History and main research of psychoneuroimmunology in China

Abstract

The concept of mind-body integration was born in China with a long history and is naturally compatible with the psychoneuroimmunology (PNI). Since PNI was introduced into China in the 1990s, increasingly Chinese researchers from different fields were attracted to the psychoneuroimmunology research of health and disease. This review includes two parts: in the first part, we summarize a brief history of the development of PNI in China from 1992 to 2012, which mainly happened before the establishment of PNIRS_China in 2013. In the second part, some representative studies in the different fields of PNI conducted in China are reviewed, mainly including conditioned immunity, emotional stress and immunity, and inflammation and depression.

Psychoneuroimmunology (PNI) has emerged as an interdisciplinary discipline since the mid-1970s, that focuses on complex interactions among behavior, nervous system, endocrinology, and immunology. It explores how the nervous system transforms psychological factors into physiological components which are related to health and disease, especially how the brain and behavior affect the immune system and how they are affected by the immune system. Through half-century development, PNI has evolved into a mainstream discipline to achieve a deep understanding of the integrative mechanisms among psychosocial factors, the nervous system, and the immune system in health and disease.

There is a long and rich history of the view of mind-body connections in China, which form the essential foundation of traditional Chinese medicine beginning before the Common Era. The earliest medical book in the Han Dynasty of China is Neijing, which systematically elaborated the theory of emotion and its clinical application from the aspects of physiology, pathology, treatment, and health preservation, and constructed a relatively theoretical system of emotion in traditional Chinese medicine, which is the cornerstone of the development of the theory of emotion in later generations (Li et al., 2018; Yan, 2018). Since the emotion theory of Neijing is compatible with the integrated theory of emotion, immunity, and disease of PNI, PNI naturally attracted the attention of some pioneer Chinese researchers shortly after its birth and was introduced into China in the early 1990s.

This review attempts to outline the developmental trajectory of PNI in China with important events, and main scientific research at different stages along with parallel timelines of PNI in the world. The content of this review includes two parts: in the first part, we summarize a brief history of developments of PNI in China from 1992 to 2012, which mainly happened before the establishment of PNIRS_China in 2013 (Kelley et al., 2020). In the second part, some representative topic studies in the different fields of PNI conducted in China are reviewed.

1. A brief introduction to the history of PNI in China

1.1. The beginning of PNI in China

In the early 1990s, some Chinese scientists from various fields, like psychology and physiology, introduced PNI into China and initiated early research on PNI.

In August 1992, Dr. Wenjuan Lin from the Institute of Psychology in the Chinese Academy of Sciences reported new work on conditioned antibody enhancement, which was conducted in Australia, at the 1992 Asian-African Psychology Conference held in Beijing, and was published in 1993 by Peking University Press in the “Proceedings of the Asian-African Psychology Conference.” (Lin et al., 1993). During the same period, Dr. Jian Xiao from the Department of Psychology at Peking University came to the PNI field with early studies on emotional stress and immunity. At that time, Laboratories of Psychoneuroimmunology were planned to be established separately at the Institute of Psychology and Peking University.

In June 1994, Wenjuan Lin published an article entitled “Developing a new Frontier Discipline - Psychoneuroimmunology” in “Discipline Development and Scientific and Technological Progress” that was published by the Science and Technology Press of China (Lin, 1994). On August 8 of the same year, the China Association for Science and Technology officially featured and headlined a document, “Developing psychoneuroimmunology as a new discipline” for this book. This officially marked the beginning of psychoneuroimmunology research in China.

1.2. The extension of PNI in China

Since the 1980s, some PNI books were published successively, in which Psychoneuroimmunology (Ader, 1981) and Psychoimmunology (Husband et al., 1993) were collected worldwide, including in Beijing Library. In 1987, Brain, behavior, and immunity as the official journal of PNIRS was chartered.

