Prolonged maternal separation induces undernutrition and systemic inflammation with disrupted hippocampal development in mice

Abstract

Objective Prolonged maternal separation (PMS) in the first two weeks of life has been associated with poor growth with lasting effects in the brain structure and function. This study aimed to investigate whether PMS-induced undernutrition could cause systemic inflammation and changes in nutrition-related hormonal levels, affecting hippocampal structure and neurotransmission in C57BL/6J suckling mice. Methods This study assessed mouse growth parameters coupled with IGF-1 serum levels. In addition, leptin, adiponectin and corticosterone serum levels were measured following PMS. Hippocampal stereology and the amino acid levels were also assessed. Furthermore, we measured myelin basic protein and synapthophysin (SYN) expression in the overall brain tissue and hippocampal SYN immunolabeling. For behavioral tests, we analyzed the ontogeny of selected neonatal reflexes. PMS was induced by separating half the pups in each litter from their lactating dams for defined periods each day (4h on day 1, 8h on day 2, and 12h thereafter). A total of 67 suckling pups were used in this study. Results PMS induced significant slowdown in weight gain and growth impairment. Significant reductions in serum leptin and IGF-1 levels were found following PMS. Total CA3 area and volume were reduced, specifically affecting the pyramidal layer in PMS mice. CA1 pyramidal layer area was also reduced. Overall hippocampal SYN immunolabeling was lower, especially in CA3 field and dentate gyrus. Furthermore, PMS reduces hippocampal aspartate, glutamate, and GABA levels, as compared with unseparated controls. Conclusion Altogether, these findings suggest that PMS causes significant growth deficits and alterations in hippocampal morphology and neurotransmission.

Maternal separation blunted spatial memory formation independent of peripheral and hippocampal insulin content in young adult male rats

“…The distance to escape, which showed a trial-dependent deficit in performance on the Barnes maze induced by maternal separation, could be a sign of abnormal development of the hippocampus as one of the main sites involved in spatial memory in the brain [ 3 , 13 ]. Several reports confirm that maternal separation results in long-term changes in the morphology of the cognitive brain structures, such as a reduction in the hippocampal volume and size of the pyramidal and granular layers [ 32 ], a reduction in the number of neurons in the dentate gyrus [ 33 ] and a reduction in the CA1 pyramidal cell layer and CA3 area and volume [ 8 ], which could lead to memory impairment [ 34 , 35 ]. Figueiredo et al [ 8 ] showed that pups have a slower linear growth and poorer weight gain following prolonged maternal separation as compared to the controls, which could be a characteristic of under-nutrition and could also be the cause of changes in the pups’ hippocampus morphology and function [ 36 ].…”

“…Several reports confirm that maternal separation results in long-term changes in the morphology of the cognitive brain structures, such as a reduction in the hippocampal volume and size of the pyramidal and granular layers [ 32 ], a reduction in the number of neurons in the dentate gyrus [ 33 ] and a reduction in the CA1 pyramidal cell layer and CA3 area and volume [ 8 ], which could lead to memory impairment [ 34 , 35 ]. Figueiredo et al [ 8 ] showed that pups have a slower linear growth and poorer weight gain following prolonged maternal separation as compared to the controls, which could be a characteristic of under-nutrition and could also be the cause of changes in the pups’ hippocampus morphology and function [ 36 ]. In contrast to the STR group, assessment of the strategy used to reach the escape box in the non-STR group revealed an increase in the frequency of using the direct strategy and a reduction in the use of the random strategy over time.…”

“…According to researchers, one of the main factors causing the long-term damaging effects of ELS on spatial memory is the persistent effects that stress can have on the neuronal structure and function of the hippocampus, which is involved in memory processing [ 7 ]. These damaging effects might be partly due to malnutrition of the pups because the maternal care they receive changes after separation from the dams [ 8 , 9 ].…”

Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease

“…Although the association between early adversity exposure and inflammation has been well-documented (See Baumeister et al, 2016; Miller et al, 2011 for review), the vast majority of studies have assessed early adversity exposure across multiple phases of child development, typically spanning infancy through adolescence. Similarly, rodent work focusing on the effects of early adversity on inflammatory markers has typically induced stress during postnatal days 2–20 (Figueiredo et al, 2016; O’Mahony et al, 2009; O’Malley et al, 2011; Roque et al, 2015). Nevertheless, there are studies hinting that the inflammatory consequences of adversity during development may vary as a function of timing of adversity exposure and these associations warrant further investigation.…”

Immediate effects of maternal separation on the development of interneurons derived from medial ganglionic eminence in the neonatal mouse hippocampus

“…Both the repeated maternal separation (RMS), such as the separation for 30 min or a few hours for several days or weeks, and the one time maternal separation (MS), such as the separation for 24 hr, have been known to be resulted in abnormal behavior, reduced volume of the hippocampus, neurogenesis, decreased interneurons and GABA level (Barbosa Neto et al, 2012;Daskalakis et al, 2014;Delpech et al, 2016;Fabricius, Wörtwein, & Pakkenberg, 2008;Figueiredo et al, 2016;Hays et al, 2012;Oitzl, Workel, Fluttert, FroÈsch, & Ron de Kloet, 2000;Schmidt, Okimoto, Dent, Gordon, & Levine, 2002;Schmidt et al, 2004;Wei et al, 2015). Since the purpose of this study is to examine the immediate effects of MS on the development of the GABA system in the hippocampus, we used MS for 24 hr on P4.…”