Environmental events can rapidly alter the expression of genes in the cerebral cortex. However, what those changes are, and how they may alter the functional adaptation of neuronal circuits and animal behavior, remains poorly understood. The current proposal seeks to identify the regional and cell-type specific changes in neuronal gene expression induced in the frontal cortex by an acute environmental stimulus, and how this influences behavior. Preliminary results from the PI?s laboratory during the prior funding period revealed the novel finding that the acute environmental stimulus of sleep deprivation rapidly upregulates serotonin 2A receptor (5-HT{2A}R) levels in the frontal cortex of mice, in a manner that requires function of the immediate early gene transcription factor Egr3. The overall goal of the current proposal is to define the cell-type specific transcriptional response of frontal cortex neurons to the acute environmental stimulus of sleep deprivation, and to determine the role of activity dependent gene expression in specific frontal cortex circuits on behavior. In this application, the research group brings together an interdisciplinary team and takes an integrated approach combining molecular, cellular, and behavioral approaches to accomplish the goal.
In Aim 1 single cell RNA-seq will be employed to define the cell-type specific changes in gene expression induced in frontal cortex neurons by the acute environmental stimulus of sleep deprivation. Parallel studies performed in Egr3-/- mice will identify the environmentally-induced gene expression changes that require this activity-dependent immediate early gene transcription factor.
In Aim 2, excitatory and inhibitory optogenetic methods will be employed to determine the role of specific cortical circuits in regulating both the 5-HT{2A}R-dependent behaviors identified during the previous funding period, and prefrontal cortex dependent spatial working memory behavior. Impact: It is anticipated that successful completion of these studies will elucidate mechanisms by which environmental stimuli rapidly alter cell-type specific gene expression in the cortex, and how this impacts specific receptors and circuits to alter frontal cortex-mediated states of alertness and processes of spatial memory formation.

Public Health Relevance

The proposed project is highly relevant to public health because it investigates how experience and environment can rapidly change the expression of genes in regions of the brain that are involved in thinking, planning, and processing information. The proposed studies will use animal models to identify how experiences and environmental stimuli change the genes being expressed in the different types of brain cells present in the frontal cortex, and will identify the role of specific brain circuits in behaviors including sleep and memory. These studies are expected to increase our understanding of how experience and environment influence the function of a critical brain region and how this affects processes such as sleep and memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH097803-06A1
Application #
9887017
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
2012-12-01
Project End
2023-10-31
Budget Start
2019-12-03
Budget End
2020-10-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Arizona
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Marballi, Ketan K; Gallitano, Amelia L (2018) Immediate Early Genes Anchor a Biological Pathway of Proteins Required for Memory Formation, Long-Term Depression and Risk for Schizophrenia. Front Behav Neurosci 12:23
Meyers, Kimberly T; Marballi, Ketan K; Brunwasser, Samuel J et al. (2018) The Immediate Early Gene Egr3 Is Required for Hippocampal Induction of Bdnf by Electroconvulsive Stimulation. Front Behav Neurosci 12:92
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Huentelman, Matthew J; Muppana, Leela; Corneveaux, Jason J et al. (2015) Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk. PLoS One 10:e0135076
Maple, Amanda M; Zhao, Xiuli; Elizalde, Diana I et al. (2015) Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner. ACS Chem Neurosci 6:1137-42

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