Under the context of PNI development in the world, academic communication on PNI research in China was continuously organized among researchers from different disciplines at a variety of meetings. In August 1995, Dr. Wenjuan Lin was invited by the International Union of Psychological Science to present a special report on Stress, Behavior, and Immunity at the Asia-pacific Psychology Conference held in Guangzhou of China, which was officially reported in the journal of Acta Psychologica Sinica (1996). In 2004, Dr. Wenjuan Lin was invited to present a keynote lecture entitled “The involvement of psychological processes in immuno-competence: Mind and health,” at the 28th International Congress of Psychology held in Beijing. The article from the keynote lecture was later published in a book entitled, “Progress in Psychological Science around the World” (Lin, 2006). Beginning in 2012, the impressive growth of PNI research in China led to the establishment of a regularly scheduled symposium at the annual meeting of the Chinese Psychology Society (CPS) and the annual meeting of Chinese Physiological Psychology (CPP), a branch of CPS. This symposium is devoted to psychoneuroimmunology in mental health and psychiatric disorders.

The Psychoneuroimmunology Research Society (PNIRS) was officially formed in 1993. Ten years later, as a PNIRS affiliate, PNIRS_China was established in 2013 by an academic forum at Dalian Medical University. Then eight years later, because of the great success of this program in promoting the science of psychoneuroimmunology in China and the whole of Asia-Oceania, PNIRS_China extended into PNIRS_Asia-Pacific in 2017 (Kelley et al., 2020). Today, the emerging field of PNI is now universally recognized in the whole of China.

2. Main research of PNI in China

Some studies in different fields of PNI were conducted by Chinese researchers during this period. In contrast to reviewing the evidence published in the extensive literature, this review is only an attempt to collect the systematic and representative studies in the PNI field of China. These studies include conditioned immunity, emotional stress and immunity, and inflammation and depression.

2.1. Conditioned immune suppression and enhancement

Immune responses, like other physiological processes, can also be modified by classical conditioning, which provides important evidence that the central nervous system regulates the immune system. In seminal research, Ader and Cohen (1975) demonstrated that the administration of a saccharin-flavored drinking solution, saccharin as the conditioning stimulus (CS) paired with an injection of cyclophosphamide (CY), an immunosuppressive agent as the unconditioned stimulus (UCS), led to conditioned behavioral and immune responses, so that eventually saccharin alone was able to induce a taste aversion behavior and suppress humoral-mediated immunity (Ader and Cohen, 1975). The conditioned immunosuppression (CIS) model subsequently was confirmed by many scientists in different laboratories and research groups in the United States, Germany, Australia, Canada, and other countries including China (Lin et al., 1998).

However, the explanation for this phenomenon is still disputed. Some believe that this is a conditioned effect on immune function, whilst others think it may be the effect of stress (Kelly et al., 1985). The conditioned taste aversion (CTA) to saccharin solution cannot rule out the existence of somehow stress effects. To further discriminate the relationship between CIS and CTA, using one trial and two trials of CS/UCS paring paradigms, Lin et al. reported that CTA occurred under both one trial and two trials of CS/UCS paring, but CIS, as assessed by spleen cell proliferation to mitogen and the number of peripheral leukocyte and lymphocyte, required 2 parings, suggesting that conditioned behavioral and immunological changes might occur independently (Lin et al., 1998). It was further found that biological immunosuppressants without obvious toxic effects as UCS can also establish conditioned immunosuppression but no conditioned taste aversion (Lin et al., 2002). In this case, the result of CIS could be the associative learning process of CS-UCS in the brain, not the CTA induced stress effect. However, various forms of conditioned immunosuppression in the literature are difficult to distinguish from the suppression of immune function by CTA-induced stress, which brings certain difficulties to study conditional mechanisms. Based on the principle of associative learning, conditioned immunomodulation should be bidirectional. That is to say, conditional stimulation can produce an immunosuppressive effect, and it could also produce an immune-enhancing effect. Establishing a model of conditioned immuno-enhancement (CIE) would be more conducive to demonstrating that conditioned immunomodulation is the result of the central nervous system regulating the immune system.

