Neurons live for scores of years, but the ion channels and receptors that are important for signaling in the brain are replaced continuously in hours and days. Therefore, maintaining stable brain function requires understanding how the brain rebuilds itself and renews itself while functioning. Moreover, mechanisms that maintain brain stability must be balanced by processes that allow flexibility for development and learning. This project develops new computational models to understand the homeostatic mechanisms in the brain that maintain stable function despite perturbations of all kinds. A variety of models of varying complexity will be developed and studied. These include biologically plausible self-regulating models that specifically describe mRNA expression and protein synthesis, trafficking and degradation. The goal is not to model all the details of these processes, but to determine how the number of steps involved in regulation, their dynamics, and the way they are coupled affect the qualitative outcome of regulation in neurons. Additionally, models of homeostatic sensors and set points will be built using plausible Ca2+- dependent biochemical reaction schemes. Studies will determine how their reaction rates influence set-points. Finally, homeostatic regulation will be examined in small networks of neurons to determine how homeostatic regulation of synaptic and intrinsic properties can produce compensation to a variety of perturbations. This work will provide insight into the effects of mutations in ion channels on network function, as well as help understand the kinds of compensations that can occur in networks as a response of long-term or short-term pharmacological treatments. Understanding homeostatic regulation in the brain will give insight into nervous system disorders such as epilepsy, chronic pain, long-term pharmacological treatments, changes in reflex pathways subsequent to spinal cord lesions, and a variety of other perturbations to nervous systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS079419-02
Application #
8743094
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brandeis University
Department
Type
DUNS #
City
Waltham
State
MA
Country
United States
Zip Code
02453
Joseph, Annelise; Turrigiano, Gina G (2017) All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control. J Neurosci 37:6778-6785
O'Toole, Sean M; Ferrer, Monica M; Mekonnen, Jennifer et al. (2017) Dicer maintains the identity and function of proprioceptive sensory neurons. J Neurophysiol 117:1057-1069
Abraira, Victoria E; Kuehn, Emily D; Chirila, Anda M et al. (2017) The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn. Cell 168:295-310.e19
Cannon, Jonathan; Miller, Paul (2017) Stable Control of Firing Rate Mean and Variance by Dual Homeostatic Mechanisms. J Math Neurosci 7:1
Choy, Julian M C; Suzuki, Norimitsu; Shima, Yasuyuki et al. (2017) Optogenetic Mapping of Intracortical Circuits Originating from Semilunar Cells in the Piriform Cortex. Cereb Cortex 27:589-601
Williams, Alex H; O'Donnell, Cian; Sejnowski, Terrence J et al. (2016) Dendritic trafficking faces physiologically critical speed-precision tradeoffs. Elife 5:
Gjorgjieva, Julijana; Drion, Guillaume; Marder, Eve (2016) Computational implications of biophysical diversity and multiple timescales in neurons and synapses for circuit performance. Curr Opin Neurobiol 37:44-52
Crittenden, Jill R; Tillberg, Paul W; Riad, Michael H et al. (2016) Striosome-dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons. Proc Natl Acad Sci U S A 113:11318-11323
O'Leary, Timothy; Marder, Eve (2016) Temperature-Robust Neural Function from Activity-Dependent Ion Channel Regulation. Curr Biol 26:2935-2941
Steinmetz, Celine C; Tatavarty, Vedakumar; Sugino, Ken et al. (2016) Upregulation of ?3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway. Cell Rep 16:2711-2722

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