Regulation of neuronal plasticity associated with neuropsychiatric disorders by the orexinergic system

Abstract

Orexins are a family of neuropeptides secreted by neurons in the lateral hypothalamus (LH). These peptides act widespreadly across the body by interacting with specific orexin receptors on target cells, which comprise the orexinergic system. Emerging evidence has revealed that the orexinergic system is tightly associated with neuropsychiatric disorders; however, the underlying mechanisms require further exploration. Neuropsychiatric disorders have also been associated with neuroplasticity, while orexins have been shown to play regulatory roles in neuronal plasticity. As such, this review aims to summarize the recent progress of research investigating the roles of the orexinergic system in neuronal plasticity and associated neuropsychiatric disorders, including addiction, depression, and schizophrenia, which may provide novel insights into the mechanism of the orexinergic system in the pathogenesis of these neuropsychiatric disorders.

Highlights

• •This review summarizes the functions of the orexinergic system in neuronal plasticity associated neuropsychiatric disorders.
• •This review postulates the potential therapeutical value of targeting the orexinergic system for these diseases.

1. Introduction

The orexinergic system consists of orexin neuropeptides and their corresponding orexin receptors. Two members of the orexin family of neuropeptides, orexin A (OXA) and orexin B (OXB), also termed hypocretin-1 and hypocretin-2, respectively, are mainly produced by neurons in the lateral hypothalamus (LH) [1,2]. In mammalian, OXA and OXB contain 33 and 28 amino acids, respectively [[3], [4], [5]]. Orexin receptors, including orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), are G-protein-coupled receptors (GPCRs) [4]. Both OXA and OXB have similar affinities for OX2R, whereas OXB has a lower affinity for OX1R [6]. The orexinergic system has a variety of roles across the body, including the regulation of cardiovascular and respiratory, sleep/awake cycle, feeding and memory [[7], [8], [9], [10], [11]]. Orexin activates basolateral amygdala neural circuits during arousal condition [12]. The selective beta 2 adrenergic agonist clenbuterol injection into the basolateral amygdala (BLA) has been shown to enhance the population spike component of long-term potentiation (LTP) in the dentate gyrus (DG), which is decreased by OX1R or OX2R antagonists [13]. These results indicate that the orexinergic system is involved in the regulation of neuroplasticity.

Neuronal plasticity is commonly defined as the capacity of the nervous system to alter its activity or structure in response to a variety of stimuli [14]. Neuronal plasticity predominantly involves morphological changes, pharmacological and biochemical adaptations such as intracellular pathway changes, neuronal network alterations such as dendritic morphology and the number of dendritic spines, and new neuron generation [15]. The fundamental molecular mechanisms underlying neuroplasticity depend on changes in related proteins, such as structural proteins, receptors, and enzymes, which can lead to alterations in related signaling pathways, metabolic processes, etc. [16]. Neuroplasticity plays a vital role in various physiological and pathological processes during development and adulthood. For example, microglia regulate the pruning of synapses during development [17]. Immune cytokine interleukin-1β (IL-1β) enhanced calcium flux via N-methyl-d-aspartate receptor (NMDAR), leading to an increase in neuronal excitability [18,19].

Neuropsychiatric disorders, such as addiction, depression and schizophrenia, can cause both physical and mental damage, leading to progressive neuronal death and behavioral changes in individuals [20]. Like neurodegeneration diseases, genetic factors and glia mediated inflammatory responses have been reported to contribute to the development of neuropsychiatric disorders [[21], [22], [23], [24], [25]]. However, neurobiological mechanisms of these neuropsychiatric disorders were still not fully clear. More and more studies have shown that these neuropsychiatric disorders are associated with neuroplasticity dysfunction. Studies have indicated that hippocampal volume decreased in patients with depression [26,27]. Systematic review and meta-analysis suggested that late-life depression was related to volume reduction of various brain regions such as the orbitofrontal cortex (OFC), thalamus, and putamen [28]. Glutamatergic input to the ventral tegmental area (VTA) was indicated to be involved in cocaine use reinstatement [29,30]. Previous studies have shown that diminished LTP- and long-term depression (LTD)-like motor cortical plasticity were observed in patients with schizophrenia [31,32]. Overall, accumulating evidences indicate that the orexinergic system participates in the pathology of neuropsychiatric disorders, including addiction, depression, and schizophrenia, which are tightly associated with defects in neuroplasticity [[33], [34], [35]]. Thus, a better understanding of the molecular mechanisms of these neuropsychiatric disorders associated neuroplasticity regulated by orexinergic system would be helpful in understanding the molecular mechanisms and developing new drugs to target these diseases.

