Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene modulates age effects on working memory
Introduction
Aging is associated with decline across a wide range of cognitive abilities (Baltes and Lindenberger, 1997) that might be relatively subtle, but nevertheless troublesome for the affected individuals and impair their quality of life. Thus, with the increase in average lifespan, understanding the mechanisms that underlie age-associated cognitive decline is of growing importance. Working memory (WM) is one of the cognitive functions most sensitive to aging (Reuter-Lorenz and Park, 2010, Sander et al., 2012) and describes the temporarily storage of information while simultaneously controlling, manipulating and protecting it from distraction to generate goal-directed behavior (Baddeley, 2003). Among other brain regions, the medial temporal lobe (MTL) and hippocampus (HC) are implicated in cognitive functions relevant to WM and particularly relevant for working-memory maintenance (Oztekin et al., 2009, Henke, 2010). Accordingly, several studies reported that the age-related decline in WM performance is associated with volume reductions in hippocampus (Bergfield et al., 2010, Penner et al., 2010, Walhovd et al., 2011, Hara et al., 2012). However, there is also some evidence from animal models and human studies indicating that HC remains structurally intact during normal aging, particularly when HC volume is corrected for total brain volume (Sullivan et al., 2005, Burke and Barnes, 2006, Knoops et al., 2012). Impairment in hippocampal-dependent memory might therefore not be due to massive cell death, but rather to HC dysfunction mediated by age-related changes to the corticotropin-releasing hormone (CRH) system and the hypothalamic-pituitary-adrenal (HPA) axis (Swaab et al., 2005, Lupien et al., 2009, Penner et al., 2010, Aguilera, 2011).
The CRH system is crucial for neuroendocrine and behavioral responses to stress (Dunn and Berridge, 1990, Owens and Nemeroff, 1992). In the hippocampus, CRH is expressed in interneurons and released into the synaptic space to activate CRH receptors (CRHR1) located on pyramidal cell dendrites in response to stress (Chen et al., 2001, Ivy et al., 2010). Previous studies have shown that CRH in hippocampus acts via CRHR1 to induce long-term potentiation (LTP) or potentiate the magnitude of LTP (Blank et al., 2002, Schierloh et al., 2007). Chronic CRHR1 occupancy negatively affects dendritic arborization in vitro and is involved in CRH-induced neuron apoptosis, while administration of a CRHR1 blocker improves memory performance and prevents dendritic atrophy and LTP attenuation (Chen et al., 2010, Maras and Baram, 2012, Zhang et al., 2012). Even though the effects of aging on CRH regulation are far from clear, the majority of studies describe increased CRH production with advancing age (Swaab et al., 2005, Aguilera, 2011). It has been suggested that low-level activation of CRHR1 for short durations may enhance hippocampal function, whereas longer exposure to high levels of CRH may be deleterious (Maras and Baram, 2012). Alterations in hippocampal CRHR1 activation might therefore play an important role for the structural, functional and cognitive impairments associated with aging.
While it is well-known that both genetic and environmental factors contribute to the progressive WM deficits emerging with aging (Finkel et al., 2005, Lindenberger et al., 2008), more than 60% of individual differences in cognitive abilities are heritable (Friedman et al., 2008) and remarkably stable across the adult lifespan (Deary et al., 2004, Finkel et al., 2005). The mechanisms by which genetic factors might promote progressive memory dysfunction remain largely unknown, though. Gene-cognition association studies on memory-related functions have mainly focused on the Brain-Derived Neurotrophic Factor (BDNF) and Catechol-O-Methyltransferase (COMT) genes (Goldberg and Weinberger, 2004, Savitz et al., 2006), and shown that aging magnifies the effect of genotype on WM performance (Lindenberger et al., 2008, Nagel et al., 2008). However, despite extensive studies on the respective effects of aging on WM, CRH regulation and hippocampus structure and function, the effects of genetic variation within the CRH receptor 1 gene on WM performance have not been described yet. Single nucleotide polymorphisms (SNPs) in the CRHR1 gene are associated with behavioral and neuroendocrine evidence of stress vulnerability or resilience. In particular, the rs110402 A and rs242924 T alleles seem to have a protective effect against major depressive disorder (MDD) in individuals exposed to moderate and severe early life stress (ELS) (Bradley et al., 2008, Polanczyk et al., 2009). Accordingly, in healthy subjects with GG genotype on both SNPs an ELS × CRHR1 genotype interaction is reflected in an elevated cortisol response to the dexamethasone/corticotropin-releasing hormone test (DEX/CRH test) (Tyrka et al., 2009). Recent results in healthy humans and animal data showed lesser BOLD-responses in the MTL in GG-homozygotes (Hsu et al., 2012) and that CRHR1 SNPs influence metabolic activity in the anterior hippocampus (Rogers et al., 2013). The mechanism by which rs110402 and rs242924 affect the function of CRHR1 is presently unknown. Variations of these polymorphisms may affect the regulation of CRHR1 receptors, resulting in increased stress vulnerability, altered neural activity and consequently affected WM performance. Aging might magnify the genetic effects on WM and be associated with more pronounced WM impairments in the less stress-resilient GG-homozygotes.
