Early-life social experiences in mice affect emotional behaviour and hypothalamic-pituitary-adrenal axis function

Abstract

Rationale

Early-life stressful experiences are associated to alterations in behavioural responses and development of psychiatric and neurodegenerative diseases. In rodents, individual housing is considered as a stressful condition whilst enriched environment can protect against stress and its negative consequences. Neuroendocrine responses to stress can also be altered by early-life experiences and seem to contribute to behavioural alterations induced by changes in housing conditions.

Objective

To develop an improved procedure of social isolation throughout development (from pre-adolescence to adulthood) in CD1 mice and to elucidate its effects on behavioural parameters related to stress and neuroendocrine responses compared to enriched or social conditions.

Materials and methods

CD1 male mice (PND 21) were housed in social/standard conditions, enriched conditions or isolated conditions during seven weeks. After that, different relevant behaviours were evaluated, including locomotor activity, anxiety-like and despair behaviour. Levels of plasma corticosterone were also analysed before and after a stressful event.

Results

CD1 mice exposed to an isolated environment exhibited higher locomotion and anxiety-like responses than animals exposed to social or enriched conditions. In addition, isolated animals showed lower basal plasma corticosterone than social or enriched ones but after a stressful event the elevation of plasma corticosterone was higher, suggesting an enhanced response of the HPA axis to a novel and stressful situation.

Conclusions

Social interaction is an important feature to display an appropriate behavioural and neuronal development. Habituation to novel stimuli is impaired in subjects exposed to social isolation and induces increased excitability response to stressful events. Social deprivation increases the possibility of altered neuronal function and could facilitate the development of neuropsychiatric disorders in adulthood.

Introduction

Early-life stressful experiences are associated to alterations in behavioural responses, such as cognition, motivation and emotional behaviours (Levine, 1985, De Kloet et al., 2005, Lai and Huang, 2011, Pechtel and Pizzagalli, 2011). Social positive interaction may lead to a normal development of the mentioned functions and protection against negative events in life.

In rodents and other experimental animals, long-term specific housing conditions can be adequately enriched with environmental stimuli and affect the ulterior development of cognitive and emotional controlling systems in the adulthood (Gutman and Nemeroff, 2002). In this sense, environmental enrichment (EE), which consists on housing the animals in large cages containing a variety of sensory-motor stimulus, such as tunnels, running wheels, toys; which are routinely changed and removed during the experimental period to enhance novelty, exploration, sensory-motor and cognitive stimulation (Nithianantharajah and Hannan, 2006, van Praag et al., 2000), has been shown to benefit behaviour in rodents, such as reduced anxiety in BALB/c and C57BL/6 mice (Roy et al., 2001, Sztainberg et al., 2010), increased exploratory behaviour or improved learning processes in rats (Cummins et al., 1973, Hoffmann et al., 2009, Peña et al., 2009). Additionally, it promotes neuronal protection through the increase of trophic factor levels, enhanced cell survival, increased neurogenesis and enhanced dendritic branching and synaptogenesis (Mattson and Magnus, 2006, van Praag et al., 2000). Furthermore, enrichment in the early-life can protect against stress, which can be a vulnerability factor for the development of neurodegenerative (Laviola et al., 2008) and other central nervous system (CNS) diseases. In contrast, social isolation/individual housing without cognitive and motor stimulation is considered as a stressful condition (Valzelli, 1973). In this sense, it is known that stressful events can activate the hypothalamo-pituitary-adrenal (HPA) axis and increase the release of corticotrophin releasing hormone (CRH) from the hypothalamic paraventricular nucleus, causing, in mice, the stimulation of the secretion of glucocorticoids, such as corticosterone (CORT) from the adrenal cortex (De Kloet et al., 1990, Armario et al., 2004, Armario, 2006, Marin et al., 2007, Jankord and Herman, 2008). Although hormonal responses to environmental clues have been studied, there is little consistent data about changes in neuroendocrine status following different home environments (Moncek et al., 2004). Therefore, several studies have found basal elevated CORT secretions in mice (Marashi et al., 2003) as well as in other mammals (De Jong et al., 2000) kept under environmental enrichment. Other studies have reported no differences in CORT levels exposed under different environmental conditions (Schrijver et al., 2002) and some have even found a reduction of CORT in enriched adult rats (Belz et al., 2003). More recently, no differences in basal CORT during the light period between enriched and standard housed post-weaned rats (Peña et al., 2009) and a lower increase in enriched ones after the exposure to a novel stimulus have been reported.

Home environmental conditions during childhood and adolescence are relevant for the development of a spectrum of important issues related to early-life experiences, such as neuronal development, behavioural responses, and potential future psychopathological states in humans (Penza et al., 2003, Carroll, 2003, McGowan and Szyf, 2010).

Many studies have investigated the effects of environmental enrichment or social isolation on behaviour. However, most of them considered only two different conditions, for instance, enrichment vs standard conditions (Konkle et al., 2010, Moncek et al., 2004, Zhu et al., 2009) or isolation vs standard conditions (Bartolomucci et al., 2003, Karim and Arslan, 2000). Additionally, it needs to be taken into account that behavioural effects of environmental conditions on rodents' development depend on the specie and even the strain used (Võikar et al., 2005, Abramov et al., 2008, Silva et al., 2011). Thus, the aim of this study was to develop an improved model of environmental enrichment in CD1 mice in which we have compared the consequences of three different home environmental conditions maintained throughout development (from pre-adolescence to adulthood) in CD1 mice: social conditions vs enriched conditions vs isolated conditions, on behavioural parameters. Indeed, pre-adolescent and adolescent periods compromise a critical period where social and environmental complexity can impact to the brain and behaviour in adulthood (Workman et al., 2011). In particular, we have analysed the capability of this mouse strain housed in different environments to adapt to a novel situation. Furthermore, we have investigated the effect of these different housing conditions on exposure to stress and its hormonal responses (plasma CORT). For that, the effects of these different housing conditions were assessed by the following parameters: i) body weight gain along the whole study (49 days); ii) locomotor activity and habituation; iii) anxiety-like responses; iv) depressive-like behaviour; and v) HPA axis functionality under a stressful situation; that is, levels of plasma CORT before and immediately after the exposure to dark–light box (an anxiety-like environment). A different environmental housing was maintained throughout the behavioural testing. The use of CD1 mice as experimental subjects allows us i) to assess the effects of different housing conditions in this particular mice strain on behaviour and HPA axis function and ii) to use, in future studies, mutant mice to elucidate the particular contribution of specific mutations.