Given the vital roles of neuronal plasticity in these neuropsychiatric disorders, as well as the important functions of the orexinergic system in regulating neuronal plasticity, we discuss the potential roles of the orexinergic system in neuropsychiatric disorders from the perspective of neuronal plasticity, including various of aspects such as neuronal circuit alterations, molecular levels, and signaling pathway changes in this review. We summarize the results of recent studies on the orexinergic system in neuronal plasticity associated neuropsychiatric disorders and postulate the potential therapeutic value of targeting the orexinergic system in these diseases.

2. Orexinergic system in neuronal plasticity

Orexin affects the electrophysiological properties of the hippocampus [[36], [37], [38]]. Field recording analysis demonstrated that treatment with 100 nM OXA led to LTP at the synapses of Schaffer collateral-CA1 in slices from the hippocampus of 8–12-week-old mice, while OXA induced LTD in hippocampal slices from 3–4-week-old mice, suggesting that the orexinergic system was involved in the regulation of neuronal plasticity in early stages of mouse development [39]. Earlier studies have reported that the application of OXA in perfusate at the dose of 30 nM induced the suppression of LTP, but had no effects on LTD in the collateral CA1 synapses of rat hippocampal slice [36]. Administration of 90 nM OXA in DG in vivo further showed that OXA significantly increased LTP in the DG of rat [37] (Fig. 1). Walling et al. found that OXA regulated LTP induced by norepinephrine (NE) in the rat DG [40]. Akbari et al. have also reported that OX1R inactivation led to LTP impairment in the hippocampus of freely-moving adult rats [41]. In addition, studies have showed that OXA (≥30 nM) significantly reduced LTP caused by the stimulation of theta bursts in Schaffer collateral-CA1 synapses of hippocampal slices of adult mice, in a manner mediated by OX1R, but not OX2R [42] (Fig. 1). The application of OXA at a concentration of 1 pM markedly inhibited the low frequency stimulation induced depotentiation of Schaffer collateral-CA1 synapses in hippocampal slices, which was regulated by both OX1R and OX2R [42] (Fig. 1). These results indicated bidirectional effects of the orexinergic system in the regulation of hippocampal plasticity. Additionally, electrophysiological recordings analysis of hippocampal slices from adult mice have reported that treatment with TCS1102, a dual antagonist of both orexin receptors, could restore depotentiation of the hippocampus induced by low frequency stimulation during conditioned place preference processes [43]. Recent studies have shown that administration of OX1R or OX2R antagonist in the basolateral amygdala significantly attenuated LTP induced by tetanic stimulation in the DG of adult rat [44] (Fig. 1). However, the established LTP in the DG of adult rat was not affected by the inhibition of OX1R or OX2R in the basolateral amygdala [44], indicating that the projection from orexin neurons to the basolateral amygdala regulated the neuronal plasticity of the DG(44).

Fig. 1.

Potential roles of orexinergic system on neuronal plasticity. Orexinergic system was reported to be involved in the modulation of LTP and LTD in CA1 region. OX1R and OX2R regulated LTP in DG. Besides, studies indicated that OX1R and OX2R regulated LTD maintenance in spinal cord.

Hippocampal neuronal plasticity plays an important role in learning and memory [45]. Behavioral analysis has indicated that the administration of OX1R antagonist SB-334867-A in the hippocampus CA1 region led to impairments in learning and memory functions, such as acquisition, retrieval, and consolidation of the Morris water maze performance in rats [46] (Fig. 1). More interestingly, during the second year, studies found that the administration of SB-334867-A in the DG of the hippocampus resulted in the dysfunction of acquisition and consolidation, but not the retrieval of memory in rats [47] (Fig. 1), indicating the orexinergic system in different subregions of the hippocampus played distinct functions in learning and memory. In addition, Morris water maze test without a visible platform revealed that an intracerebroventricular OXA injection at a dose of 1 or 10 nM significantly increased swim path length and escape latency in rat [36]. Probe test showed that OXA with the same dose and injection method led to a marked decrease in swimming time in goal region, indicating impaired effects of OXA on spatial learning [36]. In addition, Yang et al. found that orexin neuron degeneration led to long-term social memory deficiency, which could be improved by OXA administration [48]. Water maze performance revealed that orexin receptor inhibition improved memory impairment observed in a rat model of insomnia, such as a significant increase in time spent in the platform location and in the target quadrant [8]. These results indicated that the orexinergic system was closely associated with learning and memory, and that, the function of the orexinergic system in learning and memory might be closely related to the levels and active model of orexin and the corresponding receptors.

