| Depression is a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration. At its worst, depression can lead to suicide, about 10-20% individuals undergo depression overall lifetime. It is also a risk factor for many diseases, such as obesity, Cardiovascular disease and Neurodegenerative disease.Recently, it is estimated by the World Health Organization (WHO) that depression was the leading cause of disability as measured by Years Lived with Disability (YLDs) and the 4th leading contributor to the global burden of disease. By the year 2020, depression is expected to follow coronary heart disease as the second most common cause of disability.Depression is considered as a multifactorial and multigenetic disease. Clinical investigation shows that major depression is a familial disorder, and its familiality mostly or entirely results from genetic influences. Environmental influences specific to an individual are also etiologically significant. So major depression is a complex disorder does not result from either genetic or environmental influences alone but rather from both. For this reason, depression in adolescence is associated with the family environment and parents influence tightly. And numerous studies have shown that the child and adolescent offspring of depression, as compared to those of non-depression, parents are at two- to threefold greater risk for major depressive disorder and anxiety disorders .In addition, numerous clinical studies have found maternal stress or depression is detrimental to the development and cognition of offspring. It is also notable that the lifetime prevalence in women is twice than men. Sex difference in the prevalence of depression starts in early adolescence and continues until mid 50s; that is, it involves the reproductive period. Women have a tendency for depression in periods of change in reproductive hormones. These periods of change are puberty, use of birth control pills, the late luteal phase, pregnancy, the confinement period, and the menopausal transition period. However, the mechanisms underlying its pathophysiology are still poorly understood.At present, three main theories try to conceptualize the molecular and biochemical mechanisms of depression, namely the monoamine-system, the hypothalamus-pituitary-adrenal- (HPA-) systemand the neurotrophin-hypotheses. Chronic mild stress (CMS), a paradigm developed in the late 1980s as an animal model of depression, is applied in multiple animal experiments. CMS paradigm has been designed to mimic the anhedonia, a core symptom of clinical depression.It will induce lower consumption of sucrose (sweet food) postulated which reflects an hedonia (the loss of interest or pleasure) in animals.Several studies have showed that the health of progeny is associated with the maternal health in the periods of puberty and pregnancy tightly. Multiple animal experiments have demonstrated that prenatal stress or depression is related to the increased depression-like and anxiety-like behaviors in progeny. In addition, maternal stress has been associated with an increased risk of schizophrenia in male offspring. It may lead to alteration of foetal brain growth, and the decreased body weight of offspring. It is also showed that maternal stress in gestation has specific effects on neurobehavioral development in offspring. However, only a few studies have investigated the impact of maternal depression before pregnancy on their offspring in animal models, and the related neurobiological mechanisms have not been known yet. In our study, we investigated the change of neurodevelopment and synaptic plasticity of progeny of maternal ICR mice which exposed to CMS before pregnancy . We found that CMS before pregnancy could lead to the decreased survival rate of the offspring. It also decreased the neurogenesis of subgranular zone(SGZ) in hippocampus from PND7 to adult. In addition, the CMS before pregnancy had specific effects on neurobehavioral development, neuropsychological behavior, cognition and the level of some protein associated to synaptic plasticity in offspring,but no effect on the sex ratio of offspring. These studies suggest that the female depression patients should be taken good prenatal and postnatal to minimize the side effect on the development of offspring.AIM: In this study, we will investigate the effects of CMS before pregnancy on the neurobehavioral development of offspring and the changes of the expression of synaptic plasticity associated proteins.METHODS: 7 weeks ICR female mice(30-32 g) on the basis of the baseline sucrose preference score and weighting were divided into two matched groups: the chronic mild stress group (CMS group, n=18) and the non-stressed control group(Control group, n=15). The CMS group was subjected to a 6-week CMS procedure. After the 6-week CMS, the females were caged with sexually experienced males of the same strain for mating. We studied the reproduction capacity of the parental females, the neurobehavioral development of offspring, and the neurogenesis in hippocampus of offspring detected by immunostaining of Brdu (Bromodeoxyuridine).The expressions of Arc protein in neuron and GFAP protein in astrocyte of hippocampus in offspring were detected by immunohistochemical. Western blotting was used to investigate the levels of glucocorticoid receptor (GR) and brain derived neurotrophic (BDNF) in offspring. In addition, both of the mother and offspring's plasma corticosterone levels were analyzed by ELISA kit. At last, basal tissue neurotransmitter levels of brain of the offspring were measured by high-performance liquid chromatography (HPLC).RESULTS: (1) After several weeks exposed to CMS procedure, the CMS group showed significant reductions of body weight and sucrose preference, an increased immobility time in TST compared with the control group mice. (2) The survival rate of pups (of each litter) generated from the CMS group was lower than those generated from the control group from birth to weaning, but there were no differences in number and sex ratio between them. (3) The mean body weight of pups of CMS group was lower from birth to adult, but after adulthood (PND75), the body weights of two groups'offspring have no significant difference.Besides, the offspring of CMS group showed significantly slower attainment of the placing reflexes in newborn. (4) In the test of Hole-Board and Morris water task, the offspring of CMS group showed decreased capability of exploratory and memory compared with those of control,but the learning capacity was increased. (5) In hippocampus of adult offspring of CMS group, the level of 5-HT was increased, while the levels of Aspartate and NE were decreased. (6) CMS before pregnancy significantly inhibited cell proliferation in the SGZ of the offspringsfrom PND7 to PND 75 and led to a decreased hippocampus volum.Significant decrease of the hippocampal astroglia cells was also observed in PND75; (7) The levels of plasma corticosterone and GR in hippocampus showed a significant increase in the offspring of CMS group in different ages except PND3. (8) The maternal plasma corticosterone levels in CMS group was higher than those of control, but the GR expression in hippocampus has no difference between the two groups.CONCLUSION: Our study indicated that CMS before pregnancy would result in significantly decreased reproductive capacity of female mice, impaired the neurodevelopment and memory of the offspring. The main mechanism of these adverse effects is that CMS before pregnancy changes the function of HPA in progeny. |
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