Elsevier

Hormones and Behavior

Volume 111, May 2019, Pages 46-59
Hormones and Behavior

Access to a high resource environment protects against accelerated maturation following early life stress: A translational animal model of high, medium and low security settings

https://doi.org/10.1016/j.yhbeh.2019.01.003Get rights and content

Highlights

  • We developed a rodent model of resource (in)stability to compare the effects of low, medium, and high security environments.

  • Maternal care was differentially impacted by each of these environments

  • A low resource environment led to metabolic dysfunction (e.g. obesity, precocious puberty) in offspring

  • The negative effects of early life stress on metabolic dysfunction were mitigated by environmental enrichment (high security)

  • Diverse models of resource (in)stability can reveal mechanisms conferring vulnerability or resilience to early life stress

Abstract

Early life exposure to a low security setting, characterized by a scarcity of resources and limited food access, increases the risk for psychiatric illness and metabolic dysfunction. We utilized a translational rat model to mimic a low security environment and determined how this manipulation affected offspring behavior, metabolism, and puberty. Because food insecurity in humans is associated with reduced access to healthy food options the “low security” rat manipulation combined a Western diet with exposure to a limited bedding and nesting manipulation (WD-LB). In this setting, dams were provided with limited nesting materials during the pups' early life (P2-P10). This manipulation was contrasted with standard rodent caging (SD) and environmental enrichment (EE), to model “medium security” and “high security” environments, respectively. To determine if transitioning from a low to high security environment improved outcomes, some juvenile WD-LB offspring were exposed to EE. Maternal care was impacted by these environments such that EE dams engaged in high quality care when on the nest, but spent less time on the nest than SD dams. Although WD-LB dams excessively chased their tails, they were very attentive to their pups, perhaps to compensate for limited resources. Offspring exposed to WD-LB only displayed subtle changes in behavior. However, WD-LB exposure resulted in significant metabolic dysfunction characterized by increased body weight, precocious puberty and alterations in the hypothalamic kisspeptin system. These negative effects of WD-LB on puberty and weight regulation were mitigated by EE exposure. Collectively, these studies suggest that both compensatory maternal care and juvenile enrichment can reduce the impact of a low security environment. Moreover, they highlight how utilizing diverse models of resource (in)stability can reveal mechanisms that confer vulnerability and resilience to early life stress.

Introduction

Both basic and clinical research suggest that early-life stressors (e.g. abuse, neglect) can modify brain development and make an individual prone to mental illness and metabolic dysfunction in later life (Spencer et al., 2017; Walker et al., 2017; Yam et al., 2016; Pervanidou and Chrousos, 2012; Avishai-Eliner et al., 2001). For example, exposure to early-life stress increases the risk for mental illnesses, such as mood and depressive disorders, anxiety disorders, and disruptive behavior disorders (Afari et al., 2014; Green et al., 2010; Heim et al., 2008; Chapman et al., 2004; Anda et al., 2002). Moreover, early-life adversity has a positive association with metabolic dysfunctions including metabolic syndrome and the occurrence of precocious puberty (Cowan and Richardson, 2018; Pervanidou and Chrousos, 2012; Björntorp, 2008). To fully understand the relationship between early-life stress and these later life outcomes, it is necessary to develop ecologically relevant animal models in order to derive their mechanistic underpinnings. This step will be imperative for the design and testing of translational treatments and preventative methods.

The hypothalamic pituitary adrenal (HPA) axis is a fundamental feature of the stress response (Jacobson and Sapolsky, 1991). Normally each component of this axis develops simultaneously, connecting into a functional network. However severely stressful events during the perinatal period can cause them to develop out of sync, resulting in life-long modifications in how the organism responds to stressful experiences (Heim et al., 2008; Levine, 1994). Even a short period of stressor exposure during the first week of life in rodents can cause behavioral deviations and a vulnerability to physiological disruptions that parallel the clinical symptoms associated with early-life adversity (Walker et al., 2017; Champagne and Curley, 2007).Moreover, the hypothalamic-pituitary-gonadal (HPG) axis is also susceptible to early life programming, connecting the downstream effects of early adverse experiences on reproductive functioning and stress responsivity to a larger interactive network (Kentner and Pittman, 2010).

