Anxiety disorders, including panic, generalized anxiety and posttraumatic stress disorders, are common. Some symptoms of anxiety such as avoidance, increased vigilance, increased heart rate and blood pressure can be reproduced in animal models, in particular in genetically modified mice. One of these models, the 5-HT1A receptor (R) deficient mouse strain has construct validity because low 5-HT1AR level has been repeatedly found in psychiatric disorders. Although 5-HT1 AR deficient mice have been extensively characterized at the behavioral level, little is known about the molecular and cellular basis of their anxiety-like phenotype. The major goal of our funded research was to elucidate some of the neurobiological processes and mechanisms which are associated with the anxiety-like behavior of the 5- HT1 AR knockout (KO) mice. This work identified a number of gene-expression changes in the fearf'anxiety"""""""" circuit;in particular in the prefrontal cortex (PFC) and the hippocampus. The PFC-specific abnormalities involve defects in GABAergic and glutamatergic neurotransmission and associated with loss of inhibition/increased excitability. The hippocampus shows changes in cell cycle related genes (cyclin D1/2 and some cyclin dependent kinases (cdks)), which are associated with reduced proliferation and probably increased survival of postmitotic neurons during early postnatal life. The main goal of the current application is to specify the neurobiological abnormalities in the hippocampus of 5-HT1AR deficient mice including 1) the mechanism of 5-HT1AR-mediated regulation of gene expression, 2) effect of the 5-HT1AR on neuronal precursor proliferation and 3) programmed cell death during early postnatal development. Similar mechanisms may also be involved in the pathomechanism of some anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH058669-10
Application #
7782756
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Panchision, David M
Project Start
2000-09-23
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
10
Fiscal Year
2010
Total Cost
$346,648
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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