Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling
Research Highlights
►Forebrain CRHR1 deficiency attenuates memory impairments induced by chronic stress. ►Forebrain CRHR1 inactivation prevents chronic stress-induced CA3 dendritic shrinkage. ►Nectin-3 is associated with stress-induced structural changes and memory loss. ►CRHR1 interacts with chronic stress to regulate endocrine and metabolic function.
Introduction
Chronic psychosocial stress in adulthood modulates brain structure and function, resulting in cognitive deficits and an increased risk for psychiatric disorders (de Kloet et al., 2005, Lupien et al., 2009). The hippocampus, a limbic brain region critically involved in neuroendocrine regulation of stress hormones (Kim and Diamond, 2002) and spatial memory processing (Squire et al., 2007), is particularly vulnerable to uncontrollable stress (Chen et al., 2010, Joëls and Baram, 2009, Kim and Diamond, 2002). Various forms of chronic stress lead to reversible but long-lasting spatial memory impairments in adult male rodents (Bisaz et al., 2011, Conrad et al., 1996, Wright and Conrad, 2005). These effects are associated with atrophy of apical dendrites of CA3 pyramidal neurons (Kole et al., 2004, Magariños and McEwen, 1995, McLaughlin et al., 2007, Watanabe et al., 1992), suppression of hippocampal synaptic plasticity (Joëls et al., 2004, Kole et al., 2004, Pavlides et al., 2002), and altered expression of synaptic cell adhesion molecules in the hippocampus (Bisaz et al., 2011, Sandi, 2004).
The mechanisms of chronic stress-induced spatial memory impairments remain to be understood. Chronic exposure to elevated glucocorticoids has been shown to induce apical dendritic retraction of CA3 pyramidal neurons (Conrad et al., 2007, Woolley et al., 1990) and impair spatial memory (Coburn-Litvak et al., 2003), similar to the effects caused by chronic stress. Moreover, in some studies, inhibition of glucocorticoid elevations prevents spatial memory retrieval deficits due to CA3 damage (Roozendaal et al., 2001) and impairments of spatial recognition memory by chronic stress (Wright et al., 2006). It is therefore proposed that chronic stress reduces dendritic complexity of CA3 neurons, which in turn disrupts hypothalamic-pituitary-adrenal (HPA) axis function and elevates glucocorticoid levels, leading to spatial memory deficits (Conrad, 2006). However, discrepant findings have also been reported. Repeated exposure to high levels of glucocorticoids and stress produced CA3 dendritic atrophy, but failed to impair spatial memory function (Conrad et al., 2007) and even facilitated spatial memory in ovariectomized female rats (McLaughlin et al., 2005) and hippocampus-involved contextual fear conditioning (Conrad et al., 1999). Hence, factors other than elevated glucocorticoids and CA3 dendritic retraction must be responsible for chronic stress-induced spatial memory impairments.
Corticotropin-releasing hormone (CRH) and its receptors are not only key mediators of neuroendocrine and behavioral responses to stress, but are also involved in learning and memory (Arzt and Holsboer, 2006, Heinrichs and Koob, 2004, Joëls and Baram, 2009). Transient increase in CRH facilitates hippocampus-dependent learning and memory (Lee et al., 1993, Radulovic et al., 1999, Row and Dohanich, 2008), whereas prolonged exposure to elevated CRH impairs spatial memory performance (Heinrichs et al., 1996). In the hippocampus, CRH is expressed in inhibitory interneurons (Chen et al., 2001) and interacts primarily with CRH receptor 1 (CRHR1), which is enriched in dendritic spines of pyramidal neurons (Chen et al., 2004b, Van Pett et al., 2000). Acute psychological stress induces release of hippocampal CRH (Chen et al., 2004b), which activates hippocampal neurons through CRHR1 (Chen et al., 2006, Refojo et al., 2005), and leads to rapid but reversible reduction in dendritic spines of CA3 neurons (Chen et al., 2008). Additionally, chronic exposure to CRH in vitro results in atrophy of dendrites of hippocampal neurons (Chen et al., 2004a). These findings point to the possibility that a sustained elevation of endogenous CRH during chronic stress contributes to dendritic remodeling.
Chronic stress paradigms in rodents typically involve intermittent restraint for 6 h per day (Hains et al., 2009, Watanabe et al., 1992, Wright and Conrad, 2005), a monotonous procedure that may lead to habituation (Haile et al., 2001, Willner, 2005). Chronic social defeat provides a naturalistic and complex chronic stress in male mice that is relevant to human social interactions, and has a high validity for psychiatric disorders (Krishnan et al., 2007, Tsankova et al., 2006). However, the effects of such stress on dendritic arborization, specifically the role of CRH and CRHR1 in dendritic integrity and spatial memory during recurrent social defeat, have remained unclear.
