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.
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.
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| Garcia-Garcia, A L; Meng, Q; Richardson-Jones, J et al. (2016) Disruption of 5-HT1A function in adolescence but not early adulthood leads to sustained increases of anxiety. Neuroscience 321:210-221 |
| Adam Samuels, Benjamin; Leonardo, E David; Hen, René (2015) Hippocampal subfields and major depressive disorder. Biol Psychiatry 77:210-211 |
| Dranovsky, Alex; Leonardo, E David (2015) Neuroscience: The power of positivity. Nature 522:294-5 |
| Garcia-Garcia, Alvaro L; Newman-Tancredi, Adrian; Leonardo, E David (2014) 5-HT(1A) [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. Psychopharmacology (Berl) 231:623-36 |
| 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 |
| Kirshenbaum, Greer S; Lieberman, Sophie R; Briner, Tamara J et al. (2014) Adolescent but not adult-born neurons are critical for susceptibility to chronic social defeat. Front Behav Neurosci 8:289 |
| 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 |
| 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 |
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