh engages neurochemically distinct interneuron subtypes to alter the flow of sensory information in the normal and diseased hippocampus.