Modelo murino de cuidado maternal fragmentado na infância : efeitos sobre o comportamento ansioso, memória e mecanismos moleculares no hipotálamo e córtex pré-frontal

Abstract

Introduction: Fragmentation in maternal care provoked by stressful events during early life can lead to the development of psychopathologies and long-term cognitive impairments. However, the neurobiological mechanisms that possibly mediate these alterations have not been fully elucidated. Furthermore, classic preclinical models of early stress (ELS) have been reporting inconclusive results with low levels of replicability. Objectives: The objective of study 1 was to perform a systematic review in order to investigate the impact of multiple models of ELS on the maternal behavior of rats and mice. Study 2 aimed to investigate the impact of exposure to a combined model of ELS on anxiety-like behavior, as well as central and peripheral markers of hypothalamic-pituitary-adrenal (HPA) functioning. Study 3 investigated the impact of the combined ELS model on prefrontal cortex (PFC) dependent memory tasks and its relationship with the expression of dopaminergic receptors in the same region. Methods: The search strategy used in the systematic review (study 1) was carried out using three databases: PUBMED, Embase and Web of Science. In all analyzes, the ELS was compared only to the control group. Outcomes were categorized into eight maternal behaviors. The methodological quality of the studies was also evaluated. For study 2, male BALB/cJ mice were exposed to an ELS model that combines Maternal Separation (SM) with Limited Bedding (LB) from postnatal day 2 to 15. During the first week of development, the maternal behavior was assessed. At late adolescence the animals were tested in the Open Field (OF), Elevated Plus Maze (EPM) and Light/Dark (LD). After the behavioral tests, the animals were sacrificed, and the mRNA levels of glucocorticoid receptor (Nr3c1), corticotrophin-releasing hormone (Crh), and its type 1 receptor (Crhr1) were measured in the hypothalamus. In addition, plasmatic corticosterone levels were analyzed. In study 3, BALB/cJ males and females were exposed to the same combined model of early stress (SM + LB). Maternal behavior pre-SM and post-SM was assessed during the first 2 weeks of development. During adolescence, male and female mice were tested in the Y-maze and Object in Place (OIP) memory tasks. After behavioral tests, the animals were sacrificed and the mRNA levels of dopamine receptor D1 (Drd1), Drd2, and Drd3 were measured in the medial prefrontal cortex (mPFC) by Real-time qPCR. Results: In study 1, it was identified that MS exposure increases maternal behavior after post-MS, and this result was more evident in studies with rats. Regarding the LB model, an increase in the fragmentation of maternal care was observed, especially in studies with mice. Study 2 reported that mothers showed a worsening in the quality of maternal behavior and an increase in the number of exits from the nest. During adolescence, the animals of the ELS group showed an increased anxiety-like behavior in the OF, EPM and LD. Regarding biological markers, an increase in Crh levels was observed in the hypothalamus of stressed animals. Furthermore, the animals in the ELS group showed a decrease in plasmatic corticosterone levels. Study 3 identified that the ELS model increases maternal behavior only post-MS. In the cognitive tests, males and females exposed to the combined ELS model performed worse in the Y-maze and OIP. Regarding mRNA levels in the mPFC, the three genes investigated (Drd1, Drd2 and Drd3) had their expression decreased regardless of sex after exposure to the ELS model. Conclusion: In conclusion, it was observed that ELS exposure promotes maternal behavior alterations that may be related to the development of psychopathologies and cognitive impairments throughout life. Later in life, animals exposed to the proposed SM + LB model showed an increase in anxiety-like behavior, as well as central and peripheral changes in HPA axis functioning. Finally, exposure to the combined ELS model also caused impairments in PFC-dependent tasks in both sexes. Those impairments can be partly associated with changes in the expression of dopamine receptors, especially Drd1.