The aim of the current proposal is to characterize a late sensitive period for the development of anxiety and mood disorders. Evidence to date suggests that disruption of the serotonergic system during post--‐natal development in animal models results in altered anxiety and mood related behaviors in the full grown adult animal. In particular, there is evidence that proper signaling through 5--‐HT1A receptors is required in the third postnatal week for the development of normal circuits that mediate anxiety. Thus, disruptions of occurring at this time likely result in the de novo formation of aberrant circuits. In the current proposal, we intend to test the hypothesis that a later sensitive period also exists after the initial circuitry has formed. In our model, once normal circuitry that sub--‐serves anxiety and depression related behavior has formed, there is a vulnerable period during which time the circuits remain unstable and vulnerable to disruption. In this model, disruption of 5--‐HT1A signaling at this time results in aberrant circuitry through aberrant maturation and stabilization of the circuits that have already formed. The experiments proposed are aimed at defining the exact window of late vulnerability. We will do this using a transgenic mouse approach that relies on reversible knockouts of the 5--‐HT1A receptor. In addition, using reversible knockouts of 5--‐ HT1A auto and heteroreceptors, we intend to identify the specific population of receptors that is responsible for the late window.

Public Health Relevance

The 5-HT1A receptor in particular and the serotonergic system in general has been implicated in both the etiology and treatment of anxiety and depressive disorders. For the 5-HT1A receptor there is evidence from model systems that sensitive periods exist during which normal 5-HT1A function may be particulary critical. Recently, in humans a functional polymorphism that affects 5-HT1A receptor expression levels has been identified that increases susceptibility to stress and depression. Studies such as the ones proposed with this application may shed light on the mechanism of this association and may point to particularly important time in development when therapeutic interventions could have maximal effect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091427-03
Application #
8255596
Study Section
Special Emphasis Panel (ZMH1-ERB-L (02))
Program Officer
Winsky, Lois M
Project Start
2010-07-05
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$398,066
Indirect Cost
$107,225
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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Donaldson, Zoe R; Piel, David A; Santos, Tabia L et al. (2014) Developmental effects of serotonin 1A autoreceptors on anxiety and social behavior. Neuropsychopharmacology 39:291-302
Samuels, Benjamin A; Leonardo, E David; Dranovsky, Alex et al. (2014) Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors. PLoS One 9:e85136
Altieri, Stefanie C; Garcia-Garcia, Alvaro L; Leonardo, E David et al. (2013) Rethinking 5-HT1A receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior. ACS Chem Neurosci 4:72-83
Dranovsky, Alex; Leonardo, E David (2012) Is there a role for young hippocampal neurons in adaptation to stress? Behav Brain Res 227:371-5
Richardson-Jones, Jesse W; Craige, Caryne P; Nguyen, Thanh H et al. (2011) Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety. J Neurosci 31:6008-18