There is considerable evidence that cognitive competencies in old age might be enhanced by positive emotional stimuli (Broster et al., 2012, Nashiro et al., 2012). The tendency for older adults to perform better on positively valenced stimuli with regard to measures of attention and memory has been termed the age-related positivity effect (Mather and Knight, 2005, Lockenhoff and Carstensen, 2007), and it was recently shown that positive words also attenuate age-related differences in WM (Mammarella et al., 2013).
The goal of the current study was to examine the interaction effects of variation in the CRHR1 gene and age on individual differences in WM. Since GG-homozygous individuals of rs110402 and rs242924 show greater stress vulnerability, elevated cortisol response and decreased BOLD responses in WM relevant regions, we hypothesized impaired WM performance in GG-homozygotes that might be magnified by increased CRH production with advancing age.
As several previous studies demonstrated a positivity effect in older adults with enhanced memory performance for positive stimuli, we furthermore aimed to investigate whether old subjects could at least partially compensate for their memory deficits if positive stimuli were presented and whether this effect might differ depending on the genotype.
Section snippets
Subjects
All subjects were recruited from responses to advertising in local newspapers and mailing lists. Subjects were screened for psychiatric disorders using the short version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, SCID). Inclusion criteria were age 18–90 years, absence of present and past diagnosis of psychiatric or neurologic disease, absence of major or unstable general medical conditions, and ability to participate in study
Sample
Data from 20 subjects could not be evaluated because of missing n-back or questionnaire data. Furthermore, we had to exclude 24 subjects with missing genetic data, 9 subjects with rare genotype combinations (see genotyping section), 19 extreme outliers in the n-back task (performance deviating more than 3 SD from the mean) and 3 subjects with an IQ below average. This resulted in a final sample size of N = 466 (see Table 2). The sample was divided into 3 age groups (young: 18–30 yrs, n = 213;
Discussion
This study examined the interaction effects of variation in the CRHR1 gene and age on individual differences in working memory. We hypothesized that GG-homozygous individuals of rs110402 and rs242924 would show impaired WM performance that might be magnified by increased CRH production with advancing age. Our results show an impact of genotype already in middle age with significantly better performance in AT-carriers compared to GG-homozygotes. In old age, there were no significant differences
Role of the funding source
Financial support for the conduct of the research was provided by Deutsche Forschungsgemeinschaft (DFG; ECC 302-405). The funding source had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Contributors
Drs Grimm and Gärtner contributed equally to this work. Drs Grimm, Bajbouj, Heekeren, Jacobs and Heuser designed the study and supervised the project. Mr Fuge carried out the experiment. Ms Fan, Ms Feeser, Drs Grimm, Gärtner, Weigand and Aust analyzed the data. Drs Grimm and Gärtner wrote the manuscript. All authors approved the final manuscript.
Conflict of interest
All authors report neither potential conflict of interest nor financial interest.
Acknowledgments
We thank the team of Dahlem Institute for Neuroimaging of Emotion for their technical support.
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Both authors contributed equally.