Genetic and molecular tools will soon make it possible to customize the treatment of mental illnesses and other brain disorders to the individual. Until recently, for good practical reasons, science and medicine have been forced to ignore individual variability in populations to obtain statistically reliable data pooled from many individuals. But, to move towards personalized medicine, it is critically important to understand how different two healthy brains can be from each other. How much variation in synaptic strength, network structure, and intrinsic properties is consistent with adequate performance? Can some circuit parameters vary a good deal across a population of healthy individuals, while others are more tightly constrained? Are some parameters coordinately regulated so that alterations of one circuit parameter are well- compensated by others? The work proposed below takes advantage of the well-understood central pattern generating circuits found in the crustacean stomatogastric nervous system to address these questions. The present proposal combines experimental and computational experiments. These include computational work to reveal whether correlations in ion channel expression may be part of homeostatic regulation of neuronal excitability. Experimental and computational work will examine the extent of variability in a) the expression of serotonin and dopamine receptors and the currents they modulate, b) the morphological structure of identified neurons across individuals, c) the strength of identified synapses across animals, and in the location of the synaptic contacts across animals. Correlations between the activity of the circuit, and their underlying properties will lead to new insights into which relationships among synaptic and neuronal properties must be preserved in healthy brains.
Mental illness may result from relatively minor imbalances in circuit parameters that nonetheless result in significantly disordered functions. To understand what kinds of circuit parameters when perturbed lead to mental illness, it is necessary to understand how different neuronal excitability and synaptic strengths are in normal healthy brains, and how individual neuronal processes compensate for each other
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