Extracellular recordings in rat slice demonstrated that most of the neurons in the paraventricular nucleus of thalamus (PVT) could be excited by OXA and OXB [49] (Fig. 1). The OX1R antagonist SB674042 and the OX2R antagonist EMPA were found to significantly inhibit the NMDAR dependent LTD maintenance in the spinal cord of young rat [50] (Fig. 1), indicating potential regulatory roles of the orexinergic system in the modulation of PVT and spinal cord synaptic potentials. Additionally, injection of OXA into the CA1 region of 3–4 month-old rats led to an increase trend of GABA release, while OXA injection into the CA1 induced a significant increase of the release of GABA in aged rat at 27–29 months old [38]. OXA infusion into the medial septum dramatically increased the efflux of glutamate in the hippocampus of aged rat compared to the young rat [38]. The injection of OXA or OXB into the ventral tegmental area (VTA) of rat led to the significant increase of dopamine levels in the nucleus accumbens [51], indicating the important role of the orexinergic system in the modulation of neurotransmission release.

3. Neuropsychiatric disorders affected by orexinergic system regulated neuronal plasticity

3.1. Addiction

Addiction is considered a chronic and relapsed brain disease induced by drug exposure, leading to personal dysfunctions such as reduced executive functioning and controlling ability [52]. The experience of drug expending promoted by pharmacological effects was considered rewarding, which could lead to the formation of habits ultimately contributing to addiction establishment following repeated drugs exposure [53]. The molecular mechanisms underlying addiction was still remained largely unclear, although various elements have been shown to be involved in the regulation of addiction such as genetic variations and epigenetic and environmental factors [53,54].

Accumulating evidence has also demonstrated that orexinergic system was involved in addition [[55], [56], [57], [58], [59], [60]]. Earlier studies have reported that both chronic morphine treatment and morphine withdrawal induced the activation of a subset of orexin cells in mice [55]. The precipitation of morphine withdrawal significantly induced the upregulation of orexin and expression of the neuronal activation marker c-Fos in orexin neurons in the LH of mice [55] (Fig. 2A–B). Studies have also shown that the activation of orexin neurons of rat reinstated the extinguished behavior of drug-seeking, while these effects were suppressed by the application of the OX1R antagonist SB334867 [56]. Acute nicotine treatment dramatically increased the expression of c-Fos in orexin neurons in the rat LH [57] (Fig. 2B). c-Fos staining showed that orexin neurons in the rat LH were also activated by other reward-related stimulators except for morphine, such as food and cocaine [56,58] (Fig. 2B). In addition, studies have revealed a close association between the induction of c-Fos expression in orexin neurons in the LH and the preference degree of conditioned place preference of rat [56,58]. Quantitative real-time polymerase chain reaction analysis showed that high consumption of ethanol led to a remarkable increase in orexin levels in the perifornical LH of rat [59] (Fig. 2B). Morphine withdrawal induced by naloxone led to the activation of orexin cells (indicated by c-fos staining) in the perifornical LH, but not in the lateral LH of mice [61] (Fig. 2B). Moreover, orexin cells knockdown in the lateral hypothalamus induced addiction associated phenotype [62] (Fig. 2B). Intraperitoneal injection of SB-334867 in mice markedly attenuated symptoms of morphine withdrawal precipitated by naloxone [61]. Behavioral tests have shown that pretreatment with SB-334867 significantly reduced the self-administration of sucrose and conditioned cues-induced seeking behavior of sucrose and cocaine in rat [63] (Fig. 2B). Subcutaneous administration of an OX2R antagonist JNJ-10397049 in mice decreased the reinstatement and acquisition of conditioned place preference (CPP) and hyperactivity caused by ethanol in mice, while the OX1R antagonist SB-408124 had no effect on these processes [64] (Fig. 2B). OX2R inhibition in the DG of rat resulted in the significant suppression of CPP reinstatement induced by morphine priming [65] (Fig. 2B). However, OX2R inhibition demonstrated no significant effects on the reinstatement induced by the forced swim stress (FSS) [65]. OX1R blockade in the DG robustly inhibited CPP reinstatement induced by morphine priming and slightly attenuated the reinstatement induced by FSS (Fig. 2A). Additionally, the effects of OX1R inhibition in the DG of morphine-induced reinstatement were more significant than that of OX2R inhibition (Fig. 2A), indicating the diverse functions of OX1R and OX2R in reward and addiction [65]. Orexin receptor inhibition was also found to significantly decreased cocaine-induced re-potentiation in the hippocampus [66] (Fig. 2B), indicating an important role of the orexinergic system in addiction.

