Stress during a critical postnatal period induces region-specific structural abnormalities and dysfunction of the prefrontal cortex via CRF1.
During the early postnatal period, environmental influences play a pivotal role in shaping the development of the neocortex, including the prefrontal cortex (PFC) that is crucial for working memory and goal-directed actions. Exposure to stressful experiences during this critical period may disrupt the development of PFC pyramidal neurons and impair the wiring and function of related neural circuits. However, the molecular mechanisms of the impact of early-life stress on PFC development and function are not well understood. In this study, we found that repeated stress exposure during the first postnatal week hampered dendritic development in layers II/III and V pyramidal neurons in the dorsal agranular cingulate cortex (ACd) and prelimbic cortex (PL) of neonatal mice. The deleterious effects of early postnatal stress on structural plasticity persisted to adulthood only in ACd layer V pyramidal neurons. Most importantly, concurrent blockade of corticotropin-releasing factor receptor 1 (CRF1) by systemic antalarmin administration (20 μg/g of body weight) during early-life stress exposure prevented stress-induced apical dendritic retraction and spine loss in ACd layer V neurons and impairments in PFC-dependent cognitive tasks. Moreover, the magnitude of dendritic regression, especially the shrinkage of apical branches, of ACd layer V neurons predicted the degree of cognitive deficits in stressed mice. Our data highlight the region-specific effects of early postnatal stress on the structural plasticity of prefrontal pyramidal neurons, and suggest a critical role of CRF1 in modulating early-life stress-induced prefrontal abnormalities.
1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Xiao-Dun
XD
Yang
1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Xue-Mei
XM
Liao
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Andrés
A
Uribe-Mariño
1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Rui
R
Liu
1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Xiao-Meng
XM
Xie
Department of Mental Health, Dayi Hospital Affiliated to Shanxi Medical University, Taiyuan, China.
Jiao
J
Jia
1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Yun-Ai
YA
Su
1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Ji-Tao
JT
Li
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Mathias V
MV
Schmidt
Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
Xiao-Dong
XD
Wang
1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Tian-Mei
TM
Si
D000818:Animals; D000831:Animals, Newborn; D001008:Anxiety Disorders / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000002:abnormalities* / Q000187:drug effects / Q000254:growth & development* / Q000503:physiopathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011897:Random Allocation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D000099052:CRF Receptor, Type 1
D006727:Hormone Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D000099052:CRF Receptor, Type 1