The major findings of the present study were as follows. First, two-month social isolation stress induced depressive-like behaviors in aged mice. Second, increased Hcy is closely related to the depressive-like behaviors in aged mice during social isolation stress. Third, diet-induced HHcy mimicked the depressive-like behaviors and BDNF downregulation in the same manner as social isolation, while administration of vitamin B complex supplements to reduce Hcy alleviated the depressive-like behaviors and BDNF reduction in socially isolated mice. Altogether, our results suggested Hcy is likely involved in social isolation stress-induced BDNF reduction and related depressive-like behaviors.
As a response to stimulation by internal and external environmental factors, stress involves systemic reactions in several organ systems, such as the nervous system, endocrine system, and immune system [42]. Rodent models of social isolation offer the ability to study the effects of isolation under highly controlled conditions, controlling for age, duration of isolation, housing conditions, and the developmental time point of isolation. Rodents, like humans, are social creatures that thrive in group housing conditions. The literature on the impact of social isolation on affective behavior in rodents to date has largely been limited to studying the effects of single-housing isolation-induced stress during critical developmental periods in adolescence and early adulthood. To date, limited studies have assessed the impact of social isolation in aged rodents, with only two studies, to our knowledge, having assessed social behavior following at least two weeks of late-life isolation in aged rodents [43–44]. Here, we found that two-month late-life isolation induced depressive-like behaviors, enriching the understanding of the impact of social isolation in aged mice.
Our study also highlights the role of Hcy, a small amino acid that was involved in vital processes such as energy metabolism and methylation [45], in the process of stress-induced cognitive dysfunction in mice. The main source of Hcy is methionine in food intake, and Hcy is catabolized mainly in the liver in the presence of B vitamins as coenzymes. Our study found that plasma Hcy levels increased with increasing duration of social isolation stress; this finding is similar to previous findings that chronic stress may lead to Hcy accumulation by inhibiting the transcription of cystathionine β-synthase, an Hcy isomerase, in the liver [32]. High- methionine diet and administration of VBco gavage induced the emergence of cognitive impairment and alleviated stress-induced cognitive impairment, respectively [38]. Zhou, Cong et al. found that 6 weeks of chronic stress resulted in decreased autonomic activity and increased Hcy in rats; however, the administration of folic acid resulted in decreased Hcy and remission of symptoms, which the authors linked to decreased IL-6 release [46]. Another study suggested that elevated Hcy may be closely related to 5-HT metabolism in the relevant brain regions, and that methyl-donor deficiency may also lead to stress-like effects [47]. Results above suggest a potential role of Hcy in stress. Epidemiological studies have also found that Hcy is an important causative factor in neurodegenerative diseases [48]. In addition, Hcy is an independent risk factor for Alzheimer’s disease [49], and administration of B-complex vitamins may alleviate cognitive symptoms in AD patients [50]. Moreover, Hcy level negatively correlates with scores on the Cambridge Cognition Scale in the elderly [51]. Taken together, Hcy may be an important mediator of stress-induced depressive-like behaviors.
Neurotrophic factors play an important role in the production and maintenance of depression in mammals [52]. As an important neurotrophic factor, BDNF plays an important role in maintaining normal brain function; it plays a key role in the formation of synapses, growth, and the differentiation and migration of neurons [53–54]. Our study in mice showed that both stress and high levels of Hcy caused a decrease in BDNF level in the hippocampus induced depressive-like behaviors. These findings suggest that BDNF may be a downstream target molecule of Hcy in the process of stress-induced depressive-like behaviors. Inhibition of BDNF transcription results from chronic isolation stress [55], chronic social defeat stress [56], and chronic mild stress [57], suggesting that negative regulation of BDNF by stress is widespread in a variety of chronic stress processes. In addition, interference with BDNF at the dentate gyrus triggers depressive-like behavior and affects neuronal regeneration in rats [58], and knockdown of BDNF in mice inhibits neuronal plasticity and induces the onset of psychiatric symptoms such as anxiety in mice [59]. Moreover, some people found that interference with BDNF at the dentate gyrus triggers depressive-like behavior and affects neuronal regeneration in rats [58]. These findings indicate that BDNF is an important factor in the pathogenesis of mental disorders. Thus, it is particularly important to study how Hcy affects BDNF. Ma et al. found that the BDNF promoter region is regulated by methylation [60] and that administration of methyl donors reverses the psychiatric symptoms caused by Hcy during stress [46]. Therefore, the focus of our future study was to examine whether Hcy may affect BDNF transcription.
In summary, we found that social isolation stress can increase Hcy levels in aged mice, inhibit BDNF protein level and lead to depressive-like behaviors in aged mice. These findings provide new insights into the mechanisms underlying depression that caused by social isolation stress in aged mice. Finally, further interventional strategies for the occurrence and development of depression from a biological perspective should follow.