Fig. 2.

Potential neuronal plasticity regulated by orexinergic system in addiction. (A) Orexinergic system was involved in the modulation of brain plasticity associated with addiction. For example, OX2R inhibition in the DG led to a significant suppression of CPP reinstatement induced by morphine priming. OXA could lead the potentiation of NMDAR EPSCs in dopamine neurons of VTA. Both OXA and OXB led to the increase of firing frequency of some DA neurons in VTA. OXA and OXB efficiently induced the hyperlocomotion, which was mediated by dopamine and its receptors. Besides, orexinergic system directly affected the addiction. Dopamine D1-like receptor suppression prevented re-potentiation induced by OXA in hippocampus, indicating the potential roles of dopaminergic system in hippocampus plasticity regulated by orexinergic system. (B) The related studies about the roles of neronal plasticity regulated by orexinergic system in addiction was listed.

In addition, SB-334867 administration to the VTA of rat significantly blocked cocaine-induced locomotor sensitization [67] (Fig. 2A–B). Intra-hippocampal dopamine receptors were also shown to be involved in CPP induced by OXA injection in the VTA [68] (Fig. 2B), indicating the potential functions of the VTA-hippocampus circuit regulated by the orexinergic system in reward (Fig. 2A). Early studies with slice electrophysiology recording have demonstrated that both OXA and OXB increased the firing frequency and even burst firing in some dopaminergic neurons of VTA [69] (Fig. 2A). OXA potentiated the excitatory postsynaptic currents (EPSCs) regulated by NMDAR in the dopaminergic neurons of the VTA [67]. In addition, the administration of SB-334867 inhibited the excitatory currents induced by cocaine in the dopaminergic neurons of the VTA [67] (Fig. 2A). Electrophysiological analysis showed that morphine induced alteration of dopaminergic neuron plasticity in the VTA of vehicle-treated rat, such as a significant increase in the miniature EPSCs (mEPSCs) frequency of the AMPAR and a marked decrease the miniature IPSCs (mIPSC) frequency of GABA_A, which were robustly blocked by the administration of SB334867 [70]. Orexin deficiency significantly inhibited the morphine-promoted behaviors such as hyperlocomotion and place preference in mice. Intracerebroventricular administration of OXA or OXB was also found to efficiently induce hyperlocomotion in mice, an effect which was significantly suppressed by the disruption of dopamine and dopamine receptor signaling following pretreatment with haloperidol or 6-OHDA combined with desipramine [51], indicating that the effects of orexin on hyperlocomotion in mice were mediated by dopamine and its receptors [51] (Fig. 2A). In addition, immunostaining analysis showed that both OX1R and OX2R were expressed in VTA dopaminergic neurons [51]. Injection of SB334867A into the VTA was found to markedly inhibit place preference caused by morphine in rat [51] (Fig. 2B). These results suggested a role of the orexinergic system in the morphine-mediated regulation of synaptic plasticity in the VTA. Emerging evidence has also demonstrated that neuronal plasticity in the VTA played a vital role in reward and addiction [71]. Suppression of dopamine D1-like receptors prevented re-potentiation induced by OXA in the hippocampus, indicating a close relationship between the orexinergic and dopaminergic systems in hippocampal plasticity (Fig. 2A, Fig. 3A) [66]. Recent studies have demonstrated the suppression of OX1R and “cocaine and amphetamine-regulated transcript” changed impulsivity in rat, indicating orexin might be an endogenous mediator of impulsive action such as those linked to addiction [72]. OX1R and OX2R suppression in the DG significantly decreased the reinstatement of methamphetamine seeking [73] (Fig. 2B). OX1R blockade in the CA1 led to the prevention of reinstatement of drug-seeking behaviors [74] (Fig. 2B). Moreover, the orexinergic system in the VTA regulated the maintenance and relapse of methamphetamine in CPP [75]. These results indicated that the orexinergic system might regulate addiction pathology by modulating neuronal plasticity in the hippocampus and VTA. The VTA was a vital brain region for reward and motivation. GABAergic neurons and dopaminergic neurons played vital roles in these processes [76,77]. Indeed, one recent study demonstrated that VTA astrocytes released GABA to mediate GABAergic and dopaminergic neuron activity and modulated cocaine reward [77], indicating the important roles of the astrocytes in addiction by regulating GABAergic and dopaminergic neuron plasticity. Studies have reported that astrocytes were key determinants of the plasticity window, controlling critical periods of plasticity [78]. Thus, further clinical and animal experiments should be conducted to illustrate the interaction between astrocytes and VTA neurons, which will be helpful for clarifying the mechanisms of VTA plasticity in addiction.

