Review
Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains

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Abstract

Genetic factors and early life adversity both play a major role in the etiology of mood and anxiety disorders. Previous studies have shown that postnatal maternal separation (MS) can produce lasting abnormalities in emotion-related behavior and neuroendocrine responses to stress in rodents. The present study sought to examine the effects of repeated MS in eight different inbred strains of mice (129S1/SvImJ, 129P3/J, A/J, BALB/cJ, BALB/cByJ C57BL/6J, DBA/2J, FVB/NJ). Pups were separated from their dam and littermates for 180 min/day (‘MS’) or 15 min/day (‘handling’), or left undisturbed (‘facility-reared’) from postnatal days P0-P13, and tested as adults for anxiety- and depression-related behaviors. Results demonstrated no clear and consistent effects of MS or handling on behavioral phenotypes in any of the strains tested. In all strains, MS produced an increase in maternal care on reunion with pups, which may have modified MS effects. Data demonstrate that the MS procedure employed does not provide a robust model of early life stress effects on the anxiety- and depression-related behaviors in the mouse strains tested.

Introduction

There is a growing corpus of data demonstrating that exposure to traumatic events during childhood can increase later risk for a variety of neuropsychiatric conditions, including mood and anxiety disorders (de Wilde et al., 1992; Dube et al., 2001; Heim and Nemeroff 2001; Johnson et al., 2002; Kendler et al., 1995). Individuals with a history of childhood trauma also exhibit more severe mood and anxiety symptomatology and are more likely to have co-morbid neuropsychiatric and somatic disorders (Brodsky et al., 2001; Friedman et al., 2002; Gladstone et al., 1999, Gladstone et al., 2004; Matza et al., 2003; McHolm et al., 2003; Romans et al., 1995; Roy 2002; Zlotnick et al., 1995). While the neural basis of these abnormalities has not been fully delineated, childhood trauma has been associated with structural and functional abnormalities in brain regions mediating emotion, such as the hippocampus, amygdala and prefrontal cortex (Bremner et al., 1997; Carrion et al., 2001; De Bellis et al., 2000; Finamore and Port, 2000; Mathew et al., 2004; Stein et al., 1997; Teicher et al., 2003; Vythilingam et al., 2002). These findings suggest that early life represents a critically vulnerable period during which exposure to stress can bias the development of neural systems mediating emotion towards pathology later in life.

Genetic factors are also known to contribute a significant proportion to the inter-individual variation in the prevalence of mood and anxiety disorders (Kendler, 2001), yet there remains little understanding of how genes interact with early life stress to shape the pathophysiology underlying these conditions. An outstanding question is how specific gene variants might modulate the impact of early life stress to render some individuals vulnerable to later illness and leave others relatively resilient even to profound trauma (Charney, 2004; Kendler et al., 2004). In this context, recent studies have demonstrated that risk for conditions including major depression and personality disorder is increased in individuals that were exposed to childhood trauma and carry specific gene variants (e.g., in the serotonin transporter (Hariri and Holmes, 2006)). A major goal for research in this area is to better understand the neurobiological basis of known gene×environment interactions and to identify novel interactions.

Rodent models are widely used to study the neurobiological and genetic basis of anxiety and depression given the availability of well-validated behavioral, physiological, and neuroendocrine assays (Cryan and Holmes, 2005). Rats and mice are particularly well suited to studies of the effects of early life experience because they can be reared in large numbers under controlled environmental conditions. In the rat, there is a large literature describing effects of stressors applied during the early postnatal period on behavioral and endocrine phenotypes in adulthood. Perhaps the most widely studied of these models is maternal separation (MS).

During the early postnatal period, rats and mice are dependent upon the mother for warmth, food and bodily waste excretion (Gubernick and Alberts, 1983). Subjecting rats to MS during this period can result in lasting changes in various measures of emotion-related behavior and stress-reactivity. For example, separating pups from the dam and nest for 3 or more hours per day during the first two postnatal weeks has been found to produce increased anxiety-like and depression-related behaviors, and exaggerated hypothalamic–pituitary–adrenal (HPA)-axis response to stress in adulthood (for reviews, see (de Kloet et al., 2005; Levine, 2000; Meaney, 2001; Newport et al., 2002; Pryce and Feldon, 2003). Interestingly, shorter periods of separation (e.g., 15 min) have been found to produce effects on later behavioral and stress-related responses that are opposite to MS. This so-called ‘handling’ effect has been attributed to qualitative changes in maternal care resulting from separation (for reviews, see Levine, 2000; Meaney, 2001; Pryce and Feldon, 2003). However, not all studies have found effects of MS or handling on emotion-related behaviors (Lehmann and Feldon, 2000). This variability may in part relate to methodological differences, but also to the modifying influence of genetic factors. For example, a recent study found that differences in baseline anxiety-like behavior between selected rat lines determines the effects of MS (Neumann et al., 2005).