Regarding the research of conditioned immuno-enhancement, in the early 1990s, Lin and Australian researchers (1993) reported a conditioned enhancement of antibody production via a single-trial protocol, in which the protein antigen ovalbumin was used as an unconditioned stimulus (UCS) that was paired with a novel taste of saccharin (CS). An enhancement of anti-ovalbumin antibody production was observed after re-exposure to the CS alone. However, the magnitude of conditioned antibody production elicited by the CS was relatively small and the value of statistical significance between the conditioned and unconditioned groups was marginal (p = 0.048) (Husband et al., 1993). To evaluate the reliability of conditioned antibody responses, new experiments were performed at the Laboratory of Psychoneuroimmunology at the Institute of Psychology in the CAS. Different from the previous paradigm in which the test trial task was performed during the rapid increase phase in the primary antibody response, the test trial task in the new experiment was changed to the declining phase of primary antibody response (1 month after the conditioning). Thus, the CS was given alone to the conditioned rats during the declining phase of the primary antibody response. Blood samples were dynamically collected after the CS test trial day. The results demonstrated that a significant conditioned antibody response was elicited by the CS alone. Importantly, it was found that kinetic pattern of the level of conditioned anti-OVA IgG (from low to high and then to low) was similar to that of primary antigen-induced antibody responses. More interestingly, re-exposure of conditioned rats to the CS alone resulted in a significant increase of c-Fos immunoreactivity in all three areas of the insular cortex, including the agranular, dysgranular, and granular areas. These data suggest that the insular cortex is involved in the storage of immune-related information(Chen et al., 2004).

Considering the potential of the CIE model in human clinical application, another new paradigm of CIE was established, in which electro-acupuncture served as the CS and an injection of the protein antigen ovalbumin as the UCS. After one trial of CS/UCS pairing, re-exposure of animals to the CS alone resulted in significant conditioned enhancement of the anti-ovalbumin antibody. Even in deep sleep induced by anesthesia, the animals can associate a single CS with UCS and an antibody response can be elicited when re-exposure to the CS alone, while no effect of electroacupuncture per se on the anti-ovalbumin antibody production was found (Huang et al., 2004a).

The above studies evaluated and further investigated the phenomenon of conditioned immune responses in CIS and CIE with unique research strategies, providing new evidence for the communication between CNS and immunity.

2.2. Emotional stress and immunity

Emotional stress and immunity are another hot spot to investigate the effects of psycho-behavioral factors on immune function in the field of psychoneuroimmunology. In 1964, George F. Solomon and Rudolf H. Moos (1964) firstly investigated the role of emotional stress in autoimmune diseases and schizophrenia.

In China, Professor Shao-Guang Fan from the Medical School at Beijing University initiated a series of studies about the relationships between stress and the immune system since the early 1980s. He found a serum factor, a protein with a large molecular weight induced by restraint stress in mice and rats, and demonstrated this serum factor suppresses lymphocyte function (Zha et al., 1992).

In 1996, using a kind of emotional stress model-witnessing footshock stressor, Dr. Jian Xiao from Peking University (1996) demonstrated that emotional stress caused the suppression of humoral immunity, thymus involution, and impairment of spleen structure, and most of the stress effects on the immune system were reversed by the chemical sympathectomy (Xiao and Genry, 1996). Lin et al. (2003) established a new model of emotional stress, which was induced by randomly giving an empty water bottle to rats trained to drink water at daily set times for fourteen consecutive days. The data showed that the emotional stress activated both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, leading to the increased blood levels of corticosterone and catecholamine (Lin et al., 2003). This novel stress paradigm also elicited attack and exploring behaviors and suppressed several aspects of the immune function of the rats, including leukocyte counts, weight of the spleen, and the level of specific anti-ovalbumin IgG antibody production. Further experiments showed that the decrease in anti-ovalbumin antibody levels only correlated negatively with an increase in plasma norepinephrine (Shao et al., 2003). These findings demonstrate a role of psychological factors in behavioral, endocrinological and immunological functioning, and that emotional stress –induced activation of sympathetic nervous system may be more involved in humoral immunomodulation.