Fig. 3.

Potential neuronal plasticity regulated by orexinergic system in depression. (A) Orexinergic system was involved in the modulation of brain plasticity associated with depression. MAPK (such as ERK) and Akt signaling might contribute to the neuronal plasticity of PFC and hippocampal plasticity in depression. OXA induced the depolarization of GABAergic neurons in VP directly, leading to inhibition of depression behaviors. Levels of PSD95 and NR2A increased significantly in amygdala of depression subjects, indicating the dysfunction of glutamate pathway in amygdala of depression. Dopaminergic system was reported to be involved in the hippocampus plasticity regulated by orexinergic system. (B) The related studies about the roles of neronal plasticity regulated by orexinergic system in depression was listed.

3.2. Depression

Depression is a psychiatric disorder with a relatively high mortality [[79], [80], [81]]. Except of major clinical symptoms of depression, such as feelings of worthlessness, long-term sadness, and depressed mood, there were also some other severe symptoms such as cognition deficiency and retardation of thinking [82]. Some of patients with depression ultimately developed into major depression, associated with suicidal idea and committing suicide if positive intervention is not provided in the early disease stages [83,84]. Genetic factors and environmental elements have been implicated in the pathology of depression [85,86].

Earlier clinical investigation showed that cerebrospinal fluid (CSF) OXA levels were significantly decreased in suicidal patients with major depressive disorder (MDD) [87] (Fig. 3B). One follow-up clinical study showed that CSF OXA levels were significantly increased in the first year following a suicide attempt, indicating a potential relationship between the orexinergic system and depression [88] (Fig. 3B). Schmidt et al. found that CSF OXA levels were not significantly different between patients with MDD and controls [89] (Fig. 3B). A recent clinical study demonstrated that serum levels of OXA were not significantly different in female patients with depression and anxiety compared with controls, while showing that OXA levels might be related to childhood maltreatment [90]. Another clinical analysis showed that OXA levels in the hypothalamus were significantly increased in females with depression but not in male patients compared to controls [91]. A recent study reported that OXB levels were significantly increased in the plasma of patients with MDD [92] (Fig. 3B). Compared to the control group, there was a marked increase in OX2R mRNA levels in the anterior cingulate cortex of male patients with depression who committed suicide [91] (Fig. 3B). The inconsistency in these results might be due to variations in the sample number and detection methods.

Animal experiments have been conducted to clarify the relationship between the orexinergic system and depression. OX1R knockout resulted in a marked decrease in despair in depression associated behaviors such as forced swim tests in mice [93] (Fig. 3B). There was a dramatical negative correlation between OXA concentration in all subareas of the hippocampus and depression behavior, a marked curvilinear correlation between OXA concentration and depression behavior in all subregions of amygdala, and no correlation between OXA levels in the thalamic paraventricular nucleus and depression behavior in mice. In addition, OX1R transcript levels in the amygdala of mice showed a marked positive correlation with depression behavior [94], indicating complex roles of OX1R in different regions of the brain in depression. However, OX2R knockout led to a significant increase in despair of depression associated behaviors in mice, indicating that OX1R and OX2R might exert opposite functions in depression [93] (Fig. 3B). Enhancing OX2R activity decreased the depressive phenotype and OX2R activity inhibition increased depressive symptom in mice [95]. A recent study demonstrated that orexin receptor downregulation in the ventral pallidum (VP) dramatically increased depressive behavior [96] (Fig. 3A). OXA directly induced the depolarization of GABAergic neurons in the VP, leading to the inhibition of depression behaviors, indicating the regulatory roles of the projection from orexin neurons to the VP in depression [96] (Fig. 3A–B). More interestingly, social avoidance induced by psychosocial stress became more easily in rat with OX1R deficiency in the VP, indicating that OXA excited GABAergic neurons in the VP, leading to the inhibition of depression [96].