While many of the same endpoint measures of early life stress can be evaluated equally well in rats and mice, there is considerable potential for studying genetic influences on early life experience using the mouse. Techniques that allow for the functional manipulation of specific genes, such as gene-targeting and transgenesis, are routinely applied to the mouse but remain more technically demanding in the rat (Holmes, 2001; Smits and Cuppen, 2006). Moreover, there are numerous genetically inbred strains of mice available for study that have been characterized behaviorally (Crawley et al., 1997) and to some extent genetically (Beck et al., 2000). Previous studies have demonstrated that certain mouse strains differ from one another on various tests for anxiety- and depression-related behaviors and display differential sensitivity to the behavioral effects of various stressors (for reviews, see Clement et al., 2002; Holmes et al., 2005). For example, some studies have found that the BALB/cByJ strain exhibits higher anxiety-like behavior and greater neuroendocrine responses to stress than the C57BL/6J strain (Pothion et al., 2004; Shanks et al., 1994; Shanks et al., 1990; Tannenbaum and Anisman, 2003). These two strains are also known to differ in their responsivity to the influence of cross-fostering, environmental enrichment and neonatal handling (Caldji et al., 2004; Chapillon et al., 1999; Francis et al., 2003; Zaharia et al., 1996), suggesting that they may also differ in their vulnerability to the effects of an early life stressor such as MS (Anisman et al., 1998). To-date however, there has been relatively little investigation of the lasting effects of MS in the mouse (Table 1). Recent studies have found that various MS procedures produced increased anxiety-like behavior and stress-reactivity in adulthood in male C57BL/6J mice, but similar effects were not found in female C57BL/6J or male CD-1 mice (MacQueen et al., 2003; Macri and Laviola, 2004; Parfitt et al., 2004; Romeo et al., 2003; Venerosi et al., 2003).

The aim of the present study was to evaluate the effects of a repeated postnatal MS in mice on a range of tests for anxiety- and depression-related behaviors (elevated plus-maze, light/dark exploration test, novel open field, and forced swim test), and assess whether these effects differed across a genetically diverse panel of strains. Eight strains were chosen on the basis of their frequent use in studies of emotion-related behaviors and as genetic backgrounds for mutants, and their availability from a single supplier (to avoid a possible source of variation): 129S1/SvImJ, 129P3/J, A/J, BALB/cJ, BALB/cByJ C57BL/6J, DBA/2J, FVB/NJ. With the exception of 129P3/J, all of these strains are ‘group A’ priority strains in the Mouse Phenome Project; an international effort to provide the biomedical research community with phenotypic data on the most commonly used mouse strains (http://aretha.jax.org/pub-cgi/phenome/mpdcgi?rtn=docs/home). Mice were separated from the dam and physically separated from their littermates for 3 h (MS) or 15 min (‘handling’) per day on postnatal days 0–13 (controls were reared under normal facility conditions). In addition, maternal behavior was recorded at three time points relative to MS.

Section snippets

Subjects

129S1/SvImJ (129S1), 129P3/J, A/J, BALB/cJ, BALB/cByJ C57BL/6J, DBA/2J, and FVB/NJ mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and housed in breeding pairs in a single temperature- and humidity-controlled vivarium under a 12 h light/dark cycle (lights on at 0600 h). As described previously, clear differences emerged in the fertility and fecundity of the 8 inbred strains over the course of a 12-month period of breeding (Millstein et al., 2006). Briefly, while >90% breeding

Elevated plus-maze

In males there was a significant effect of strain for %time in the open arms (F2,178=32.10, P<.01) and %entries into the open arm (F4,178=25.22, P<.01), but no main effect of MS condition and no MS condition×strain interaction for either measure. Significant strain differences in %time in the open arms were FVB/NJ>129S1=DBA/2J=C57BL/6J=BALB/cByJ (Fig. 1A). Strains differed in %entries into the open arms were FVB/NJ>DBA/2J>129S1=C57BL/6J=BALB/cByJ (data not shown). There was a significant

Strain differences in anxiety- and depression-related behaviors

Present data provide a replication and extension of previous studies demonstrating differences in anxiety- and depression-related behaviors across inbred strains of mice. As compared to the other four strains tested, FVB/NJ mice exhibited the highest levels of open arm exploration in the elevated plus-maze (EPM) and the highest scores for time spent in the light and the number of light/dark transitions in the light/dark exploration (LD) test, irrespective of MS condition or sex. FVB/NJ mice

Acknowledgements

We are grateful to Dr. Isabel Mansuy and Dr. Larry Young for valuable advice. Research supported by the National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Behavioral Research Program and the National Alliance for Research on Schizophrenia and Depression.

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