2.3. Inflammation and depression

In the early 1990s, the link between cytokines and depression was made in Smith’s “macrophage theory of depression” in which he noted specifically that IL-1 secreted by macrophages was responsible for the depression (Smith, 1991). Maes (1999) proposed the inflammatory response system (IRS)- activation model of major depression. Subsequently, there was growing evidence that increased inflammation is present not only in depression but also in psychosis and other psychiatric disorders. That evidence implies a potentially “causal” role of inflammation in the onset of psychiatric disorders. In 2014, a new field, immunopsychiatry, was first termed by Khandaker and colleagues(Khandaker et al., 2015), in which an immune-mediated etiology for behavioral alterations and psychiatric symptoms is highlighted.

2.3.1. Cytokines and depression

Based on the hypothesis of “inflammatory response model of depression” (Maes, 1999), Chinese researchers studied the role of inflammatory cytokines in depression by using models of stress-induced and inflammation-induced depression. For the study of stress-induced depression, You et al. demonstrated an imbalance of pro-/anti-inflammatory cytokines in the hippocampus and other brain areas in chronic mild stress (CMS)-induced rat model of depression. They found heightened expression of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 in the hippocampus, cortex, hypothalamus, and spleen in the CMS group than in controls (You et al., 2011). Pan et al. reported that the anti-inflammatory cytokine IL-10 could reverse depressive-like behavior in the depression model induced by chronic swim stress (Pan et al., 2013). To study inflammation-induced depression, peripheral injections of lipopolysaccharide (LPS), cytokine inducer, inducted models are used frequently in the literature. By systematically observing the effects of single and repeated peripheral administration of different doses of LPS on the behavioral time course of rats, Pan et al. (2007) found that depressive-like behavior induced by a single injection of LPS lasted only a few hours, whereas repeated peripheral LPS injections induced behavioral tolerance. The altered behavior within 24 h post-LPS could be argued as being sickness and hardly be regarded as a model of depression. To overcome the shortcomings of the short duration of altered behavior, Tang et al. (2014) established a novel and effective model of neuro-inflammation induced depression by means of repeated lateral ventricle LPS injections. To investigate whether specific and common risk factors involving cytokines exist in both depression models induced by chronic stress or by neuroinflammation, Guan et al. (2015) compared central changes in pro-inflammatory markers (TNF-α, IL-1β, and IL-6) in several brain areas (hippocampus, prefrontal cortex, and amygdala) using two well-established animal model of depression: chronic swim stress and central LPS infusion (Guan et al., 2015). They found a similar pattern with increased expression of brain cytokines, especially the increase of TNF-α in the hippocampus was the common and significant change, suggesting that TNF-α could be one of common risk factors for inflammation in depressive disorders.

In addition, the interactive effects of chronic stress and inflammatory changes on depression have been investigated. Several studies reported that peripheral inflammatory activation by LPS led to an increased susceptibility to subsequent stress exposure, manifested by earlier, stronger, and longer expression of depressive behaviors induced by chronic stress (Pan et al., 2013), while treatment by anti-inflammatory medication aspirin or anti-inflammatory factor IL-10 alleviated depressive-like behavioral changes (Huang et al., 2004b; Pan et al., 2013).

Neuroendocrine and immune systems acting in concert may have roles in the development and the maintenance of the depression. Wang et al. (2011) found that chronic blockade of glucocorticoid receptors by RU486 significantly enhanced a significant increase in the serum production of TNF-α and prolonged peripheral LPS-induced depressive-like behaviors (Wang et al., 2011). A recent study further found that the phosphorylation of serine 246 sites (grser246) of glucocorticoid receptor was involved in the regulation of depression caused by central LPS infusion (Zhang et al., 2020a). These findings suggest that GR function could be an important contributing factor to the development of inflammation-induced depression.

