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.