Early-life experience reduces excitation to stress-responsive hypothalamic neurons and reprograms the expression of corticotropin-releasing hormone.
Increased sensory input from maternal care attenuates neuroendocrine and behavioral responses to stress long term and results in a lifelong phenotype of resilience to depression and improved cognitive function. Whereas the mechanisms of this clinically important effect remain unclear, the early, persistent suppression of the expression of the stress neurohormone corticotropin-releasing hormone (CRH) in hypothalamic neurons has been implicated as a key aspect of this experience-induced neuroplasticity. Here, we tested whether the innervation of hypothalamic CRH neurons of rat pups that received augmented maternal care was altered in a manner that might promote the suppression of CRH expression and studied the cellular mechanisms underlying this suppression. We found that the number of excitatory synapses and the frequency of miniature excitatory synaptic currents onto CRH neurons were reduced in "care-augmented" rats compared with controls, as were the levels of the glutamate vesicular transporter vGlut2. In contrast, analogous parameters of inhibitory synapses were unchanged. Levels of the transcriptional repressor neuron-restrictive silencer factor (NRSF), which negatively regulates Crh gene transcription, were markedly elevated in care-augmented rats, and chromatin immunoprecipitation demonstrated that this repressor was bound to a cognate element (neuron-restrictive silencing element) on the Crh gene. Whereas the reduced excitatory innervation of CRH-expressing neurons dissipated by adulthood, increased NRSF levels and repression of CRH expression persisted, suggesting that augmented early-life experience reprograms Crh gene expression via mechanisms involving transcriptional repression by NRSF.
Korosi
Aniko
A
Anatomy/Neurobiology and Pediatrics, University of California Irvine, Irvine, California 92697, USA.
Shanabrough
Marya
M
McClelland
Shawn
S
Liu
Zhong-Wu
ZW
Borok
Erzsebet
E
Gao
Xiao-Bing
XB
Horvath
Tamas L
TL
Baram
Tallie Z
TZ
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008297:Male; D008426:Maternal Deprivation; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
D003346:Corticotropin-Releasing Hormone; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D012097:Repressor Proteins; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D050599:Vesicular Glutamate Transport Protein 2; D000099229:RE1-Silencing Transcription Factor