| Orx-S dysfunction role in the field of Immunopsychiatry |
Potential role of neuroinflammation in the pathophysiology of ADHD has been supported by a recent review171 Associations between parental autoimmune diseases and ASD or ADHD in offsprings172,173 Anti-sense transcript to the HLA-DQB1 locus on chromosome 6 is elevated roughly twofold in people with ADHD174 Recent study with a large dataset suggested the role of HLA genes in ASD and intellectual disability175 HLA polymorphisms can possibly distinguish regressive and non-regressive ASD176 HLA-DPA1*01-DPB1*04 sub-haplotype “may exert a protective effect against regression”176
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Orx-A may reduce the production of pro-inflammatory cytokines, suggesting its immunomodulatory role164 Connection between the Orx-S, “the HPA-axis, and associated glucocorticoid secretion and/or sympathetic tone” may point toward the influence of orexin signaling pathways on peripheral immune function27,178 Sleep, stress, and peripheral immune responses interact robustly, highlighting orexin's central role in this relationship27 HLA and the T-cell receptor variants have strong predisposing effects on the destruction of orexinergic cells, and this destruction may be considered an autoimmune event179 HLA-DPB1*04:02 shows the strongest protection from narcolepsy180 Orexin activates the GAD65 network of the LH submodule which governs physical activity158 |
| Orx-S dysfunction may be associated with alterations of the microbiome-gut-brain axis |
Microbiome-gut-brain axis alterations might be responsible for the appearance of NDDs in children (ie, in ADHD)181 Association between alteration of gut microbiota composition and ASD has been suggested by recent meta-analysis182 |
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| Interplay between vitamin D and steroids with Orx-S may explain their role in NDDs |
Steroid abnormalities of various kinds (cortisol, testosterone, estrogens, progesterone, and vitamin D) have been linked with ASD, suggesting an underlying cholesterol-steroid hormone pathway184
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Several possible mechanisms proposed to explain association between vitamin D deficiency and high risk of sleep disorders, one of which pointed to vitamin D receptor expression in human brain areas that play important roles in sleep regulation, such as the hypothalamus185 Orexin stimulates adrenocorticotropin and the secretion of corticosteroids12 Orexin receptors have been detected in many peripheral tissues, such as adrenal glands and male reproductive tract29,170 Sexual dimorphism of the Orx-S29,105 “Orexin stimulation induces an increased steroidogenesis”170 Orx-S might “act in a steroid-sensitive manner” on activation of the mesolimbic dopaminergic system81 Orx-S relate to testosterone production186
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| Potential of orexin for orchestrating heart rate variability |
Children with ADHD may exhibit an autonomic dysfunction - HRV's overall reduction and sympatovagal imbalance187 Different HRV measures may give significant insights into sustained attention, as well as in the impairments of behavioral and emotional regulation in ADHD188 HRV as indicator of “flexible and adaptive autonomic response systems”, has become a crucial part of the pathogenetic triad in proposed unifying theory for ASD189 |
HRV during periods of non-stress was associated with greater stress resilience190 HRV belongs to the RDoC arousal domain8 Chronic lack of orexin results in a “blunted circadian variation of heart rate”191
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| CACNA1C, as a novel explanation model for pathogenesis of some psychiatric disorders, could associates with the Orx-S dysfunction |
CACNA1C gene is associated with various psychiatric conditions194 Association between CACNA1C voltage-gated calcium channel gene, autism, ADHD, schizophrenia and bipolar disorder195 |
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