Puberty is the process of hormones orchestrating physiological changes that turns an organism from its sexually immature to its sexually mature state. During early development, kisspeptin in particular plays a role in the secretion of sex steroids (e.g. lutenizing hormone and follicle stimulating hormone) and the onset of puberty (Kauffman et al., 2007; Skorupskaite et al., 2014). Precocious puberty is when an organism experiences puberty significantly earlier than its species predicted time. In humans, the occurrence of precocious puberty is indicated by significant pubertal markers such as the development of secondary sex characteristics (e.g. pubic hair and breast development) before age 8 or menarche before age 9 (Kaplowitz and Hoffman, 2018; Barker and Kappy, 2011; Cesario & Hughes, 2007). Causes of precocious puberty include infection or trauma directed to the parts of the brain that control reproduction (Cowan and Richardson, 2018; Kaplowitz and Hoffman, 2018), in addition to early life stress (Li et al., 2014; Kelly et al., 2017; Virdis et al., 1998). Precocious puberty is associated with short adult stature, emotional distress (i.e. depression), and other central nervous system abnormalaties (Kaplowitz and Hoffman, 2018; Cesario & Hughes, 2007; Chalumeau et al., 2002; Angold and Worthman, 1993). Both males and females can experience precocious puberty but it effects girls 10 times more frequently (Cesario & Hughes, 2007). Thus, precocious puberty could be considered a sex-dependent characteristic of humans who undergo early-life stress. Precocious puberty due to early life stress has also been reported in animal models of maternal separation and litter isolation (Cowan and Richardson, 2018; Kentner et al., 2018; Grassi-Oliveira et al., 2016). Notably, sex-dependent precocial puberty is preventable by probiotic treatment (Cowan and Richardson, 2018) and sensory enrichment can also delay reproductive accerated maturation precipitated by early-life adversity (Kentner et al., 2018).

Parental care has a critical influence on offspring development and negative experiences mediated through the parent-offspring relationship can significantly impair developmental outcomes. In the rodent laboratory, the dynamics of these relationships can be manipulated experimentally by changing the circumstances of the nest environment (Perry et al., 2018; Walker et al., 2017; McLaughlin et al., 2016; Connors et al., 2015; Kenny et al., 2014; Champagne and Curley, 2007; Levine, 2001; Gilles et al., 1996). One commonly used model of early-life adversity is the limited bedding model (LB) which involves reducing the availability of bedding materials that a dam uses to construct a nest for herself and her pups (Perry et al., 2018; Walker et al., 2017; Rice et al., 2008; Gilles et al., 1996). The lack of materials is a maternal stressor as it decreases the dam's ability to construct a satisfactory nest (Perry et al., 2018; Walker et al., 2017) which influences the way that she interacts with her offspring (Rice et al., 2008; Champagne and Curley, 2007). Dams housed with limited bedding have lower nest construction quality scores, have poorer nursing habits, and have been reported to step-on and rough handle their pups (Perry et al., 2018; Heun-Johnson and Levitt, 2016; Sullivan and Holman, 2010; Ivy et al., 2008). These maternal behavioral patterns show that the LB paradigm can cause care fragmentation and maltreatment (Perry et al., 2018; Walker et al., 2017; Gilles et al., 1996). There is evidence to support that this adversity causes long-term negative consequences on cognitive development, motor skills, and socialization of offspring (Gilles et al., 1996).

As it stands, the LB protocol can be translated to the experience of a low resource or ‘insecure’ environment for humans. As established earlier, poor access to resources impacts how a dam interacts with her pups and this is also true of human parents. Socioeconomic status can affect parental care quality. For example, high economic pressure has been positively correlated to the use of punitive or authoritarian parenting (Leinonen et al., 2003). These parenting strategies are associated with conduct disorders and disruptive behavior disorders in children (Stormshak et al., 2010). Additionally, lower socioeconomic status is related to low birth weight, asthma, deficient language development, and fewer pre-academic skills (Burchinal et al., 2000; Aber et al., 1997;). The rodent LB protocol is most useful for modeling an impoverished environment because, in addition to the stress from lack of physical resources, it can cause behavioral modifications in the mother known to affect a child's development and adult outcomes.

