ReviewEarly life manipulations alter learning and memory in rats
Highlights
► Analyzed over 230 studies from 77 papers and classified into three task categories. ► Duration (brief or prolonged) has opposing effects on spatial/relational memory tasks only. ► Timing (during postnatal week 3 or not) led to opposing outcomes on spatial/relational tasks only. ► Performance was impaired in aversive conditioning and enhanced in inhibitory learning tasks by early life stress. ► Explained discrepancies in literature on early life stress and learning and memory.
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.
Section snippets
Approach
We gathered as thorough a collection of published papers as possible and then probed for patterns in the results. A literature search (Medline) of studies published up to January 2012 was performed by combining the key phrases of “early life” or “postnatal stress”, “maternal separation or deprivation”, “neonatal or postnatal handling”, or “isolation”. These results were crossed with the keywords of “learning, memory, or conditioning” and then crossed with “rat”. Only studies in which the full
Methods
We gathered results from the papers and tabulated them in the following way. Significant or trends toward significant findings in specific tasks were categorized as an impairment or an enhancement, or otherwise considered a non-significant effect. Each experiment within a paper was a separate study or case. If rats of both sexes or both adult and aged rats were assessed, these were separate cases. To determine factors that contribute to enduring effects of early life manipulations on learning
Early life manipulations
Various early life manipulations are believed to be stressful. In most cases, the pup is separated from the dam but may also be isolated from its littermates. Some investigators use the terms “handling” or “maternal separation” regardless of whether the pup was isolated individually or remained huddled with littermates. We distinguish between “separation” and “isolation” such that separation refers to procedures in which pups were allowed to huddle with littermates and isolation refers to
Stress and the developing rat
For many days after birth, altricial rat pups need a great deal of maternal care in order to survive (Rosenblatt and Snowdon, 1996). Pups actively elicit care from the dam through olfactory, visual, and auditory cues that prompt her to retrieve and groom them (Brewster and Leon, 1980, Smotherman et al., 1974, Stern and Johnson, 1989). Pups are active participants in the licking interaction and nursing that usually follows such grooming (Stern and Johnson, 1989, Stern and Johnson, 1990).
Early life stress effects on learning and memory: task categorization
We compiled the studies from over 75 papers and classified them into three task types as seen in Fig. 2. Task categories were initially identified based on known neurobiological and behavioral distinctions as well as by the manner in which early life stress affected performance and this categorization was confirmed by discriminant function analysis. The first category is aversive conditioning. It includes context (CtxF) and cue (CueF) fear conditioning, inhibitory avoidance (IA), eyeblink
Early life stress effects on learning and memory: aversive conditioning tasks
The first category of tasks includes several aversive conditioning procedures. As seen in Fig. 2, much of the research that examined aversive conditioning in adult rats with early life manipulations utilized context or cue fear conditioning procedures (CtxF and CueF). The other aversive conditioning tasks are IA, FPS, EBC, and CTA. All of these tasks, except CTA, involve aversive foot shock presentations. The CTA procedures are presumed to involve aversive effects of a drug (or radiation)
Early life stress effects on learning and memory: inhibitory learning
The second category of learning and memory tasks is the inhibitory learning of LI tasks. LI refers to impaired or decreased CR to a CS if the animal was exposed to it prior to conditioning (Lubow, 1997). Typically, animals are first given repeated presentations of a light or tone stimulus without US. Then, this stimulus is paired with a US such as food or shock. Overall, results suggest LI performance is enhanced by early life manipulations.
Eighteen experiments in six publications examined
Early life stress effects on learning and memory: spatial/relational memory tasks
A vast majority of studies reporting on effects of early life manipulations on learning and memory utilize spatial or relational memory tasks and most use Morris water maze as described below and seen in Fig. 2. Other memory tasks include OR and other maze tasks such as radial arm, YM and TM tasks. The memory tasks in this category are similar in that they evaluated either working or reference memory or both. Working memory is when the animal acts on information gained during a session such as
Unconditioned effects that may influence learning/memory performance
Learning and memory performance may be altered by early life manipulations due, in part, to primary effects on unconditioned behaviors reflective of fear or anxiety. Although it is beyond the scope of this paper to review this literature, we examined results from the papers discussed in the current review (Table 6). Two procedures used often are elevated plus maze (EPM) and open field (OF). In EPM, time spent in or entries into open arms reflect decreased unconditioned anxiety. Typical
Enduring hormonal and neural effects of early life manipulations in the adult rat
Because the hippocampus develops and differentiates during the postnatal period in rodents (Altman and Bayer, 1990), early life manipulations may cause enduring effects on cellular or intracellular factors in this region. Indeed, the hippocampus (or amygdala) is well known for contributing to learning and memory as well as to stress responsivity (Kim and Diamond, 2002, Kim and Jung, 2006, Lupien and McEwen, 1997). In addition to effects on neurochemical and neurohormonal systems, other known
Conclusions
The main findings of this analysis of the literature on the effects of early life manipulations on learning and memory is that the factors of duration and timing of the manipulation contribute to performance in spatial memory tasks in adult rats. Performance in aversive conditioning tasks is impaired in most cases but this effect is less likely to be seen if the manipulations extend into the third postnatal week. Enhanced performance in inhibitory learning is seen regardless of these factors.
