Marian Joels

UMC Utrecht, The Netherlands

Adverse conditions early in life present a serious risk factor for the development of psychopathology in adulthood, especially in genetically vulnerable individuals (Heim et al., 2008). As an example, we recently studied the relation between early life conditions and scores on the Beck Depression Inventory in a population of young adults (age 18-25) without overt psychiatric problems (Vinkers et al., 2014). A very strong correlation between the two parameters was apparent, both in the discovery and a (older) replication cohort. A composite cumulative stress index composed of early life trauma, number of life events and daily hassles was significantly associated with depression both in the discovery and replication sample, especially in those individuals with high levels of trait neuroticism. Several animal models were developed to study the effects of early life adversity under highly controlled conditions, the latter with respect to the genetic background and environmental circumstances. One such model makes use of natural variations in the interaction of the dam with her litter (Zhang et al., 2013). There is a wide range in the amount of licking and grooming dams bestow on their litter, as well as the degree of arched-back nursing. It was shown that pups from mothers displaying a low (as opposed to a high) degree of licking-grooming behavior and arched-back nursing have relatively low expression of corticosteroid receptors in the hippocampus, less efficient negative feedback of their hormonal stress response, as well as a low degree of structural plasticity in the hippocampus (Zhang et al., 2013). We showed that hippocampal functional plasticity in these pups from low (compared to high) licking-grooming mothers is also impaired (Champagne et al., 2008). There even appears to be a significant correlation between the amount of licking-grooming received by individual pups from their mother and the adult hippocampal glucocorticoid receptor expression and ability to induce synaptic plasticity (Van Hasselt et al., 2012). Results from other studies are largely in line with these examples, showing that early life adverse conditions generally increase anxiety, impair higher cognitive functions and reduce the ability for structural and functional plasticity in adulthood (Loi et al., 2016). Yet, early adversity does not invariably lead to a negative outcome later in life. Firstly, the consequences of early life adversity appear to differ greatly between male and female subjects. In rodents, females particularly show aberrant function in tests probing depressive-like behavior, stressful learning (like fear conditioning), anxiety related behavior and less so in social behavior or non-stressful hippocampal dependent learning (overview in Loi et al., 2016). This contrasts with males who besides deficits in depressive-like behavior also show impaired non-stressful hippocampal dependent learning, and to a lesser degree in stressful learning, social behavior and anxiety related behavior. Interestingly, male rodents overall show a stronger behavioral phenotype after early life stress than females (Loi et al., 2016), which is somewhat unexpected given the higher prevalence of psychopathology in women. A second factor determining the outcome of early life adversity is the context under which behavioral performance is tested in adulthood. While (male) offspring of low compared to high licking-grooming mothers showed impaired non-stressful contextual learning in adulthood, they outperformed the high licking-grooming offspring when tested for contextual memory under stressful conditions (Champagne et al., 2008). A highly similar pattern was observed in adult male rats who had been separated from their mother for 24h at postnatal day 3 (Oomen et al., 2010). In both models, hippocampal synaptic plasticity mirrored the behavioral pattern. Thus, adverse early life conditions were associated with poor long-term potentiation (in the CA1 region and dentate gyrus) when corticosterone levels were low, but when stress hormone levels were raised long-term potentiation was highly efficient; the opposite pattern was observed in the adults who grew up under more favorable conditions. This led to the hypothesis that early life circumstances have an influence on brain development such that the brain is optimally prepared for comparable (matching) conditions later in life. Only when early life and adult conditions do not match, a situation of increased vulnerability to psychopathology results. This idea –known as the match-mismatch hypothesis (Champagne et al., 2009; Nederhof and Schmidt, 2012)- has recently found support in human literature too (Nederhof et al., 2014).