Apart from the involvement of GR functioning, the MAPKs signaling pathways have also received the most attention. Systematic research from Lin’s group was conducted to investigate whether and how the three major MAPK pathways: the extracellular signal-related kinases 1/2 (ERK1/2), the c-Jun N-terminal kinases 1/2 (JNK1/2), and p38 MAPK participated the occurrence of depression induced by neuroinflammation. It was found that the decrease of ERK signaling and the increase of JNK and p38 signaling in the hippocampus were associated with depressive behaviors induced by LPS administration, and reversing the dysregulation by specific antagonist rescued the behavioral and inflammatory changes (Tang et al., 2018; Zhang et al., 2020a; Zhao et al., 2018b). The serial studies demonstrated the differential effects of neuroinflammation on the three major MAPK pathways, suggesting that they are involved in the pathology of depression and that they may act both independently and interactively in the regulatory mechanisms of depression.

Neuroplasticity, especially synaptic plasticity and neurogenesis has been increasingly recognized as a downstream convergence involved in depressive disorders. To investigate whether inflammation-induced depression could be associated with hippocampal neurogenesis dysfunction, Tang et al. showed that central inflammatory activation by central LPS administration inhibited hippocampal neurogenesis, including decreased cell proliferation and newborn cell survival. The decreased hippocampal neurogenesis in cell proliferation was significantly correlated with the depressive-like phenotypes (Tang et al., 2016). Additionally, I.C.V. exogenous fibroblast growth factor 2 (FGF2), one crucial molecule modulating cell proliferation and survival in the CNS, prevented the increased release of pro-inflammatory factors, the impaired hippocampal neurogenesis as well as the decreased phosphorylation of ERK1/2 under neuroinflammation state and reversed depressive-like behaviors(Tang et al., 2017). These suggest that hippocampal neurogenesis might be one of the biological mechanisms underlying inflammation-associated depression.

2.3.2. Microglia and depression

Microglia, the resident immune cells in the brain, are critical to maintaining CNS homeostasis and rapid response to microenvironmental stimuli. Accumulating evidence from both the clinical observations and animal experiments indicates that microglia play a key role in the etiology of depression, and it is therefore increasingly considered a microglial disease (Jia et al., 2021; Yirmiya et al., 2015).

In recent years, the role of microglia in depression has been extensively investigated by Chinese researchers. Using the neuroinflammation-induced model of depression, several studies reported that LPS induced depressive-like behaviors and increased the hippocampal microglia activation and inflammatory response, including the up-regulated release of microglia-derived pro-inflammatory cytokines (Tang et al., 2018; Zhang et al., 2020b). Chronic stress (e.g. chronic mild stress) induced depressive animals showed extensive activation of microglial cells in the prefrontal cortex, nucleus accumbens, and hippocampus, the brain regions related to emotional and cognitive regulation(Su et al., 2017). Of note, early adverse experiences, such as maternal immune activation, maternal sleep deprivation, and maternal separation, long-termly increased the susceptibility of depression in offspring across the later period (including adolescence and adulthood), which was associated with the dysregulation of microglial phenotype, manifested by the increase of primed microglial cells (Han et al., 2019; Zhao et al., 2015).

There are several suggested mechanisms underlying links between microglial dysregulation and depression. Central high mobility group box-1 (HMGB1) is usually released from neural cells (including neurons and microglia) to inform adjacent (or remote) cells of infection and/or injury, therefore functionally as an “alarmin” or “danger signal” involved in the initiation of innate immunity and inflammation. A series of researches from Wang’s group reported that the active release of central HMGB1 was involved in both LPS-induced and chronic stress-induced depressive behavior through the ignition of neuroinflammatory response and/or the kynurenine pathway (Lian et al., 2017; Wang et al., 2018; Wu et al., 2015). The improvement of the inflammatory condition by minocycline, an inhibitor of microglial activation, prevented the depressive-like behavior by inhibiting the release of HMGB1 from microglia and neurons (Wang et al., 2019a).