On the other hand, environmental enrichment (EE) in the animal laboratory can translate to a high resource/high security situation and has been shown to rescue the effects of insecure “stressful” environments (Francis et al., 2002; Bredy et al., 2003; Bredy et al., 2004). Indeed, previous studies have shown that environmental complexity in early life can mitigate the effects of a number of early-life stressors including inflammation, poor maternal care, and neonatal brain injury (Kentner et al., 2016; Schneider et al., 2006; Bredy et al., 2004; Bredy et al., 2003; Pedrini Schuch et al., 2016; Durán-Carabali et al., 2018), highlighting its potential to mitigate the effects of LB, which to our knowledge has not been directly explored previously. Quantifying/mapping the therapeutic benefits of this housing condition has translational value in that enrichment protocols have been successfully utilized in clinical settings (Janssen et al., 2014; White et al., 2015; Woo and Leon, 2013; Woo et al., 2015), underscoring its acceptability and feasibility for use with patients.

Importantly, EE has also been shown to effect the quality of maternal care (Connors et al., 2015; Welberg et al., 2006; Sale et al., 2004; Durán-Carabali et al., 2018), but these effects have been underexplored. While there is some research focusing on defined periods of enrichment exposure (e.g. either pre- or postnatally; Cancedda et al., 2004; Rosenfeld and Weller, 2012), the number of studies evaluating dams in lifelong (or a combined pre- and postnatal) EE exposure are limited (Connors et al., 2015; Welberg et al., 2006; MacRae et al., 2015; Durán-Carabali et al., 2018). Moreover, some using this protocol have utilized co-parenting in the homecage, making the individual contribution of rodent dams difficult to assess. For this reason, we were interested in evaluating maternal care quality across the continuum of resource rich and poor animal laboratory conditions. Given the strength of maternal care quality in shaping offspring outcomes, it is important to understand differences in parent-offspring interactions as a function of environmental complexity. Environmental enrichment is an enhanced laboratory condition promoting the expression of species typical behaviors, when designing animal models for translational research it is imperative to consider environmental complexity and its impact on neurobiological indicies when trying to understand both the underlying etiology of disease and neurotypical development.

One imperative for improving animal models of early-life stressors is to simulate multiple adverse childhood experiences (ACEs). The 2016 National Survey of Children's Health reported that one in ten children experience three or more ACEs and that poverty is one of the most commonly experienced stressors (Sacks and Murphey, 2018). Experiencing multiple ACEs is associated with increased risk for both metabolic and psychiatric diseases in adulthood (Sacks and Murphey, 2018; Afari et al., 2014; Pervanidou and Chrousos, 2012; Heim et al., 2008; Chapman et al., 2004; Anda et al., 2002). While there are many early-life stressors that could be incorporated into the LB paradigm, diet is of special interest considering the association of both food insecurity and obesity with a variety of metabolic and psychological outcomes (Spencer et al., 2017; Yam et al., 2016). Food insecurity is the condition of ones' diet being restricted in terms of variety, nutrition, and amount of food (Eicher-Miller and Zhao, 2018). Children who are food insecure are more likely to have poor outcomes including, but not limited to, generally poor health and greater number of hospitalizations, psychosocial and behavioral problems, worse developmental outcomes, and are more likely to suffer from childhood obesity (Gundersen and Kreider, 2009). When examining the relationship between food security and low-income women it was found that food insecurity and diet quality were inversely related; those who were identified as food insecure had lower levels of perceived neighborhood safety, had a higher body mass index, and had lower access to healthy food options (Sanjeevi et al., 2018). A Western diet (WD) is characterized by high levels of refined sugars and saturated fats, and low fiber content which are all associated with obesity (Francis and Stevenson, 2012). In animal models, high-fat and sugar diets can cause impairments of the hippocampus and dysregulation of the HPA axis (Boitard et al., 2015; Maniam et al., 2015). In humans there is a higher occurrence of psychological disturbances (e.g. mood, anxiety, somatoform and eating disorders) among adolescents who are obese in addition to reduced hippocampal volume, which is associated with depression (Kalyan-Masih et al., 2016; Björntorp, 2008; Campbell et al., 2004; Britz et al., 2000). On its own early-life stress causes increased vulnerability to metabolic syndromes which is only exacerbated by food insecurity (Yam et al., 2016; Tilburg et al., 2010). For example, early-life stress induced by the LB model paired with a WD in male rats was associated with higher body fat and a positive correlation between white adipose tissue and object recognition scores indicative of cognitive impairments (Yam et al., 2016).

