Serotonin Signaling through Prefrontal Cortex 5-HT1AReceptors during Adolescence Can Determine Baseline Mood-Related Behaviors.
Lifelong homeostatic setpoints for mood-related behaviors emerge during adolescence. Serotonin (5-HT) plays an important role in refining the formation of brain circuits during sensitive developmental periods. In rodents, the role of 5-HT1Areceptors in general and autoreceptors in particular has been characterized in anxiety. However, less is known about the role of 5-HT1Areceptors in depression-related behavior. Here, we show that whole-life suppression of heteroreceptor expression results in a broad depression-like behavioral phenotype accompanied by physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper (mPFC-DRN) circuitry. These changes include increased basal 5-HT in a mPFC that is hyporesponsive to stress and decreased basal 5-HT levels and firing rates in a DRN hyperactivated by the same stressor. Remarkably, loss of heteroreceptors in the PFC at adolescence is sufficient to recapitulate this depression-like behavioral syndrome. Our results suggest that targeting mPFC 5-HT1Aheteroreceptors during adolescence in humans may have lifelong ramifications for depression and its treatment.
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA.
Alvaro L
AL
Garcia-Garcia
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA.
Qingyuan
Q
Meng
Department of Psychiatry, Columbia University, New York, NY 10032, USA.
Sarah
S
Canetta
CESP, University Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry 91290, France.
Alain M
AM
Gardier
CESP, University Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry 91290, France.
Bruno P
BP
Guiard
Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA; Department of Anesthesiology, Columbia University Medical Center, New York, NY 10032, USA.
Christoph
C
Kellendonk
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA. Electronic address: ad722@cumc.columbia.edu.
Alex
A
Dranovsky
Dranovsky-Leonardo (ADL) Lab, Division of Integrative Neuroscience, Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Box 87, New York, NY 10032, USA. Electronic address: el367@cumc.columbia.edu.
E David
ED
Leonardo
D000339:Affect / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology; D017660:Autoreceptors / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology*; D003863:Depression / Q000378:metabolism / Q000503:physiopathology; D065847:Dorsal Raphe Nucleus / Q000378:metabolism; D008297:Male; D051379:Mice; D017397:Prefrontal Cortex / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D017660:Autoreceptors; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin
5-HT(1A); DRN; adolescence; anxiety; depression; development; mPFC; serotonin