title: Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function.
abstract: Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2-P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2-P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors.
authors.affiliation: Columbia University, New York, New York 10027.
authors.forename: Tahilia J
authors.initials: TJ
authors.lastname: Rebello
authors.affiliation: Columbia University, New York, New York 10027.
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Yu
authors.affiliation: University of Toronto, Toronto, Ontario ON M5S 1A8, Canada.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Goodfellow
authors.affiliation: Columbia University, New York, New York 10027.
authors.forename: Martha K
authors.initials: MK
authors.lastname: Caffrey Cagliostro
authors.affiliation: Columbia University, New York, New York 10027.
authors.forename: Anne
authors.initials: A
authors.lastname: Teissier
authors.affiliation: Columbia University, New York, New York 10027.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Morelli
authors.affiliation: Columbia University, New York, New York 10027.
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Demireva
authors.affiliation: Columbia University, New York, New York 10027.
authors.forename: Alexei
authors.initials: A
authors.lastname: Chemiakine
authors.affiliation: Columbia University, New York, New York 10027, New York State Psychiatric Institute, New York, New York 10032, and Macedonian Academy of Sciences and Arts, 1000 Skopje, Macedonia.
authors.forename: Gorazd B
authors.initials: GB
authors.lastname: Rosoklija
authors.affiliation: Columbia University, New York, New York 10027, New York State Psychiatric Institute, New York, New York 10032, and Macedonian Academy of Sciences and Arts, 1000 Skopje, Macedonia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dwork
authors.affiliation: University of Toronto, Toronto, Ontario ON M5S 1A8, Canada.
authors.forename: Evelyn K
authors.identifier: http://orcid.org/0000-0002-5994-6090
authors.initials: EK
authors.lastname: Lambe
authors.affiliation: Columbia University, New York, New York 10027, New York State Psychiatric Institute, New York, New York 10032, and jag46@columbia.edu.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Gingrich
authors.affiliation: Columbia University, New York, New York 10027, New York State Psychiatric Institute, New York, New York 10032, and.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Ansorge
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000150:complications / Q000378:metabolism*; D001522:Behavior, Animal; D003863:Depression / Q000150:complications / Q000378:metabolism*; D005108:Extinction, Psychological; D005239:Fear; D005260:Female; D008297:Male; D051379:Mice; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D012701:Serotonin
keywords: SSRI; anxiety; development; mouse; prefrontal cortex; serotonin