Early life stress accelerates behavioral and neural maturation of the hippocampus in male mice

Nitenson

Lichtman

et al. 2017

Neurobiology of Stress

Disruptions in early life care, including neglect, extreme poverty, and trauma, influence neural development and increase the risk for and severity of pathology. Significant sex disparities have been identified for affective pathology, with females having an increased risk of developing anxiety and depressive disorder. However, the effects of early life stress (ELS) on cognitive development have not been as well characterized, especially in reference to sex specific impacts of ELS on cognitive abilities over development. In mice, fragmented maternal care resulting from maternal bedding restriction, was used to induce ELS. The development of spatial abilities were tracked using a novel object placement (NOP) task at several different ages across early development (P21, P28, P38, P50, and P75). Male mice exposed to ELS showed significant impairments in the NOP task compared with control reared mice at all ages tested. In female mice, ELS led to impaired NOP performance immediately following weaning (P21) and during peri-adolescence (P38), but these effects did not persist into early adulthood. Prior work has implicated impaired hippocampus neurogenesis as a possible mediator of negative outcomes in ELS males. In the hippocampus of behaviorally naïve animals there was a significant decrease in expression of Ki-67 (proliferative marker) and doublecortin (DCX-immature cell marker) as mice aged, and a more rapid developmental decline in these markers in ELS reared mice. However, the effect of ELS dissipated by P28 and no main effect of sex were observed. Together these results indicate that ELS impacts the development of spatial abilities in both male and female mice and that these effects are more profound and lasting in males.

Section: Resultsmentioning

confidence: 88%

Early life stress leads to developmental and sex selective effects on performance in a novel object placement task

Nitenson

Lichtman

et al. 2017

Neurobiology of Stress

“…Therefore, several of the motor phenotypes cannot be attributed to acute effects of valproate on motor function or sedation. In recent work, we have shown that early life stress induced by alterations in maternal care can profoundly impact behavioral development of mice, with significant effects on somatic development [36]. In order to account for potential differences in maternal care, each litter contained mice from all treatment groups including saline controls (e.g.…”

Section: Discussionmentioning

confidence: 99%

Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice

Pimentel

2017

Epilepsy & Behavior

Valproic Acid (Valproate) has been used for over 30 years as a first line treatment for epilepsy. In recent years, prenatal exposure to valproate has been associated with teratogenic effects, limiting its use in women that are pregnant or of childbearing age. However, despite its potential detrimental effects on development, valproate continues to be prescribed at high rates in pediatric populations in some countries. Animal models allow us to test hypotheses regarding the potential effects of postnatal valproate exposure on neurobehavioral development, as well as identify potential mechanisms mediating observed effects. Here, we test the effect of early postnatal (P4-P11) valproate exposure (100mg/kg and 200mg/kg) on motor and affective development in two strains of mice, SVE129 and C57Bl/6N. We also assessed the effect of early valproate exposure on regional BDNF protein levels, a potential target of valproate, and mediator of neurodevelopmental outcomes. We found that early life valproate led to significant motor impairments in both SVE129 and C57Bl/6N mice. Both lines of mice showed significant delays in weight gain, as well as impairments in the righting reflex (P7–8), wire hang (P17), open field (P12 and P21), and rotarod (P25 and P45) tasks. Interestingly, some of the early locomotor effects were strain and dose dependent. We observed no effects of valproate on early markers of anxiety-like behavior. Importantly, early life valproate had significant effects on regional BDNF expression, leading to a near 50% decrease in BDNF levels in the cerebellum of both strains of mice, while not impacting hippocampus BDNF protein levels. These observations indicate that postnatal exposure to valproate may have significant, and region specific effects, on neural and behavioral development, with specific consequences for cerebellar development and motor function.

“…Furthermore, use of this paradigm allows for a sustained induction of ELS throughout a defined period during the first weeks of life, limits experimenter impact associated with handling and observation, and limits the introduction of additional variables that can impact neurodevelopment, including sustained effects on thermoregulation and malnutrition. This model has been well characterized, leads to reliable induction of stress in pup, and effects that have been replicated by more than a half a dozen labs (64, 66, 67, 72, 74–77). In addition, this form of manipulation appears to have potent effects on the development of circuits underlying both the fear response as well as regulation of the stress axis (78, 79).…”

Section: Modeling Early Life Stress In the Laboratorymentioning

confidence: 95%

“…The characterization of these developmentally regulated learning processes was performed using a mouse model without context pre-exposure facilitation effect (CPFE) procedures in effort to best parallel real-life traumatic experiences in which cues and contexts are experienced simultaneously. This contextual fear suppression has been replicated in adolescent mice when using background contextual fear conditioning (67) yet not when adolescent mice receive context pre-exposure facilitation effect (CPFE) in foreground contextual conditioning (135). Additionally, these studies employed a mouse model, as opposed to the more common rat model, which has been popularized in fear-conditioning studies for its robust and easily assayed behavioral responses.…”

Section: Sensitive Periods: Fear Learning and Elsmentioning

confidence: 98%

“…In rodents, multiple paradigms exist to induce early life stress (ELS) through manipulation in maternal care, including maternal handling (58), maternal separation (59, 69), maternal deprivation (68, 70), natural variation in the quality of maternal care (71), and maternal bedding manipulation paradigms (61, 62, 64, 67, 72). The recent use of maternal bedding manipulation paradigms offers advantages over other approaches as (1) it mirrors loss of resources to care for the young, (2) induces stress in the dam resulting in reliable changes in the dynamic interactions between mother and pup (e.g.…”

Section: Modeling Early Life Stress In the Laboratorymentioning

confidence: 99%

See 1 more Smart Citation

Emotional learning, stress, and development: An ever-changing landscape shaped by early-life experience

Pattwell

Neurobiology of Learning and Memory

2017

The capacity to learn to associate cues with negative outcomes is a highly adaptive process that appears to be conserved across species. However, when the cue is no longer a valid predictor of danger, but the emotional response persists, this can result in maladaptive behaviors, and in humans contribute to debilitating emotional disorders. Over the past several decades, work in neuroscience, psychiatry, psychology, and biology have uncovered key processes underlying, and structures governing, emotional responding and learning, as well as identified disruptions in the structural and functional integrity of these brain regions in models of pathology. In this review, we highlight some of this elegant body of work as well as incorporate emerging findings from the field of developmental neurobiology to emphasize how development contributes to changes in the ability to learn and express emotional responses, and how early experiences, such as stress, shape the development and functioning of these circuits.