Furthermore, animal studies have indicated that antidepressant treatment increased Akt signaling in both the hippocampus and prefrontal cortex (PFC) [[97], [98], [99]]. A decrease in the expression of extracellular regulated kinase (ERK) was found in both the PFC and hippocampus of patients with depression [100] (Fig. 3B). In addition, the expression of some synaptic associated proteins, such as SAPs and synapsin decreased in the hippocampus of depression [101] (Fig. 3B). It has been reported that the orexinergic system induced the activation of ERK [102]. As discussed previously, the orexinergic system regulated hippocampal plasticity [[36], [37], [38]]. In addition, prefrontal cortical spine density dysfunction was associated with depression associated behaviors (Fig. 3A). Moreover, spine formation of the prefrontal cortex was vital for sustaining the antidepressant effects by ketamine [103] (Fig. 3B). Medial prefrontal cortex associated plasticity is essential for cue-potentiated feeding (CPF). Orexin signaling mediated the CPF process in the medial prefrontal cortex, indicating an important roles for the orexinergic system in regulating prefrontal cortex plasticity in rat [104]. Levels of PSD95 and NR2A were found to be significantly increased in the amygdala of subjects with depression, indicating dysfunction of the glutamate pathway in the amygdala of depression (Fig. 3A–B) [105,106]. Inhibition of OX1R or OX2R in the basolateral amygdala impaired clenbuterol-induced LTP in the rat hippocampus [13]. OX1R inhibition decreased the depressive behaviors and increased the PSD95 levels in the PFC of a rat model of depression [107] (Fig. 3B). Thus, it is possible that the orexinergic system regulated depression by modulating the hippocampal, prefrontal cortical, or amygdalar plasticity (Fig. 3A).

Collectively, these results all supported the existing knowledge that depression was a complex psychiatric disorder. Most studies on the roles of plasticity regulated by the orexinergic system in depression have focused on the alterations of the levels of orexin and plasticity associated proteins, and behavioral effects, etc. in patients or animal model of depression (Fig. 3B). The molecular mechanisms underlying the potential roles of the orexinergic system associated neuronal plasticity in depression required further investigation. For example, studies have shown that GPCRs such as 5-HT1AR are involved in the pathogenesis of depression [108]. Our previous results showed that 5-HT1AR formed heterodimers with OX2R and affected downstream signaling pathways, such as the ERK pathway [109]. As described above, a significant decrease in ERK activation has been observed in depression, indicating an important role of ERK pathway in depression [100]. Recent research demonstrated that 5-HT1AR formed heterodimers with other receptors such as FGFR1 [110]. Thus, investigation of 5-HT1AR-OX2R or 5-HT1AR associated heterodimers with other receptors will provide new insights into the mechanisms underlying neuroplasticity regulated by the orexinergic system in depression.

3.3. Schizophrenia

Schizophrenia is a devastating mental disease with cognitive impairments in working memory, executive functioning, and attention [111]. Schizophrenia is usually characterized by both positive and negative symptoms. Positive symptoms primarily consist of hallucinations and delusions, while negative symptoms include lots of aspects such as apathy, as well as a loss of social interest, motivation and pleasure [112]. However, the exact etiology has not yet been elucidated [113,114] (Fig. 4A).

Fig. 4.

Potential neuronal plasticity regulated by orexinergic system in schizophrenia. (A) Orexinergic system was involved in the modulation of brain plasticity associated with schizophrenia. Hippocampal hyperactivity might enhance dopaminergic neuronal population activity in the VTA, which possibly led to dopamine dysfunction in schizophrenia. Additionally, dopamine D2 receptor levels in the nucleus accumbens could be increased by OXA. Thus, neuronal plasticity of Hippocampus-VTA or striatum pathway might contribute to the pathology of schizophrenia. (B) The associated studies about the functions of neuronal plasticity regulated by orexinergic system in schizophrenia were listed.

