Hippocampal Dysfunction and Cognitive Impairments Provoked by Chronic Early-Life Stress Involve Excessive Activation of CRH Receptors

Abstract

Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF 1 ) located on pyramidal cell dendrites. Additionally, chronic CRF 1 occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF 1 receptors. Central or peripheral administration of a CRF 1 blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF 1 interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF 1 occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.

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.…”

“…The CRH family comprises several ligands (CRH and urocortins 1, 2 and 3) and two receptors, CRH receptor 1 (CRHR1, to which CRH and urocortin 1 bind preferentially) and the CRH receptor 2 (CRHR2), both present in the hypothalamus as well as in limbic brain areas including the amygdala and hippocampus (Binder and Nemeroff, 2010). In addition to its key role in modulating peripheral responses through the activation of the hypothalamusepituitaryeadrenal (HPA) axis, the CRH/CRHR1 system plays a critical role in mediating some types of anxiety and depression responses (Dunn and Berridge, 1990;Contarino et al, 1999;Steckler and Holsboer, 1999;Muller et al, 2003;Muller and Wurst, 2004;Todorovic et al, 2005;Ivy et al, 2010;Wang et al, 2012). Application of CRHR1 antagonists exerts anxiolytic and antidepressant-like effects in animals with high levels of anxiety and in animals that have been pre-exposed to stressors (Keck et al, 2001;Lancel et al, 2002;Sandi et al, 2008).…”

“…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.…”