This application describes experiments that analyze the neural circuitry of the hippocampal formation (HF), the brain area most clearly implicated in memory and disorders such as Alzheimer's and related dementias. It combines neuron-specific transgene expression with electrophysiological techniques to study the transformation of information in the mammalian hippocampal formation at the cellular and network level. The approach is similar to the nodal analysis performed by engineers to analyze electronic circuits. Here, however, the nodes are neural cell types rather than electrical components. The nodes are specified by transgenic """"""""driver"""""""" lines which direct the expression of various transgenes (depending upon which transgenic """"""""payload"""""""" lines they are crossed to) enabling cell type specific changes in activity. Performing this nodal analysis, we manipulate the activity of one node while recording from others, much as when a potentiometer controlling the impedance of an amplifier circuit changes audio output when manipulated. We do so by driving the expression of transgenes which increase or decrease the membrane potential of neurons when activated either by specific drugs or wavelengths of light. We can then manipulate the activity of an identifiable population of primary neurons in the HF circuit while recording the activity of others gaining a functional understanding of how information is transformed from one region to the next.
Understanding the function of the hippocampal formation is extremely relevant to human health and well- being. Dysfunction in this brain area causes profound memory deficits, and is linked with Alzheimer's and other age-related dementia. Furthermore, dysregulation of neural activity in the hippocampal formation is one of the leading causes of epilepsy. Finally, understanding how the different parts of the hippocampal formation interact also has direct relevance to the treatment of patients with stroke or other trauma, as changes in activity following the original insult can drive hyper-excitability resulting in additioal cell death.
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