The decrease of neurogenesis is an important pathophysiological basis of depression, and microglia take part in neurogenesis, synaptic pruning, removing debris, etc. The dysregulation of microglial synaptic pruning was demonstrated to promote the development of depression-like symptoms (Cao et al., 2021). Using both inflammation- and chronic stress-induced model of depression, a series of research demonstrated that the inhibition of neurogenesis in emotion-regulating brain areas, especially the hippocampus and prefrontal cortex, is involved in the generation of depressive-like behaviors and cognitive deficits, which can be ameliorated by enhancing microglia-mediated neurogenesis (Han et al., 2020; Tang et al., 2018; Zhao et al., 2014). Tang et al. (2018) found that FGF2 infusions reversed the LPS-induced depressive-like behaviors and inhibited the hippocampal microglia activation and the release of pro-inflammatory cytokines (including IL-1β, IL-6, and TNF-α). SU5402, an FGFR inhibitor itself evoked depressive-like behaviors, induced microglia activation, and increased production of pro-inflammatory cytokines (Tang et al., 2018). These data emphasize that microglia-mediated neurogenesis impairment involves in the pathophysiology of depression.

Microglia, with high plasticity, display pro-inflammatory, or anti-inflammatory phenotype, which exert neurotoxic or neuroprotective effects on neurogenesis, respectively. Several pathways involved in the regulation of microglial activation and the relationship with depressive behaviors have been investigated. The PPARγ signaling is an important mediator for switching the phenotype of microglia. It was found that CMS could induce depressive behaviors and the PPARγ-mediated alteration of microglial activation phenotype. The treatment with Pioglitazone, an agonist of PPARγ, alleviated depressive behaviors by inducing a pro-neurogenic microglial phenotype (Zhao et al., 2016b). The central IL-4 has been known to promote the switch of microglia into a neuroprotective phenotype. In a chronic stress model of depression, the inhibited IL-4 signaling in the hippocampus was observed. The overexpression of brain IL-4 programmatically induced Arg1+ microglia (a pro-neurogenic phenotype) and increased neurogenesis in this area, as well as alleviated behavioral outputs in stress-treated mice (Zhang et al., 2021a). BDNF signaling is an important pathway involved in microglia-mediated effects on neurogenesis in depression and antidepressant treatment (Yao et al., 2022; Zhang et al., 2021a). These suggest that the switching of the microglial activation phenotype may have therapeutic potential in depression (Zhang et al., 2018).

2.4. Anti-inflammatory strategy in the treatment of depression with Traditional Chinese medicine

2.4.1. General view of depression in Traditional Chinese medicine

Traditional Chinese medicines (TCM) are widely used in China and other countries for the treatment of mental disorders (Dai et al., 2022; Wang et al., 2019b). In China, TCM has a history of thousands of years, and is currently a significant part in the whole medical system, practiced alongside Western medicine. TCM is characterized by its emphasis on the whole, including the whole person, the environment, and their interactions. TCM has distinct diagnostic and therapeutic systems: A certain category of syndrome (Zheng,证候) is diagnosed on the basis of the patterns of patient's pulse, tongue and other collections of symptoms; the corresponding formula consisting of multiple herbs or other natural products, and/or groups of acupuncture points (meridians) are prescribed for treatment (Chen et al., 2018). TCM pays special attention to the relationships between emotion (mind) and body, and has established the view at the very early time that affective disorders are one of the major causes of many diseases. From the point view of TCM, depression originates from the stagnation of the Qi movement following stressful events (Ren and Chen, 2017). Overtime, the stagnant Qi becomes excessive and could be transformed into heat/fire, and eventually the uncontrolled heat/fire impairs the capability of brain to regulate emotion, so that patients show depressive disorders. Therefore, the basic principle for the treatment is to clear the heat/fire and to invigorate the circulation of Qi. The clearing of heat/fire is very close to control of the inflammation, and invigoration of the stagnant Qi is more related to remedy the distress-induced flatulence.

