Early life manipulations alter learning and memory in rats

Abstract

Much research shows that early life manipulations have enduring behavioral, neural, and hormonal effects. However, findings of learning and memory performance vary widely across studies. We reviewed studies in which pre-weaning rat pups were exposed to stressors and tested on learning and memory tasks in adulthood. Tasks were classified as aversive conditioning, inhibitory learning, or spatial/relational memory. Variables of duration, type, and timing of neonatal manipulation and sex and strain of animals were examined to determine if any predict enhanced or impaired performance. Brief separations enhanced and prolonged separations impaired performance on spatial/relational tasks. Performance was impaired in aversive conditioning and enhanced in inhibitory learning tasks regardless of manipulation duration. Opposing effects on performance for spatial/relational memory also depended upon timing of manipulation. Enhanced performance was likely if the manipulation occurred during postnatal week 3 but performance was impaired if it was confined to the first two postnatal weeks. Thus, the relationship between early life experiences and adulthood learning and memory performance is multifaceted and decidedly task-dependent.

Introduction

Mental health disorders can be extremely debilitating to the individual and their family and inflict great costs on society. In the United States, the prevalence of having any disorder in a 12-month period is over 26% with 7% of the population classified as having more than one major disorder (Kessler et al., 2005). Prevention, an effective way to reduce occurrences of the problems, can be enhanced by identifying risk factors. While genetic factors are important, the environmental factor of early life trauma increases susceptibility to depression (Heim and Nemeroff, 2001), post-traumatic stress disorder (PTSD) (Yehuda et al., 2001), schizophrenia (Howes et al., 2004), and addiction (Gordon, 2002). Stress affects neural and hormonal systems that contribute to emotional and cognitive processes associated with mental disorders. Further, acute stress in adulthood can precipitate or exacerbate symptoms of mental disorders. The variability in an individual's response to stress during adulthood may relate to differences in early life experiences that helped to shape the neural and hormonal responses to stress. A better understanding of the long-term consequences of early life stress could improve prevention strategies for mental disorders, particularly for those that are affected by stress.

Animal models provide an essential tool to understand the mechanisms by which the enduring effects of early life stress become manifest. Research conducted with animals allows control over the environmental manipulation of early life stress. This provides the ability to examine specific parameters of the manipulation, such as the postnatal timing or duration of the stress, in order to determine the critical factors that contribute to the enduring effects of the stress. Animal studies have reduced variability because consistency over factors such as housing or litter size can be maintained and genetic factors controlled by employing rats of a specific strain. Finally, research with animals allows assessing hormonal or neural changes such as neurogenesis or effects on protein levels in specific brain regions. Nonetheless, animal models must be evaluated to ensure their validity because they are only useful if they produce effects comparable to those seen in humans.

The overall purpose of this review is to synthesize results from the literature on early life manipulations in rats in order to determine how it affects learning and memory performance in adulthood. We focus on learning and memory because of the many discrepancies in this literature. There is a need to understand how early life stress alters these processes because it will shed light on early trauma as a risk factor for the many mental disorders that associate with altered learning and memory processing. While other reviews have been written on early life stress (e.g., Brunson et al., 2003, Catalani et al., 2011, Francis et al., 1999a, Kaufman et al., 2000, Kehoe and Shoemaker, 2001, Lehmann and Feldon, 2000, Levine, 2001, Macri and Wurbel, 2006, Meaney et al., 1996), none have had this focus. Thus, this is a unique perspective to this literature.

Early life manipulations have been reported to enhance, impair, or have no effect on learning or memory performance in the adult. These inconsistencies may reflect procedural variations in early life stress models or differences in assessments of learning and memory. There is a need to find the commonalties and differences within this literature in order to identify parameters that can explain and predict outcomes from studies and enhance the validity of the animal models utilized. Some a priori questions examined in this review include whether brief vs. prolonged manipulations have opposing effects on learning and memory as suggested for effects on stress hormone systems (Francis et al., 1999a). This assumption may not hold for learning and memory tasks (Brunson et al., 2003). In addition to duration, we hypothesize that timing of the manipulation is important in whether learning or memory is altered. Other factors that may play a role in the effects of early life manipulations on performance in learning and memory tasks include sex and strain of the rat. Finally, we deemed that the type of task was important in determining the outcome of the study.

In this paper, we first present our approach to constructing the review. Second, we describe the methods of collecting and synthesizing information from the literature. Third, we briefly describe rat development including maternal effects and changes in stress hormone systems. Next, we explain the various early life manipulations used in publications discussed herein. Then, we summarize results reported in the literature on the effects of early life manipulations on learning and memory tasks presented by task-type category and discuss unconditioned effects that may have affected outcomes of these studies. Subsequently, we discuss enduring effects of early life manipulations on the stress hormone and central nervous systems of adult rats. Finally, we present a model to help synthesize results reported upon and provide a heuristic to test predictions in future studies.