In the present study, we adapted rodent caging systems to simulate low, medium, and high security environments and evaluated their effects on maternal care and offspring development. The ‘insecure’ housing was modelled by a combination of WD-LB exposure, while standard rodent caging served as a ‘medium security’ environment. In contrast, a high resource environment was modelled by housing a subset of animals in EE. Between these settings we compared differences in maternal care and tested the hypothesis that early life stress caused by a low resource scenario would result in poor maternal care and associated metabolic dysfunction, including precocious puberty in offspring. Finally, we tested whether weaning into EE could rescue some of the adverse outcomes associated with the early-life stress protocol.

Section snippets

Animals and housing

The experiment was approved by the MCPHS Institutional Animal Care and Use Committee and was carried out in compliance with the recommendations from the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Thirty-six female and twelve male virgin Sprague-Dawley rats were acquired from Charles River (Wilmington, MA) and habituated in same-sex pairs; vivarium kept at 20 °C on a twelve-hour light/dark cycle (0700–1900 light) in larger sized cages

Maternal body weights

A repeated measures ANOVA revealed a significant interaction between time and housing for maternal body weights (F(3.956, 59.337) = 4.743, p = 0.002; Fig. 2). LSD post hocs did not show a difference across housing groups for maternal body weight at either baseline or P22, however significant group differences were observed across the course of the study with WD rats showing significantly greater weight gain compared to SD controls (Week 2: p = 0.001; Weeks 3 and 4: p = 0.0001) and EE animals

Discussion

The present experiments were designed to assess the impact of high, medium, and low security environments on maternal care quality and, in tandem, to evaluate the maturation and neurobehavioral outcomes of male and female offspring. The results show that resource insecurity and environmental complexity differentially affect maternal behavior, but not along a continuum ranging across defined categories from ‘low’ to ‘high’ quality, as one might expect. Instead, circadian timing greatly

Acknowledgements

The authors would like to extend their thanks to both Amanda Speno and Isabella Connors for technical assistance. This project was funded in part by NIMH under Award Number R15MH114035 (to ACK) and by the National Science Foundation (NSF CAREER IOS-1552416 to D.A.B). The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the financial supporters.

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      During the light phase, there was a significant main effect of early life condition for pup directed licking/grooming (Mann-Whitney U = 14.50, p = 0.009; Fig. 2D) and maternal self-grooming (Mann-Whitney U = 23.50, p = 0.049; Fig. 2D); WD-LB dams engaged in both behaviors more frequently than SD. Passive nursing (Mann-Whitney U = 19.50, p = 0.035; Fig. 2E) and total nursing behaviors (Mann-Whitney U = 14.50, p = 0.008; Fig. 2E) were elevated in WD-LB dams during the dark phase, again an effect that only emerged in the later postnatal period but was not present in the early postnatal period (Strzelewicz et al., 2019). Only the light phase effects were sustained with the combined light/dark phase observations on P15 (pup licking: Whitney U = 146, p = 0.009; maternal grooming: Mann-Whitney U = 24.50, p = 0.08; Fig. 2F).

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