2.4.2. Current research on TCM treatment of depression by immunomodulation

There are many treatment approaches in TCM, including Tai Chi, Qigong, Chinese herbal medicine, acupuncture and moxibustion, etc. Here we focus on pharmacological interventions to depression. The concept of immunity was not explicitly developed in TCM, although TCM was the first to use immunization for the control of epidemics(Kuchta et al., 2021). It has been shown that most herbs used in TCM have some immunomodulatory effects (Li, 2000; Wu et al., 2015; Zhang et al., 2016; Zhang et al., 2020c; Zhang and Xiao, 2021). In terms of the function of herbs in TCM treatment, two types of herbs are most directly related to immunity: the heat/fire-clearing and the body-tonifying types. The heat/fire-clearing herbs are specialized in fighting excessive inflammatory responses, and the body-tonifying herbs are those capable to strengthen the weakened immune system, normally associated with chronic disease. For treatment of depression, these two kinds of drugs are often both prescribed in the formula. In terms of TCM, excessive of heat/fire is critical for pathology of depression. Therefore, treatment of depression with TCM is often inextricably linked to extinguishment of inflammation.

In fact, Hypericum perforatum, used as the antidepressant in Europe, has the property of heat/fire-clearing in TCM. Hypericin is the main effective component of Hypericum perforatum. A recent study showed that Hypericin can reverse glucocorticoid metabolism, increase estrogen expression, and then inhibit the NLRP3 inflammasome activation, which may underlie its antidepressant effects on postpartum depression (Zhai et al., 2022). Hyperoside, an quercetin-derivative, is also another effective ingredient in Hypericum perforatum. A study showed Hyperoside attenuated inflammation induced by LPS in HT22 cells via upregulating SIRT1 to activities Wnt/β-Catenin and Sonic Hedgehog pathways, responsible for attenuation of LPS-induced depression-like behaviors (Huang et al., 2021).

Other herbs characteristic of heat/fire-clearing, including Fructus Gardeniae, Radix Scutellariae, Rhizoma Anemarrhenae and Cortex Moutan Radicis, are commonly in the formula for antidepressant treatment. For example, Fructus Gardeniae is an important ingredient in two classical formula that have evidenced antidepressant effects: Yueju Pill and Jiawei Xiaoyao Pill. In a pharmacological study of Fructus Gardeniae, it was found that the effeictive components such as geniposide, geneipin and crocin in Fructus Gardeniae can play a neuroprotective role by inhibiting the inflammatory pathway and oxidative stress reaction (Cheng et al., 2018; Zhang et al., 2015; Zhao et al., 2018a). Quercetin, widely found in many herbs inluding Hypericum perforatum and Fructus Gardeniae, also demonstrated rapid antidepressant response in the LPS-induced depression model, in which a quick and selective alleviation of AKT-mediated inflammation signaling was required for quick improvement of the neuroplasticity critical for the rapid antidepressant response (Sun et al., 2021). It is worth to mention that Fructus Gardeniae is one of the few herbs that can elicit rapid antidepressant effects. A study showed the synergism of two major compounds of the herb plays a central role, by targeting a peptide PACAP. PACAP is well-known for its potency in inflammation regulation at both system and brain levels, and thus a target for neuropsychiatric and neurological disorders (Zhang et al., 2015, Zhang et al., 2022). Radix Scutellariae is an important component of Xiaochaihu Decoction. Experimental studies in vivo and in vitro showed that Radix Scutellariae, and particularly the effective compound Baicalin, can exert antidepressant effects, mainly through normalization of the hyperactivity of HPA axis, inhibition of NLRP3 inflammasome activation and HMGB1/TLR4/NF-ΚB pathways (Jin et al., 2019), inhibition of malignant over-expression of TLR4 through PI3K/AKT/FoxO1 pathways (Guo et al., 2019), attenuation of the expression levels of pro-inflammatory cytokines in hippocampus, prefrontal cortex and serum, reduction of the apoptosis, and increase neurogenesis in the hippocampus (Liu et al., 2019; Piao et al., 2004; Zhao et al., 2016a).

