This is a request to consolidate three ongoing NINDS-funded proposals that deal with neuromodulation (R37 NS 17813), temperature compensation (R01 NS 81012), and computational models of homeostatic regulation of intrinsic excitability (Project #4 of P01 NS07949). Together these projects comprise a coherent attempt to understand brain circuit stability in the face of: a) extensive neuromodulation, b) constant and rapid turnover of ion channels and receptors, and c) degenerate and multiple solutions at the single neuron and circuit level. These questions arise from years of computational and experimental work using the small circuits of the crustacean stomatogastric ganglion (STG), but address general problems relevant to all nervous systems, from invertebrates to humans. Future experiments will combine experimental and computational work to understand the correlations in biological parameters in neurons and networks that allow any given parameter to be variable while the circuit itself retains robustness. Animal to animal variability in response to perturbations will be measured, the strengths of all of the synapses in STG circuits will be measured, and the regulation of multiple neuromodulator receptors by single neurons will be studied. Additionally, self-tuning models will be developed to find sets of neuronal parameters that allow neurons to maintain stability in response to perturbations. This work will illuminate the extent to which the same animal can potentially generate similar behavior by substantially different (degenerate) circuit mechanisms at different times. If so, this can shed light on how larger circuits may switch between a number of degenerate circuit mechanisms to generate stable behaviors over time.

Public Health Relevance

Neurons must constantly rebuild themselves as the membrane proteins that give rise to synaptic connectivity and electrical excitability are replaced. At the same time, brain circuits must be stable. The goals of this project are to understand how individual animals achieve robust function over time in the face of the need to respond flexibly to environmental perturbations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS097343-05
Application #
10059279
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Gnadt, James W
Project Start
2016-12-01
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02453
Marder, Eve (2018) The voice of evidence. Elife 7:
Ori, Hillel; Marder, Eve; Marom, Shimon (2018) Cellular function given parametric variation in the Hodgkin and Huxley model of excitability. Proc Natl Acad Sci U S A 115:E8211-E8218
Bronk, Peter; Kuklin, Elena A; Gorur-Shandilya, Srinivas et al. (2018) Regulation of Eag by Ca2+/calmodulin controls presynaptic excitability in Drosophila. J Neurophysiol 119:1665-1680
Rosenbaum, Philipp; Marder, Eve (2018) Graded Transmission without Action Potentials Sustains Rhythmic Activity in Some But Not All Modulators That Activate the Same Current. J Neurosci 38:8976-8988
Marder, Eve (2017) The importance of remembering. Elife 6:
Otopalik, Adriane G; Sutton, Alexander C; Banghart, Matthew et al. (2017) When complex neuronal structures may not matter. Elife 6:
Nusbaum, Michael P; Blitz, Dawn M; Marder, Eve (2017) Functional consequences of neuropeptide and small-molecule co-transmission. Nat Rev Neurosci 18:389-403
Marder, Eve; Gutierrez, Gabrielle J; Nusbaum, Michael P (2017) Complicating connectomes: Electrical coupling creates parallel pathways and degenerate circuit mechanisms. Dev Neurobiol 77:597-609
Otopalik, Adriane G; Goeritz, Marie L; Sutton, Alexander C et al. (2017) Sloppy morphological tuning in identified neurons of the crustacean stomatogastric ganglion. Elife 6:
Marder, Eve (2017) Beyond scoops to best practices. Elife 6:

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