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.

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH046742-25
Application #
8584992
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Glanzman, Dennis L
Project Start
1990-04-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
25
Fiscal Year
2014
Total Cost
$351,945
Indirect Cost
$129,195
Name
Brandeis University
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Marder, Eve; Goeritz, Marie L; Otopalik, Adriane G (2015) Robust circuit rhythms in small circuits arise from variable circuit components and mechanisms. Curr Opin Neurobiol 31:156-63
Shruti, Sonal; Schulz, David J; Lett, Kawasi M et al. (2014) Electrical coupling and innexin expression in the stomatogastric ganglion of the crab Cancer borealis. J Neurophysiol 112:2946-58
Brookings, Ted; Goeritz, Marie L; Marder, Eve (2014) Automatic parameter estimation of multicompartmental neuron models via minimization of trace error with control adjustment. J Neurophysiol 112:2332-48
Marder, Eve; O'Leary, Timothy; Shruti, Sonal (2014) Neuromodulation of circuits with variable parameters: single neurons and small circuits reveal principles of state-dependent and robust neuromodulation. Annu Rev Neurosci 37:329-46
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O'Leary, Timothy; Williams, Alex H; Caplan, Jonathan S et al. (2013) Correlations in ion channel expression emerge from homeostatic tuning rules. Proc Natl Acad Sci U S A 110:E2645-54
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Williams, Alex H; Calkins, Andrew; O'Leary, Timothy et al. (2013) The neuromuscular transform of the lobster cardiac system explains the opposing effects of a neuromodulator on muscle output. J Neurosci 33:16565-75

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