The body-tonifying herbs have a high correlation with the Qi deficiency symptoms found in TCM studies. Qi deficiency occurs frequently following remission of a major disease or in patients suffering from chronic disease. These people normally have deficient immune systems and reduced energy, and thus treated with body-tonifying herbs. For example, Radix Ginseng is the most famous body-tonifying herb and is a constituent herb in Xiaochaihu decoction and many other classic formulae (Chen et al., 2019a; Chen et al., 2019b). Radix Ginseng can promote the overall energy metabolism, including neuroimmune systems (Jiang et al., 2018; Wang et al., 2017; You et al., 2017). Ginseng Total Saponins and Ginsenoside Rg1, the representative components of Radix Ginseng, has been found to inhibit the activity of inflammatory pathway by reducing the over-expression of pro-inflammatory factors and the activation of microglia and astrocytes, so as to play an antidepressant role (Fan et al., 2018; Jin et al., 2017; Kang et al., 2011; Zhang et al., 2021b). Another widely used body-tonifying herb is Lycium barbarum, which is also used as food for its high safety profile (Potterat, 2010). The effective components, Lycium barbarum polysaccharide-glycoprotein (LBP) has been used as the supplement in China. A recent clinic trial showed that LBP administration reduced depressive symptoms in adolescents with subthreshold depression (Li et al., 2022). LBP is found beneficial for enhancing the activity of gut microbiota, improving body immunity and systemic inflammation induced by oxidative stress (Xing et al., 2016; Xu et al., 2022). In general, LBP is a promising neuronal protector with potent ameliorative effects on key pathological events, such as oxidative stress, inflammation, apoptosis and cell death with minimal side effects (Chen et al., 2014; Gao et al., 2015; Zhang et al., 2012). It is believed that the tonifying herbs may exert more on improving the anti-inflammation cytokines and re-balance of the immune systems, but research addressing this issue appears still lacking.

3. Summary and prospects of PNI in China

The concept of body-mind integration was born in China with a long history and is naturally compatible with the PNI. Since PNI was introduced into China in the 1990s, increasingly Chinese researchers from different fields were attracted to the psychoneuroimmunology research of health and disease. Along with the development of PNI in the world, important and unique contributions in various fields, including mainly including conditioned immunity, emotional stress and immunity, and inflammation and depression, were made by Chinese researches.

Immunological dysregulation is increasingly recognized as a common determinant factor for different diseases, including depression, dementia, and other neuropsychiatric disorders (Bauer and Teixeira, 2019). In fact, the regulation of immunity by TCM is also ranked as the top priority scientific issue to be addressed by Chinese science community. On the one hand, increasing evidence from molecular signaling and compound-specific perspectives reveals more information about the involvement of neuroimmune modulation of depression, dementia, and other neuropsychiatric disorders (Seo et al., 2018). This kind of research, more easily accepted by the Western academic community, is expected to thrive in the near future. On the other hand, there are relatively few studies to unravel the mechanism of the holistic regulation of the neuroimmune axis from a systemic and interaction perspective, which is considered to be more reflective of the characteristics of herbal formulation (Chen and Guo, 2017). This certainly requires new explorations, including creating innovative study paradigms (Chen et al., 2018). Even so, it is possible to reveal new mechanisms of therapeutic targets for depression from TCM treatment in terms of specific efficacy, combined with modern systems biology and other molecular biology tools (Zhang et al., 2022). Combination of traditional Chinese medicine with modern neuroimmunological and systems biology tools may result in innovative and exciting discoveries, which will ultimately promote the integration of traditional Chinese medicine with Western medicine, benefiting to combat with the challenges of brain diseases to mankind.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82071517, U21A20364, 31771217; 81673625; 81874374; 82174002), Sichuan Science and Technology Program (2020YJ0225) and the Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences (No. E2CX4115CX).

Declaration of competing interest

The authors declare they have no competing interests in this research.

Data availability

Data will be made available on request.