Earlier studies have shown that CSF OXA levels were not altered in schizophrenia patients with mild sleep disorder [115] (Fig. 4B). Compared with normal controls, patients with schizophrenia displayed increased levels of plasma OXA [116] (Fig. 4B). Further analysis showed that higher OXA levels were associated with fewer negative and disorganized symptoms [116]. Studies on Japanese subjects by Tsuchimine et al. showed that the levels of plasma OXA in patients with schizophrenia were not significantly different from those in controls [117] (Fig. 4B). A recent study indicated that plasma OXA levels might affect the body mass index of inpatients with chronic schizophrenia in China [35]. Studies on patients with schizophrenia from Zhejiang University School of Medicine revealed that the plasma levels of OXA were significantly decreased in female patients with schizophrenia [118] (Fig. 4B). Postmortem analysis of the human samples collected from the Netherlands Brain Bank also showed that the hypothalamic levels of OXA were significantly decreased in female patients with schizophrenia (Fig. 4B). mRNA levels of OX2R in the superior frontal gyrus also displayed a decrease trend in female patients with schizophrenia [118]. However, compared to healthy male subjects, both OX1R and OX2R mRNA levels were tend to increase in male subjects with schizophrenia [118]. A recent study also showed a significant reduction in plasma OXA levels in schizophrenia patient with metabolic syndrome [119] (Fig. 4B). The inconsistency in the changes of OXA in patients with schizophrenia might result from the different ages and diseases stages of the subjects. Moreover, studies have indicated that OX1R polymorphism was associated with polydipsia in schizophrenia [120,121]. These results indicated that dysfunction of the orexinergic system contributed to the pathology of schizophrenia.

Dendritic spines of pyramidal neurons were significantly decreased in the PFC of the schizophrenia brain [122] (Fig. 4A–B). Bioinformatics analysis based on transcriptome data has also indicated that critical periods associated plasticity was dysregulated in schizophrenia [123]. Patients with schizophrenia showed a reduction in hippocampal volume [124] (Fig. 4B). Exercise has been shown to contribute to the hippocampal volume increase and improvement of the symptom of schizophrenia subjects, indicating that hippocampal plasticity was involved in this process [[125], [126], [127]] (Fig. 4B). Orexin receptors inhibition decreased attentional deficiency induced by NMDAR hypofunction in a rat model of schizophrenia [128] (Fig. 4B). Additionally, OXA mediated neuronal plasticity in the hippocampus and OX1R inhibition rescued obesity-related hippocampal plasticity impairments in mice [129]. There was also evidence to indicate abnormal dopamine transmission in the striatum in schizophrenia [130,131] (Fig. 4B). Animal studies demonstrated that hippocampal hyperactivity might enhance dopaminergic neuronal population activity in the VTA, which possibly led to dopamine dysfunction in schizophrenia [132,133] (Fig. 4B), indicating an important role for the hippocampus-VTA pathway in the pathology of schizophrenia (Fig. 4A). Recent studies have shown that an antipsychotic drug risperidone significantly improved the structural neuroplasticity of the nucleus accumbens and modulated inflammation related pathway in a rat model of schizophrenia [134] (Fig. 4B). Moreover, OXA significantly increased the expression of dopamine D2 receptor in the nucleus accumbens of rat [135], indicating a regulatory role of the orexinergic system in striatal plasticity (Fig. 4A). Besides, studies have shown that orexin modulated dopamine neuron in the VTA, which was associated with schizophrenia [136] (Fig. 4A). These results indicated that neuronal plasticity in the hippocampus-VTA or stratum pathway, which was regulated by the orexinergic system, was involved in schizophrenia. Moreover, D2 receptor pathway regulated inflammation in neurodegenerative disease [137]. Studies have demonstrated that neuroinflammation contributed to schizophrenia pathology [138]. Inflammatory factors such as tumor necrosis factor (TNF) have been suggested to regulate neuroplasticity, indicating an important role of inflammation in mediating neuroplasticity [139]. It was speculated that glial mediated neuroinflammation might be an important molecular mechanism underlying neuroplasticity regulated by the dopamine/D2 receptor pathway in schizophrenia.