Acknowledgments
Funding from the following sources provided support for the preparation of this manuscript: DA 02117 (TAK) and MH64457 (JJK).
References (210)
- et al.
Effects of early experience on adrenocortical reactivity
Physiology & Behavior
(1969) - et al.
Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats
Psychoneuroendocrinology
(2007) - et al.
Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: involvment of the HPA axis
Psychoneuroendocrinology
(2009) - et al.
Early postnatal maternal deprivation in rats induces memory deficits in adult life that can be reversed by donepezil and galantamine
International Journal of Developmental Neuroscience
(2009) - et al.
Neonatal isolation stress alters bidirectional long-term synaptic plasticity in amygdalo-hippocampal synapses in freely behaving adult rats
Brain Research
(2008) - et al.
Brief vs. long maternal separations in infancy: contrasting relationships with adult maternal behavior and lactation levels of aggression and anxiety
Psychoneuroendocrinology
(2001) - et al.
Chronic stress effects on memory: sex differences in performance and monoamergic activity
Hormones and Behavior
(2003) - et al.
Prenatal restraint stress and motherless rearing disrupts expression of plasticity markers and stres-induced corticosterone release in adult female Sprague–Dawley rats
Brain Research
(2007) - et al.
Mechanisms of emotional arousal and lasting declarative memory
Trends in Neurosciences
(1998) - et al.
Reversal of prenatal diazepam-induced deficit in a spatial-object learning task by brief, periodic maternal separation in adult rats
Behavioural Brain Research
(2005)
Progeny of mothers drinking corticosterone during lactation has lower stress-induced corticosterone secretion and better cognitive performance
Brain Research
Maternal corticosterone during lactation permanently affects brain corticosteriod receptors, stress response and behaviour in rat progeny
Neuroscience
Maternal corticosterone influences behavior, stress response and corticosteroid receptors in the female rat
Pharmacology Biochemistry and Behavior
Maternal corticosterone effects on hypothalamus-pituitary-adrenal axis regulation and behavior of the offspring in rodents
Neuroscience and Biobehavioral Reviews
Sex differences in spatial and non-spatial Y-maze performance after chronic stress
Neurobiology of Learning and Memory
Prior exposure to a single stress session facilitates subsequent contextual fear conditioning in rats: evidence for a role of corticosterone
Hormones and Behavior
Environmental and tactile stimulation modulates the neonatal handling effect on adult rat spatial memory
International Journal of Developmental Neuroscience
The effects of sex and neonatal maternal separation on fear-potentiated and light-enhanced startle
Behavioural Brain Research
Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems
Psychoneuroendocrinology
Early life stress decreases hippocampal BDNF content and exacerbates recognition memory deficits induced by repeated D-amphetamine exposure
Behavioural Brain research
Comparative aspects of the brain growth spurt
Early Human Development
Differential effects of neonatal handling on anxiety, corticosterone response to stress, and hippocampal glucocorticoid and serotonin (5-HT)2A receptors in Lewis rats
Psychoneuroendocrinology
A new one-trial test for neurobiological studies of memory in rats. I. Behavioral data
Behavioural Brain Research
Maternal care and the development of stress responses
Current Opinion in Neurobiology
The role of corticotropin-releasing factor-norepinephrine system in mediating the effects of early experience on the development of behavioral and endocrine responses to stress
Biological Psychiatry
Social isolation stress during the third week of life has age-dependent effects on spatial learning in rats
Behavioural Brain Research
Early maternal deprivation reduces prepulse inhibition and impairs spatial learning ability in adulthood: no further effect of post-pubertal chronic corticosterone treatment
Behavioural Brain Research
Maternal behavior in F344/N and Lew/N rats: effects on carrageenan-induced inflammatory reactivity and body weight
Physiology & Behavior
Early environmental stress and biological vulnerability to drug abuse
Psychoneuroendocrinology
Effects of brief and long maternal separations on the HPA axis activity and the performance of rats on context and tone fear conditioning
Behavioural Brain Research
The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies
Biological Psychiatry
Neurocircuitry of stress: central control of the hypothalamic–pituitary–adrenocortical axis
Trends in Neurosciences
Effects of early postnatal handling on brain beta-adrenoceptors and behavior in tests related to stress
