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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Toth, Miklos (2015) Mechanisms of non-genetic inheritance and psychiatric disorders. Neuropsychopharmacology 40:129-40
Oh, J-E; Chambwe, N; Klein, S et al. (2013) Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment. Transl Psychiatry 3:e218
Hartrampf, Steffen; Dudakov, Jarrod A; Johnson, Linda K et al. (2013) The central nervous system is a target of acute graft versus host disease in mice. Blood 121:1906-10
Rajadhyaksha, Anjali M; Ra, Stephen; Kishinevsky, Sarah et al. (2012) Behavioral characterization of cereblon forebrain-specific conditional null mice: a model for human non-syndromic intellectual disability. Behav Brain Res 226:428-34
Zupan, Bojana; Toth, Miklos (2012) Fmr-1 as an offspring genetic and a maternal environmental factor in neurodevelopmental disease. Results Probl Cell Differ 54:243-53
Bortolozzi, A; Castañé, A; Semakova, J et al. (2012) Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol Psychiatry 17:612-23
Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B et al. (2011) Cocaine analog coupled to disrupted adenovirus: a vaccine strategy to evoke high-titer immunity against addictive drugs. Mol Ther 19:612-9
Guilloux, Jean-Philippe; David, Denis J P; Xia, Lin et al. (2011) Characterization of 5-HT(1A/1B)-/- mice: an animal model sensitive to anxiolytic treatments. Neuropharmacology 61:478-88
van Velzen, A; Toth, M (2010) Role of maternal 5-HT(1A) receptor in programming offspring emotional and physical development. Genes Brain Behav 9:877-85
Gleason, G; Liu, B; Bruening, S et al. (2010) The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc Natl Acad Sci U S A 107:7592-7

Showing the most recent 10 out of 18 publications