4. Conclusion

Neuronal plasticity dysfunction has been shown to play vital roles in the pathology of neuropsychiatric disorders including addiction, depression, and schizophrenia [56,58,106,134]. Emerging evidence has also demonstrated that the orexinergic system was involved in neuronal plasticity such as hippocampus neuronal plasticity and VTA neuronal plasticity [36,69]. Additionally, the orexinergic system has been implicated in regulating the pathogenesis of these neuropsychiatric disorders [140,141]. Thus, identification of the roles of orexinergic system in these neuropsychiatric disorders is both meaningful and promising, and will help to develop new drugs targeting neuronal plasticity for the treatment of these neuropsychiatric disorders.

Addiction, depression and schizophrenia were complex mental diseases caused by genetic and environmental factors, etc. However, genetic elements, signaling pathways, and neuronal circuit alteration have been shown to lead to the neuroplasticity changes [15]. As discussed previously, neuroplasticity dysfunction was a vital factor that contributed to the development of these neuropsychiatric disorders [[28], [29], [30], [31], [32]]. Studies have demonstrated that some common neuronal circuit and signaling pathways were involved in the pathology of these neuropsychiatric disorders. Future studies should focus on the common points associated with neuroplasticity in these neuropsychiatric disorders. For example, dopaminergic signaling was a vital pathway in the regulation of various of physiological processes, and has been reported to participate in the pathogenesis of these three neuropsychiatric disorders [142,143]. Orexinergic system has been indicated to regulate dopaminergic signaling [144]. To investigate the functions of the orexinergic system associated with dopaminergic pathway might provide new avenues for the development of novel drugs for the treatment of these diseases. Studies have indicated that there were three main neural circuits regulated by the dopaminergic system in the VTA and SN, including the mesolimbic, mesocortical and nigrostriatal pathways [145]. Dopaminergic neurons were usually identified by tyrosine hydroxylase (TH) immunohistochemistry as TH was rate-limiting enzyme of dopamine synthesis. These dopamine-producing cells were designated as A cells [146,147]. The nigrostriatal pathway mainly involved the projections from A9 cells located in the SN pars compacta to the dorsal striatum, and has been reported to be involved in the control of motor function and goal-directed behaviors, such as reward associated cognition [148]. Projection from A10 cells in the VTA to the ventral striatum, PFC, and other related regions mainly constituted the mesolimbic and mesocortical pathways. The mesolimbic pathway regulated motivation and reward, indicating the potential roles of mesolimbic pathway in addiction [145,146,149,150]. Evidence has indicated that depression and schizophrenia were associated with different pattern of the nigrostriatal and the mesolimbic dopamine dysfunction [151]. Studies have provided clues that chronic stress affected the mesolimbic and mesocortical dopaminergic system [146,152]. These results suggested there might exist a potential relationship between these neuropsychiatric disorders from aspect of dopaminergic pathway. Thus, single-cell sequencing could be performed to investigate gene and protein expression alterations in A9 and A10 cells in different animal models of these neuropsychiatric disorders combined with orexin knockdown or overexpression, which will be helpful in identifying the common or specific pathways or molecules responsible for the balance of these pathways and the development of these diseases. Furthermore, genetic analysis, such as Genome-Wide Association Studies with clinical studies could be performed to screen the potential key factor associated with these neuropsychiatric diseases. Cellular and molecular experiments should be performed to verify the molecular targets screened based on the results of single-cell sequencing and genetic analysis.

Funding

The work was supported by the National Natural Science Foundation of China (No.82301629, No. 31701247), Natural Science Foundation of Shandong Province (No.ZR2021QC039), Traditional Chinese Medicine Technology Development Project of Shandong Province (#2019-0462), Innovation and Entrepreneurship Project for College Students of Jining Medical University (cx2023020z) Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University (JYHL2021MS05).

Ethics approval

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Submission declaration and verification

The manuscript is not under consideration for publication elsewhere and its publication is approved by all authors.

CRediT authorship contribution statement

Fei Cao: Writing – original draft, Writing – review & editing. Zhengyang Guo: Writing – original draft. Xiaodan Ma: Writing – original draft. Xuezhi Li: Writing – review & editing, Supervision. Qinqin Wang: Writing – review & editing, Project administration, Funding acquisition.

Declaration of competing interest

The authors declare that they have no competing interest.