Brain Research
Hippocampal neurochemistry is involved in the behavioural effects of neonatal maternal separation and their reversal by post-weaning environmental enrichment: a magnetic resonance study
Behavioural Brain Research
Maternal separation decreases hippocampal cell proliferation and impairs cognitive performance but has little effect on stress sensitivity and anxiety in adult Wistar rats
Behavioural Brain Research
Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats
Brain Research
Importance of early environment in the development of post-traumatic stress disorder-like behavior
Behavioural Brain Research
Effects of early adverse experiences on brain structure and function: clinical implications
Biological Psychiatry
Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review
Neuroscience and Biobehavioral Reviews
Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning
Trends in Neurosciences
Early life stress and vulnerability to addiction: translational studies with neonatal isolation of rat pups
The immediate and enduring effects of neonatal isolation on maternal behavior in rats
International Journal of Developmental Neuroscience
Sex-selective effects of neonatal isolation on fear conditioning and foot shock sensitivity
Behavioural Brain Research
Early life stress impairs fear conditioning in adult male and female rats
Brain Research
Memory impairments and hippocampal modifications in adult rats with neonatal isolation stress experience
Neurobiology of Learning and Memory
Neonatal handling alters learning in adult male and female rats in a task-specific manner
Brain Research
Effect of neonatal isolation on outcome following neonatal seizures in rats—the role of corticosterone
Epilepsy Research
Changes in licking behaviour of rat mother following handling of young
Animal Behavior
Long-term effects of repeated maternal separation on three different latent inhibition paradigms. Pharmacology
Biochemistry and Behavior
The maternal separation paradigm and adult emotionality and cognition in male and female Wistar rats. Pharmacology
Biochemistry and Behavior
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Sex-dependent changes of hippocampal synaptic plasticity and cognitive performance in C57BL/6J mice exposed to neonatal repeated maternal separation
2023, NeuropharmacologyCitation Excerpt :At the same time, we found no significant alterations in female mice in both behavioral tests. In line with our data, a vast number of experimental and clinical evidence confirms that early-life stress, including that associated with maternal separation, might exert deleterious effects on brain structure and function later in life (Reincke and Hanganu-Opatz, 2017; Hedges and Woon, 2011; Kosten et al., 2012; Levine, 2005; Gutman and Nemeroff, 2002). Moreover, our data demonstrating that RMS failed to affect spatial memory in female mice, differ from other reports showing that early-life stress leads to cognitive impairments, reduced numbers of CA3 neurons, and altered maternal behavior in adult female mice (Reshetnikov et al., 2020).
Effects of Early Life Adversities upon Memory Processes and Cognition in Rodent Models
2022, NeuroscienceCitation Excerpt :This effect was associated with fewer spines in mPFC layer II/III pyramidal neuron basal dendrites at PND21 and lower apical dendrite length, two months after extinction training (Rincel et al., 2018). H adult male rats also showed a slightly reduced rate of cued-fear extinction learning, together with impaired extinction recall (Stevenson et al., 2009b), contradicting their general lower emotionality and resistance to forming strong aversive memories (Kosten et al., 2012). Contextual memory on the other hand was similarly extinguished independently of the early life treatment (Stevenson et al., 2009b).
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2022, Developmental Cognitive NeuroscienceCitation Excerpt :Thus far, few studies have examined the different moderating effects of experimental operations on the cognitive flexibility of rodents according to maternal and peer factors, but some studies have focused on other cognitive functions such as learning and memory abilities. We have reviewed these previous studies and found that the experimental operations of separation and isolation, however, had no different effects on the outcomes of learning and memory (Kosten et al., 2012), which is inconsistent with our results. This might be due to the different cognitive types for learning, memory, and cognitive flexibility.
Early life stress influences basal ganglia dopamine receptors and novel object recognition of adolescent and adult rats
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