To address these issues, we subjected conditional forebrain CRHR1-deficient mice and wild-type controls to chronic social defeat stress. The effects of chronic stress were evaluated, with a focus on cognitive function and its structural and molecular substrates. We hypothesized that chronic social defeat stress would impair spatial memory in a CRHR1-dependent manner, so that forebrain CRHR1 deficiency would protect from the memory impairments provoked by chronic stress.
Section snippets
Animals
Transgenic mice with postnatal inactivation of the Crhr1 gene in forebrain neurons (CRHR1Camk2aCre mice) were generated as described previously (Müller et al., 2003) (see Supplementary Materials and Methods). All animals were housed under a 12-hour light/dark cycle (lights on at 6 AM) and constant temperature (22 ± 1 °C) with free access to both food and water. The experiments were carried out in accordance with European Communities Council Directive 86/609/EEC. The protocols were approved by the
Forebrain CRHR1 deficiency attenuates object recognition and spatial memory impairments induced by chronic social defeat stress
We evaluated the cognitive performance of the animals using the object recognition test, which involves medial temporal lobe structures including the hippocampus (Dere et al., 2007, Squire et al., 2007). A significant condition × genotype interaction effect [F(1,32) = 4.253, p < 0.05] on object preference was observed. Control wild-type and control and stressed CRHR1Camk2aCre mice displayed intact memory as shown by significantly more exploration of the novel object than the familiar one in the
Discussion
Chronic stress induces spatial memory impairments and dendritic remodeling. In the current study, we demonstrate that forebrain CRHR1 deficiency attenuates spatial memory deficits and prevents the dendritic regression of CA3 neurons and the loss of hippocampal nectin-3 expression induced by chronic social defeat stress. Moreover, the metabolic and neuroendocrine effects of chronic social defeat stress are also dependent on CRHR1 in the forebrain region. Together, our findings suggest that the
Acknowledgments
We thank Stefanie Unkmeir and Robert Menz for their technical assistance. This work was supported by the European Community's Seventh Framework Program (FP7, Project No. 201600), the Bundesministerium für Bildung und Forschung within the framework of the NGFN-Plus (FKZ: 01GS08151 and 01GS08155) and by the Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215).
References (75)
- et al.
CRF signaling: molecular specificity for drug targeting in the CNS
Trends Pharmacol. Sci.
(2006) Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress
Neuroscience
(2004)Chronic administration of corticosterone impairs spatial reference memory before spatial working memory in rats
Neurobiol. Learn. Mem.
(2003)Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1
Brain Res.
(1999)Stress and cognition: are corticosteroids good or bad guys?
Trends Neurosci.
(1999)The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents
Neurosci. Biobehav. Rev.
(2007)- et al.
A method for vibratome sectioning of Golgi–Cox stained whole rat brain
J. Neurosci. Methods.
(1998) Long-term effects on feeding and body weight after stimulation of forebrain or hindbrain CRH receptors with urocortin
Brain Res.
(2000)Learning impairment in transgenic mice with central overexpression of corticotropin-releasing factor
Neuroscience
(1996)Involvement of nectins in the formation of puncta adherentia junctions and the mossy fiber trajectory in the mouse hippocampus
Mol. Cell. Neurosci.
(2006)
Bidirectional shift in the cornu ammonis 3 pyramidal dendritic organization following brief stress
Neuroscience
Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions
Cell
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors
Neuroscience
Involvement of afadin in the formation and remodeling of synapses in the hippocampus
Biochem. Biophys. Res. Commun.
Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: possible involvement of CA1 neurons
Neuroscience
The effects of chronic stress on hippocampal morphology and function: an evaluation of chronic restraint paradigms
Brain Res.
Psychosocial stress affects energy balance in mice: modulation by social status
Psychoneuroendocrinology
Direct visualization of glucocorticoid receptor positive cells in the hippocampal regions using green fluorescent protein transgenic mice
Neuroscience
Post-training administration of corticotropin-releasing hormone (CRH) enhances retention of a spatial memory through a noradrenergic mechanism in male rats
Neurobiol. Learn. Mem.
Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence
Psychoneuroendocrinology
Visualization of glucocorticoid receptor in the brain of green fluorescent protein-glucocorticoid receptor knockin mice
Neuroscience
Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons
Brain Res.
Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons
Brain Res.
Metabolic consequences and vulnerability to diet-induced obesity in male mice under chronic social stress
PLoS ONE
Effects of third intracerebroventricular injections of corticotropin-releasing factor (CRF) on ethanol drinking and food intake
Psychopharmacol. Berl.
Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity
Proc. Natl Acad. Sci. USA
Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress-induced cognitive impairments
Hippocampus
Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning
J. Neurosci.
Object recognition memory and the rodent hippocampus
Learn. Mem.
Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety
Nat. Biotechnol.
Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians
Int. J. Obes. Relat. Metab. Disord.
Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis
J. Neurosci.
Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus
Proc. Natl Acad. Sci. USA
Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent
Mol. Psychiatry
Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone
J. Neurosci.
Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling
Proc. Natl Acad. Sci. USA
What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus?
Behav. Cogn. Neurosci. Rev.
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