A final consideration is the importance of genetic background. We concentrated on the mineralocorticoid receptor (MR), to which corticosteroids bind with high affinity. This receptor has multiple single nucleotide polymorphisms. Two of these (rs5522 and rs2070951) are in linkage disequilibrium and inherited as haplotypes (Derijk et al., 2006). Haplotype 2 was shown, in vitro, to result in high MR transcriptional activity and relatively high MR expression. Klok et al (2011) reported that MR haplotype 2 is associated with higher dispositional optimism, less rumination and reduced thoughts of hopelessness, at least in women. Furthermore, haplotype 2 was found to moderate the relationship between childhood maltreatment and depressive symptoms in a sex-dependent manner (Vinkers et al., 2015). Thus, female haplotype 2 carriers were relatively protected from depressive symptoms in the face of multiple life events, whereas the opposite was observed in men. Preliminary observations in rodents confirm that high MR expression levels may protect against behavioral deficits resulting from adverse early life conditions (Kanatsou et al., unpublished observation), but this awaits further investigation. All in all, early life stress is generally considered to be a risk factors for later life cognitive performance. The net result, however, is sex-dependent, depends on the context in which the individual has to perform and is moderated by genetic background. The developmental period between the occurrence of adverse situations in early life on the one hand and the manifestation of behavioral deficits on the other hand provides a window for interventions. The efficacy and mechanism of such interventions might yield new leads to curtail negative outcome after early life adversity.

References

Champagne DL, Bagot RC, van Hasselt F, Ramakers G, Meaney MJ, de Kloet ER, Joëls M, Krugers H (2008) Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci 28: 6037-45

Champagne DL, de Kloet ER, Joëls M (2009) Fundamental aspects of the impact of glucocorticoids on the (immature) brain. Semin Fetal Neonatal Med. 14:136-42.

DeRijk RH, Wüst S, Meijer OC, Zennaro MC, Federenko IS, Hellhammer DH, Giacchetti G, Vreugdenhil E, Zitman FG, de Kloet ER (2006) A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. J Clin Endocrinol Metab 91: 5083-9

Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008) The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33: 693-710

Klok MD, Giltay EJ, van der Does AJ, Geleijnse JM, Antypa N, Penninx BW, de Geus EJ, Willemsen G, Boomsma DI, van Leeuwen N, Zitman FG, de Kloet ER, DeRijk RH (2011) A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females. Transl Psychiatry 1: e62

Loi M, Mossink JC, Meerhoff GF, Den Blaauwen JL, Lucassen PJ, Joëls M (2016) Effects of early-life stress on cognitive function and hippocampal structure in female rodents. Neuroscience in press.

Nederhof E, Schmidt MV (2012) Mismatch or cumulative stress: toward an integrated hypothesis of programming effects. Physiol Behav 106: 691-700

Nederhof E, Ormel J, Oldehinkel AJ (2014) Mismatch or cumulative stress: the pathway to depression is conditional on attention style. Psychol Sci. 25:684-92.

Oomen CA, Soeters H, Audureau N, Vermunt L, van Hasselt FN, Manders EM, Joëls M, Lucassen PJ, Krugers H (2010) Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J Neurosci. 30: 6635–45

Van Hasselt FN, Cornelisse S, Zhang TY, Meaney MJ, Velzing EH, Krugers HJ, Joëls M (2012) Adult hippocampal glucocorticoid receptor expression and dentate synaptic plasticity correlate with maternal care received by individuals early in life. Hippocampus 22:255-66.

Vinkers CH, Joëls M, Milaneschi Y, Kahn RS, Penninx BW, Boks MP (2014) Stress exposure across the life span cumulatively increases depression risk and is moderated by neuroticism. Depress Anxiety 31:737-45.

Vinkers CH, Joëls M, Milaneschi Y, Gerritsen L, Kahn RS, Penninx BW, Boks MP (2015) Mineralocorticoid receptor haplotypes sex-dependently moderate depression susceptibility following childhood maltreatment. Psychoneuroendocrinology 54:90-102.

Zhang TY, Labonté B, Wen XL, Turecki G, Meaney MJ (2013) Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology 38:111-23.