UMMS Affiliation

Department of Neurobiology; Weaver Lab

Date

12-1-2013

Document Type

Article

Medical Subject Headings

ARNTL Transcription Factors; Aging; Animals; Basic Helix-Loop-Helix Transcription Factors; Brain; CLOCK Proteins; Cerebral Cortex; Circadian Rhythm; Corpus Striatum; Gene Expression Regulation; Gliosis; Hippocampus; Homeostasis; Locomotion; Mice, Inbred C57BL; Mice, Knockout; Mice, Neurologic Mutants; Nerve Degeneration; Nerve Tissue Proteins; Neuroglia; Neurons; Oxidation-Reduction; Oxidative Stress; Period Circadian Proteins; RNA Interference; Sleep Disorders, Circadian Rhythm

Disciplines

Neuroscience and Neurobiology

Abstract

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Rights and Permissions

Citation: J Clin Invest. 2013 Dec;123(12):5389-400. doi: 10.1172/JCI70317. Epub 2013 Nov 25. Link to article on publisher's website

The JCI is an open access journal. All research content is freely available immediately upon publication, and all articles published in the JCI are deposited in PubMed Central (PMC). Users are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles under the "fair use" limitations of US copyright law. Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf.

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to article in PubMed

PubMed ID

24270424

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.