Single-Cell Transcriptional Changes in Hypothalamic Corticotropin-Releasing Factor–Expressing Neurons After Early-Life Adversity Inform Enduring Alterations in Vulnerabilities to Stress

Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses

“…As noted above, reduced surface expression of phosphatidylserine will reduce neuronal synapse interaction with microglial MerTK, leading to attenuated synapse engulfment ( Park et al, 2021 ; Scott-Hewitt et al, 2020 ). In support of a neuron-to-glia information flow induced by ELA, a recent single-cell transcriptomics analysis of these hypothalamic CRH cells identified profound effects of ELA, which were apparent already by the end of the ELA period ( Short et al, 2021 ). Importantly, these ELA-induced changes were specific to CRH-expressing neurons residing in the dorsomedial PVN, in accord with the specificity of microglial deficits reported here.…”

“…We next determined the enduring consequences of ELA and of activating microglia early in life on the hormonal responses to stress of adult control and ELA mice. ELA augmented adrenal weights, in accord with our prior work ( Avishai-Eliner et al, 2001 ; Brunson et al, 2005 ; Short et al, 2021 ). Remarkably, chemogenetic microglial activation prevented the ELA-induced increase in adrenal weight (F 3,24 = 11.11, p < 0.0001; one-way ANOVA; p < 0.05, Holm-Sidak’s multiple comparisons test; Figure 4D ).…”

Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala

“…The expression, and potentially function, of Crh and its receptors are influenced by early life experiences ( Eghbal-Ahmadi et al, 1997 ; Bolton et al, 2020 ; Short et al, 2021 ). Therefore, we tested for effects of rearing condition on the expression of Crh -related genes in the amygdala.…”

“…Thus, an extensive amount of work has focused on the elements of care that might constitute ELA. Indeed, the quantity and quality of postnatal care influences neurodevelopmental outcomes, especially with regard to the programing of stress circuits ( Norman et al, 2012 ; Glod and Teicher 1996 ; Herzog and Schmahl 2018 ; Nelson et al, 2020 ; Short et al, 2021 ).…”

“…One identified candidate mechanism involves long-lasting molecular changes, which alter the level and timing of expression of crucial genes supporting neurodevelopment ( Fiori and Turecki, 2016 ; Nestler 2012 ; Vaiserman and Koliada 2017 ; Peña et al 2019 ; Bolton et al, 2020 ). Indeed, significant effects of ELA on the transcriptome have been established ( Short et al, 2021 ; Bolton et al, 2020 ). One key molecular target that has been identified to be impacted by maternal signals is corticotropin releasing hormone ( Crh ).…”