Dynamic assembly and disassembly of the actin cytoskeleton underlies diverse cellular processes, including cell division, developmental polarity and intracellular transport. These changes can be local or global, transforming cell state. Extracellular signals mediate experience-induced changes of actin dynamics within synaptic microdomains of neurons. Recent evidence suggests that actin dynamics of the cell body, distinct from those in the synapse, also may be necessary for neurons to sense and respond to extracellular stimuli. We predict that this process contributes to plasticity of behavior by altering transcription. Our overarching goal is to understand how experience signals long-term state changes in neurons that, in turn, change behavior. We hypothesize that glutamatergic neurotransmission changes actin organization, and this is permissive for transcriptional activation. We will test this hypothesis in the suprachiasmatic nucleus (SCN), a brain site with established molecular substrates necessary for temporal organization of behavior. The SCN is a cell-based, ~24-h clock driven by spatial and temporal oscillations that regulate transcription. Specifically, we hypothesize that signaling cascades initiated by glutamate engage the actin cytoskeleton of SCN cells, changing localization of key transcriptional regulators that alter clock state. We will examine the nature and necessity of such changes in actin and their effects on transcriptional activation of clock genes. We will evaluate these mechanisms in rat and mouse models: cell cultures, brain slices and behaving animals.
Specific aims will: 1) characterize and localize stimulus-induced changes in actin; 2) find the role of actin changes in clock function and behavior, and 3) determine the role of actin changes in regulating transcription. We will use cell biological methods, dynamic imaging, biochemistry, neurobiological measures, and behavioral analyses. The breadth of this systems-based analysis will generate insights into how experience is transformed into long-lasting modification in brain state and behavior. This will enhance the understanding of substrates of long-lasting neural state change, with broad relevance for public health and disease prevention. Dysfunctions in the actin system cause severe neurological disorders, including those of cognition, neurodegeneration, movement and autonomic control. Sleep disorders, learning/memory impairments, drug-addiction and aging will be direct beneficiaries. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086870-02
Application #
7488953
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Twery, Michael
Project Start
2007-08-25
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$387,500
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Bothwell, Mia Y; Gillette, Martha U (2018) Circadian redox rhythms in the regulation of neuronal excitability. Free Radic Biol Med 119:45-55
Kandalepas, Patty C; Mitchell, Jennifer W; Gillette, Martha U (2016) Melatonin Signal Transduction Pathways Require E-Box-Mediated Transcription of Per1 and Per2 to Reset the SCN Clock at Dusk. PLoS One 11:e0157824
Gillette, Martha U; Wang, Tongfei A (2014) Brain circadian oscillators and redox regulation in mammals. Antioxid Redox Signal 20:2955-65
Abbott, Sabra M; Arnold, Jennifer M; Chang, Qing et al. (2013) Signals from the brainstem sleep/wake centers regulate behavioral timing via the circadian clock. PLoS One 8:e70481
Gillette, Martha U (2013) Introduction to biological timing in health and disease. Prog Mol Biol Transl Sci 119:xi-xvi
Millet, Larry J; Gillette, Martha U (2012) Over a century of neuron culture: from the hanging drop to microfluidic devices. Yale J Biol Med 85:501-21
Govindaiah, Gubbi; Wang, Tongfei; Gillette, Martha U et al. (2012) Activity-dependent regulation of retinogeniculate signaling by metabotropic glutamate receptors. J Neurosci 32:12820-31
Wang, Tongfei A; Yu, Yanxun V; Govindaiah, Gubbi et al. (2012) Circadian rhythm of redox state regulates excitability in suprachiasmatic nucleus neurons. Science 337:839-42
Millet, Larry J; Gillette, Martha U (2012) New perspectives on neuronal development via microfluidic environments. Trends Neurosci 35:752-61
Cecala, Christine; Rubakhin, Stanislav S; Mitchell, Jennifer W et al. (2012) A hyphenated optical trap capillary electrophoresis laser induced native fluorescence system for single-cell chemical analysis. Analyst 137:2965-72

Showing the most recent 10 out of 17 publications