Abstract
Objective: To observe the changes of depression-like behavior in SD rats caused by Maternal Separation (MS) stress, and to explore the effects of probiotics on antidepressant-like behavior and on cAMP/CREB signaling pathway.
Methods: Newborn SD rats were selected as experimental subjects and divided into MS+NS group (mother-infant isolation + placebo group), CON+NS group (control + placebo group), MS+P group (mother-infant isolation + probiotic group), and CON+P group (control + probiotic group) by random number table method, 12 rats in each group. At PND22-49, probiotic colonies of 1×109 CFU (0.1 ml) were given by gavage daily in the MS+P and CON+P groups and the corresponding dose (1 ml/100g) was given according to the daily body weight change, and the corresponding saline dose (1 ml/100g) was given by gavage daily in the MS+NS and CON+NS groups according to the body weight change. The behavioral performance of the offspring rats was examined by sugar-water preference test, open field test and forced swimming test at PND50-56, and the rats were executed at PND57, blood was collected to isolate the serum, and brain tissue was taken for laboratory tests.
Results: After probiotic intervention, FST increased, OPT increased and SPT decreased. probiotics both improved maternal-infant separation-induced weight loss and depression-like behavior to some extent.Compared with the model group, the probiotic intervention resulted in an increase in the number of neurons in the CA1 region of the hippocampus, an improvement in morphological structure, a decrease in serum-related inflammatory factors, and an increase in serum 5-HT concentration and a decrease in CORT concentration in rats. In addition, the probiotic intervention significantly increased the expression levels of cAMP, CREB and BDNF in the hippocampus of mother-infant isolated rats.
Conclusion: Probiotics alleviate anxiety/depression-like behavior in SD rats, which may be associated with activation of the cAMP/CREB signaling pathway. The protective effect of probiotics, a therapeutic food care,on their prevention or alleviation of MS-induced depression-like behaviors provides an experimental basis for the application of probiotics to alleviate or ameliorate anxiety/depression.
Keywords: Maternal separation; depression; Brain; cAMP/CREB signaling pathway; Probiotics
Introduction
Depression is a growing health problem. It is a mental disorder with significant depressed mood, reduced mobility, and slowed thinking as the main symptoms[1, 2]. With the development of social economy and changes in social environment, mental disorders such as depression show a rising trend. According to the World Health Organization, more than 32 million people worldwide suffer from depression each year, Depression is expected to be one of the public health problems plaguing the world by 2030[3]. In China, there are more than 95 million people with depression, of which children and adolescents account for about 20%[4]. Currently, it is widely believed that depression is common in children and adolescents, but depressive symptoms in children and adolescents are not always similar to adult depression and can have some adverse consequences if left unrecognized and untreated.
That mother-infant separation is a model of early life stress and that this model of early life stress disrupts neurological development.To a large extent, this causes behavioral deficits, neuronal morphological damage, triggers dendrites to appear atrophy-like, reduces inter-synaptic connectivity, and ultimately leads to depressive-like behavior[5]。Mejia has confirmed that mother-infant separation can have some negative effects on the hippocampus of rats, which may lead to disruption of neurological development and even impairment of cognitive and emotional functions[6]. Petanjek has shown that the number of excitatory synapses in the brain during infancy and childhood has far exceeded that of adults by a factor of 2-3 and is the period when the brain is most sensitive to external environmental stimuli[7]. More than 60% of left-behind children have some psychological problems[8], mainly associated with the lack of maternal love and neglect during infancy or childhood[9]. This prolonged separation from the mother, or the presence of some disharmonious and unintimate parent-child relationship (parent-child conflict, poor parenting practices, abuse or neglect, etc.), causes children to have adjustment difficulties and increases the occurrence of depressive-like behaviors[10, 11]. These undesirable behavioral or psychological problems are key factors that induce a variety of emotional dysfunctions in children such as depression and anxiety.This shows a close correlation between psychiatric disorders and pathological lesions or environmentaldamage to the brain during development, which is consistent with the study of Marín et al[12].
Since existing antidepressants generally have low cure rates, high relapse rates, and many side effects (gastrointestinal discomfort such as diarrhea and vomiting), and other disadvantages, Long-term use will bring financial and psychological burden and stress to families and individuals[13], It is important to develop complementary products that have a preventive effect and mitigate side effects, among which the use of probiotics may be an effective means of combating depression-like behavio[14]. It has been shown that lactobacilli can maintain intestinal flora homeostasis, produce beneficial immunomodulation, and relieve depression and anxiety in the host[15]. It hasbeen shown that the use of Bifidobacterium spp. can produce beneficial metabolites through the intestine, including: serotonin, histamine, and gamma-aminobutyric acid, improving depression-like behavior,social behavior[16]. It has been shown that Bifidobacterium shortumcan reduce blood creatinine and cortisol concentrations in the serum of mice in a chronic unpredictable stress model, restore normal function of the HPA axis, and improve depression[17]. Sun showed that Lactobacillus plantarum can alleviate anxiety and depression due to chronic stress[11]. Hazuki showed that after oral administration of Lactobacillus swiss, mice in a depression model improved social interaction behavior after gene expression in the vomeronasal nucleus, suggesting that this strain has an important role in relieving stressful emotions[18]. It is thus clear that probiotics, as active microorganisms, can interact positively with the host to alleviate mood disordersand prevent stress-induced changes in the intestinal flora, thus conferring health benefits to the host.
The pathogenesis of depression is unclear, with the main monoaminergic neurotransmission hypothesis[19]、Change in intestinal flora[20]、Immunoinflammatory response[21]、Hypothalamic-pituitary-adrenal[22]. However, more researchers are inclined to study antidepressant signaling pathways, analyze the association between their related signaling pathways, proteins, genes, etc., and actively search for potential, antidepressant-related mechanisms[13, 23]. Among them, the cAMP/CREB signaling pathway is regarded as an important player and regulator of depression pathogenesis, which can regulate synaptic plasticity, cytoplasmic division, transcription, and modulation of the HPAaxis[24, 25].cAMP is the most classical second messenger, a key factor in cell signaling, involved in the onset, development and regression of organismal physiopathology[24]. In the central nervous system, inhibition of the cAMP/PKA signaling pathway affects neuronal excitability, synaptic activity, and ultimately leads to the pathological outcome of depression[24]. In the presence of memory impairment, neurological disorders, addictive or emotional dysfunction, CREB-mediated transcription may be impaired, blocking downstream signaling pathways[26]. Inhibition of the cAMP/CREB signaling pathway affects neuronal excitation and synaptic plasticity, while activation of the cAMP/CREB signaling pathway will provide antidepressant effects[27]. Studies have shown that the pathogenesis of depression is related tothe fact that some antidepressants activate the PKA/CREB signaling pathway, which regulates the active expression of BDNF[28]. Therefore, this experiment intends to investigate and study the probioticsfrom cAMP/CREB signaling pathway to improve the depression-like behavior of mother-infant separated offspring rats.