Forebrain CRF₁Modulates Early-Life Stress-Programmed Cognitive Deficits

Abstract

Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF 1 ), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF 1 knock-out (CRF 1 -CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF 1 in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF 1 deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF 1 -CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF 1 signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.

CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors

“…Although drug treatments tackling CRHR1 have been envisioned as potentially promising anxiolytic and antidepressive drugs (Kunzel et al, 2003;Refojo and Holsboer, 2009), recent evidence in rodents suggests that they could also be effective in modifying not only actual pathological manifestations at adulthood but also the developmental trajectories linking early adversity to adult psychopathology. These rodent studies showed that exposure to stress during the two first postnatal weeks leads to increased central CRH and CRHR1 expression, and altered a number of behaviors in tests of emotion and cognition (Plotsky et al, 2005;Ivy et al, 2010;Wang et al, 2011Wang et al, , 2012. Importantly, they also found that some of the long-term behavioral alterations could be reversed by inhibiting CRHR1 function (e.g., through CRHR1 antagonist treatment or conditional forebrain CRHR1 knockout) in the developmental period occurring immediately after early life stress (Ivy et al, 2010;Wang et al, 2011Wang et al, , 2012.…”

“…These rodent studies showed that exposure to stress during the two first postnatal weeks leads to increased central CRH and CRHR1 expression, and altered a number of behaviors in tests of emotion and cognition (Plotsky et al, 2005;Ivy et al, 2010;Wang et al, 2011Wang et al, , 2012. Importantly, they also found that some of the long-term behavioral alterations could be reversed by inhibiting CRHR1 function (e.g., through CRHR1 antagonist treatment or conditional forebrain CRHR1 knockout) in the developmental period occurring immediately after early life stress (Ivy et al, 2010;Wang et al, 2011Wang et al, , 2012. So far, all those studies involved maternal stress during the first two postnatal weeks.…”

“…In rodents, early life stress e induced during the very early postnatal period by either maternal separation or unstable maternal care e was found to lead to increased anxiety-like behaviors and cognitive deficits in association with increased central CRH and CRHR1 expression (Plotsky et al, 2005;Fenoglio et al, 2006;Ivy et al, 2010;Wang et al, 2011Wang et al, , 2012. Manipulation of the CRHR1 system during development during the aftermath of early life stress exposure was found to prevent some of the longterm behavioral alterations observed at adulthood.…”

“…Manipulation of the CRHR1 system during development during the aftermath of early life stress exposure was found to prevent some of the longterm behavioral alterations observed at adulthood. Thus, in a model of unstable maternal care, either the administration of a CRHR1 antagonist in the developmental period following the maternal stress manipulation (Ivy et al, 2010) or a conditional forebrain CRHR1 deficiency occurring once the stressful episode has elapsed (Wang et al, 2011(Wang et al, , 2012 were found to prevent the emergence of anxiogenic effects and cognitive impairments induced by unstable maternal care. These findings suggest that early interventions tackling the CRHR1 system following exposure to early life stress might be an effective approach to prevent the incidence of psychopathologies in later life.…”

Stress during a Critical Postnatal Period Induces Region-Specific Structural Abnormalities and Dysfunction of the Prefrontal Cortex via CRF1

“…Recently, we and others reported the crucial role of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF 1 ) in modulating the negative effects of early-life stress on the development and plasticity of the hippocampus (Ivy et al, 2010;Liao et al, 2014;Wang et al, 2011;Wang et al, 2013). Because CRF-and CRF 1 -expressing neurons are found in mPFC (Alon et al, 2009;Kühne et al, 2012), this system may also modulate the effects of early-life stress on the development of mPFC pyramidal neurons and prefrontal function.…”