Nicotine, a psychostimulant present in tobacco that likely underlies addictive smoking behavior, binds to nicotinic acetylcholine receptors (nAChRs) in the central nervous system, initiating addiction. Activation of these ligand-gated ion channels by their endogenous agonist, acetylcholine (ACh), results in membrane depolarization and cellular excitation. Chronic exposure to nicotine upregulates the high-affinity alpha4beta2 nAChR subtype that has been implicated in addictive behavior in a cellular- and subcellular compartment-specific manner. These receptors are upregulated rapidly during nicotine exposure, reaching approximately half-maximal upregulation within a day. Thus, following even brief nicotine exposure, the expression of nAChRs within the brain is altered in specific pathways.
The hippocampus is a structure important for learning and memory that has been implicated in the cognitive effects of nicotine and in addiction. Principal neurons within the hippocampus are place cells that encode an animal’s position within its environment and may also fire in response to non-spatial cues, such as the presence or absence of an object or reward. The place fields of these cells are thought to arise from integration of the inputs from the principal cells in layers II and III of entorhinal cortex (grid cells). Alpha4beta2 nAChRs are located on the axons of medial perforant pathway, which projects from the layer II cells in medial entorhinal cortex to the dentate gyrus, and on the temporoammonic pathway, which is the direct projection from layer III cells in medial entorhinal cortex to the CA1 region, and following chronic nicotine treatment there is an upregulation of alpha4-containing nAChRs in the medial perforant pathway. Thus, the alpha4beta2 nAChRs are posed to influence the integration of this information and, following nicotine treatment, upregulation of these receptors may alter this.
We can visualize these receptors using fluorescently tagged knock-in mice and determine the exact location of the receptors and whether this is altered after nicotine treatment. Additionally, we can use in vivo electrophysiology to determine how upregulating these receptors impacts the function of hippocampal place cells, the post-synaptic targets of the pathways containing the receptors, and grid cells in entorhinal cortex (which may have upregulated receptors somatodendritically as well as on the axonal projections). This study will determine how nicotine treatment and the subsequent upregulation of alpha4beta2 nAChRs on specific pathways within the hippocampus can modulate hippocampal activity.