microRNA and the Stress Response
In response to stress, the brain activates neuronal systems linked to the motor, autonomic, neuroendocrine, cognitive, and emotional outputs designed to adapt to the demand. Inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of mood disorders. Cellular mechanisms governing this regulation are not fully understood.
MicroRNAs (miRNAs) are a subset of endogenous small RNA molecules that regulate gene expression post-transcriptionally, by mediating mRNA degradeation or translational repression. miRNAs were shown to respond to various cellular stressors and are abundant in the nervous system; but research on neurons has mainly focused in the context of development and neurodegenerative disorders. Recently, it has been suggested that miRNAs play a role in psychiatric disorders such as schizophrenia and autism, and several studies have implicated miRNAs in normal adult brain mechanisms such as neural plasticity and memory, sleep related processes and circadian-clock modulation. Moreover, analysis of miRNA expression revealed differential miRNA expression in various sub-regions of the adult brain; suggesting specific functions for miRNAs in these areas.
Ongoing studies in our laboratory explore miRNA regulation over the expression of stress-related genes and the effects of stress and stress mediators on miRNA expression both in-vivo in different brain regions and in-vitro using neuronal cell cultures.
We studied the effect of miRNA depletion specifically in the CeA, on anxiety-like behavior in adult mice and examined amygdalar miRNA expression profile following a stressful event."
Summary of selected projects:
miRNA malfunction causes spinal motor neuron disease (In collaboration with Dr. Eran Hornstein lab.)
Defective RNA metabolism is an emerging mechanism involved in ALS pathogenesis and possibly in other neurodegenerative disorders. In a work recently published in PNAS1 we show that microRNA (miRNA) activity is essential for long-term survival of postmitotic spinal motor neurons (SMNs) in vivo. Thus, mice that do not process miRNA in SMNs exhibit hallmarks of spinal muscular atrophy (SMA), including sclerosis of the spinal cord ventral horns, aberrant end plate architecture, and myofiber atrophy with signs of denervation. Furthermore, a neurofilament heavy subunit previously implicated in motor neuron degeneration is specifically up-regulated in miRNA-deficient SMNs. We demonstrate that the heavy neurofilament subunit is a target of miR-9, a miRNA that is specifically down-regulated in a genetic model of SMA. These data provide evidence for miRNA function in SMN diseases and emphasize the potential role of miR-9–based regulatory mechanisms in adult neurons and neurodegenerative states. (Haramati et al., Proc Natl Acad Sci U S A 107:13111-13116, 2010).
MNDicer^mut mice exhibit spinal cord ventral horn sclerosis and axonopathy. (For further information on this figure, please refer to the article by Haramati et al., Proc Natl Acad Sci U S A 107:13111-13116, 2010).
