Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats

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Summary

Exposure to early stressful adverse life events may increase vulnerability to psychopathology in adult life. There are important memory disturbances in stress-related psychiatric disorders. Therefore, there is much interest in understanding the mechanisms responsible for interactions between stress and cognition. Male Wistar rats that experienced 3-h daily separations from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood a depressive-like behaviour in the forced swimming test, increased hypothalamic–pituitary–adrenal (HPA) axis responsiveness to stressors and elevated CRF mRNA in the paraventricular nucleus of the hypothalamus (PVN). In the hippocampus of MS rats, there was a lower glucocorticoid receptor density. MS produced significant learning impairments both in the Morris water maze and in the novel object recognition test (NORT). The glucocorticoid receptor antagonist mifepristone and the β-adrenoceptor antagonist propranolol were able to completely reverse the increased immobility time in the forced swimming test and the memory deficits in the NORT observed in MS rats. Our data support the hypothesis that elevated secretion of glucocorticoids may be associated to behavioural and cognitive deficits in MS rats. The stress hyperresponsiveness observed in MS rats could be attributed, at least in part, to an impaired feedback sensitivity mediated by hippocampal glucocorticoid receptors. It can also be suggested the possible involvement of the noradrenergic system in cognitive impairments mediated by glucocorticoids in the MS model.

Introduction

Depression is a common mental disorder, and currently a major public health concern. Although to date the underlying neurobiology of depression remains elusive, there is an increasing evidence implicating stress in brain disturbances thought to underlie certain forms of depression or particular components of the depressive syndrome (Kessler, 1997; Kendler et al., 1999; Van Praag, 2004). There are important memory disturbances in stress-related psychiatric disorders (Bremner and Narayan, 1998; Bremner et al., 2003), and therefore, there is much interest in understanding the molecular mechanisms responsible for interactions between stress and cognition. The hypothalamic–pituitary–adrenal (HPA) axis is an essential component of an individual's capacity to cope with stress and in fact, a hyperactivity of the HPA axis is observed in the majority of patients with depression (review by Arborelius et al., 1999; De Kloet et al., 2005). Stress stimulation of the axis starts when corticotropin releasing factor (CRF) released by the paraventricular nucleus of the hypothalamus (PVN) stimulates the release of corticotropin (ACTH) from the anterior pituitary, which in turn, stimulates secretion from the adrenal cortex. Many of the behavioural consequences of stress are thought to be mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones (De Kloet et al., 1998; Oitzl et al., 2001; Roozendaal et al., 2006a) and subsequent alteration in gene expression (see review by Berton and Nestler, 2006).

It is well documented that corticosteroids modulate learning and memory processes in animals and humans in a complex manner. A transient increase in circulating corticosteroids associated with a learning task has been shown to facilitate memory consolidation (Roozendaal et al., 1999; Buchanan and Lovallo, 2001; Abercrombie et al., 2003). However, it has also been shown that acute stress produces a deficit in hippocampal long-term potentiation (Foy et al., 1987), and the elevation of circulating corticosterone concentrations by systemic administration of corticosterone or glucocorticoid receptor agonists exerts an inhibitory influence on learning and memory retrieval (Bodnoff et al., 1995; Roozendaal et al., 2003; Roozendaal et al., 2004b, Roozendaal et al., 2004c). It has been suggested that the effects of glucocorticoids on memory depend on noradrenergic activation of the amygdala and interactions of the amygdala with other brain regions, mainly hippocampus and frontal cortex (review by Roozendaal et al., 2006b).

There is compelling evidence that exposure to early stressful adverse life events may increase vulnerability to psychopathology in adult life. In fact, individuals who experience early trauma, such as parental loss, sexual abuse or physical assault in childhood, present an increased risk for suffering depression later in life (Heim and Nemeroff, 2001). Based on these arguments, it has been shown that prolonged periods (>1 h) of maternal separation (MS) during the first weeks of life result in animals with behavioural and neuroendocrine signs of elevated stress reactivity as adults (Anisman et al., 1998; Ladd et al., 2000; Lehman and Feldon, 2000; Ploj et al., 2003). In addition to an increase in immobility time in the Porsolt forced swimming test, anhedonia, and an enhanced anxiety-like behaviour, MS animals exhibit a dysfunction of the HPA axis reactivity to stress and therefore, the MS model in rat is considered nowadays as a robust model of enhanced stress responsiveness and depressive-like behaviour (Ladd et al., 2000; Van den Hove et al., 2005).

In this study we hypothesized that (i) neonatal MS would lead to cognitive deficits in adulthood; (ii) such an effect could be dependent on a dysfunction of the HPA axis, specifically to a hypersecretion of corticosterone. To test these hypotheses, Wistar rats that experienced 3-h daily separations from the dam during the first 3 weeks of life were tested in adulthood for HPA axis responsiveness, depressive-like behaviour, presence of cognitive deficits and the effect of the glucocorticoid receptor antagonist mifepristone on behavioural performance in MS rats. Furthermore, the involvement of the noradrenergic system in corticosterone-mediated effects will be also investigated.

Section snippets

Animals

All the experiments were carried out in strict compliance with the recommendations of the EU (DOCE L 358/1 18/2/1986) for the care and use of laboratory animals. Timed-pregnant Wistar rats were provided on gestation day 16 from Charles River Laboratories (Portage, MI, USA), individually housed in a temperature (21±1 °C) and humidity (55±5%) controlled room on a 12-h light/dark cycle with food and water freely available.

Maternal separation

All litters were born within a 2-day period. As previously described (Huot et

Behavioural characterization

Locomotor activity was not modified by rearing (Student's t-test), and total path length travelled was 6910.01±300.92 for AFR (n=10) and 7704.13±378.52 (n=10) for MS rats.

In the Porsolt forced swimming test (Fig. 1A), MS (n=10) produced a significant increase in immobility compared with AFR (n=10) rats (Student's t-test, p<0.05).

In the sucrose intake test, there was an interaction [F1,34=3.66, p<0.05] between rearing condition (AFR vs MS) and water/sucrose intake. Even though all animals tested

Discussion

In humans, the experience of adverse events early in life is associated with an increased risk of development of psychiatric disorders in adulthood. This association has led to the belief that stress of early adverse experiences programs changes in the brain, which persist throughout lifetime and predispose an individual to the development of depression (Heim and Nemeroff, 2001). Rat models of early life adversity include those in which the neonatal animals are periodically deprived of contact

Acknowledgements

This work has been supported by the Newmood integrated project (EC, LSHM-CT-2004-503474). B. Aisa has a scholarship from Gobierno de Navarra (Spain).

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