The complex mammalian central nervous system results, in part, from the varied cell types formed during development; oxytocin may regulate cell growth, differentiation, and contact with other cells
[76]. ELS can cause neuroinflammation that damages the developing brain, which then enters an overactivated state that can also be induced by bacterial, environmental chemicals, or neuronal injury or death
[77]. Astrocytes are the primary cell type implicated in the neuroinflammatory response; they account for 20–40% of all glial cells, and the brain’s balance of nutrient delivery and metabolism is dependent on astrocytes. While astrocytes contain many small fibers that penetrate into the local environment and react to various stimuli, neurons have distinctive dendrites and axons that allow long-distance projections
[78]. While astrocyte calcium transients can last anywhere from minutes to hours, neuronal electrical activity lasts only a few milliseconds
[78]. Optogenetic photostimulation of CeA axon terminals causes the release of OXT, which creates calcium transients in adjacent astrocytes
[79]. In the hippocampus, mPFC, and ACC, ELS decreases the number of astrocytes
[80][81]. Microglia are also important to the neuroinflammatory response; microglia secrete the pro-inflammatory cytokines IL-1, TNF-α, and C1q to activate astrocytes
[82]. Microglia are highly sensitive to the neural environment, and although there is evidence that OXT affects microglia responsiveness in neuroinflammation, the mechanism of this influence is unclear
[29]. Glial cells have functions beyond support; astrocytes and microglia release neuromodulators, and oligodendrocytes produce myelin that facilitates neurotransmission and neuronal oscillations
[83][84][85][86].
5. Potential Therapy Strategies of Oxytocin in ELS-Related Neuropsychiatric Disorders
Early-life stress can impair social behavior and contribute to a variety of stress-related diseases. Oxytocin is released into several brain regions closely associated with stress-related disorders, such as the amygdala, hypothalamus, hippocampus, and NAc. Social rewards are important for social interaction, and social reward disorder is closely related to neuropsychiatric disorders in stress-related diseases. Oxytocin is closely connected to social reward and plays an important role in stress-related neurological disorders. At present, oxytocin has been studied in numerous clinical trials of social disorders-related diseases. Dysregulation of dopaminergic signaling is associated with a variety of neuropsychiatric and neurological disorders, including ASD, Parkinson’s disease, and depression
[87].
For these reasons, oxytocin has been investigated clinically as a treatment for these stress-induced mental disorders, though oxytocin does not easily cross the blood-brain barrier. Delivery of oxytocin has been attempted via intranasal administration, though details have not been confirmed
[52]. Intranasal oxytocin can reach CSF and blood circulation, though it is unclear that oxytocin can reach concentrations in the brain that would produce clinically meaningful behavioral effects; microdialysis methods are questionable and have not been performed in humans. However, a recently developed mechanism enables oxytocin transport from the periphery to the central nervous system. After intranasal, subcutaneous, or intravenous administration, oxytocin level rises in the amygdala, hypothalamus, and other regions because RAGE, a membrane-associated receptor of advanced glycation end products, binds to and transports peripheral oxytocin via endothelial cells
[52][88].
5.1. Autism Spectrum Disorder
ASD is characterized by limitations in repetitive behavioral patterns, poor social interaction, and negligible perception. Both ASD and antisocial disorder have deficits of empathy and social cognition deficits. Because OXTR is distributed primarily in social-behavior-connected brain regions, such as the olfactory bulbs, lateral septum, and piriform cortex, oxytocin may regulate social behavior in ASD
[89]. Children with ASD have lower plasma oxytocin levels but higher precursor levels than healthy controls, suggesting that oxytocin processing may contribute to ASD
[90]. Autism may be connected to dysfunction of the amygdala, a major component of the cortico–striatal–thalamo–limbic system and emotional circuit involved in regulating emotional stress; oxytocin treatment can reduce amygdala activity and the fear response
[91].
Clinical trials have examined the potential of oxytocin as a treatment for ASD, but the findings have been conflicting. In one study, 32 ASD children aged 6–12 years were given intranasal oxytocin for 4 weeks, and this treatment improved the social skills of ASD children
[92], while a study of 16 ASD patients aged 12–19 showed that oxytocin treatment improved emotion recognition
[93].
Though clinical studies indicate the therapeutic potential of oxytocin for social-disorder-related diseases such as ASD, the mechanism of these effects is still unclear. Social behaviors can be studied in rodent models to measure defects related to brain function and disease.
Numerous animal studies have connected ASD and oxytocin, and clinical studies suggest a connection between ASD and inflammation; ASD patients have increased levels of pro-inflammatory cytokines in the brain (e.g., TNF-α, IFN-γ, and IL-6)
[94]. In ASD animal models, microglia activation and increased peripheral and central TNF-α, IL-1β, and IL-6 have been observed
[95], and the anti-inflammatory effects of oxytocin may play a role in this. Plasma oxytocin levels of male ASD patients are negatively correlated with the inflammation-related molecule IFN-γ-induced protein-16
[96][97].
A disorder of the central oxytocin system was found in Cntnap2 knock-out mice. A central hypothesis of ASD etiology is that long-term developmental disconnection causes abnormal resting-state functional connectivity, and this long-range disconnection may result from developmental events
[98]. Patients with ASD have reduced functional connectivity in the cerebellum, fusiform gyrus, and occipital brain, and have lower levels of medium- and short-range functional connectivity in the posterior cingulate cortex and mPFC, indicating the distance-dependence of ASD dysfunction
[99].
5.2. Schizophrenia
Schizophrenia is a neurodevelopmental condition with genetic predispositions and an origin connected to stress during critical periods of development
[100]; the condition has positive symptoms (delusions, hallucinations, thinking abnormalities), negative symptoms (anhedonia, sadness, social isolation, faulty thinking), and cognitive dysfunction
[101]. Previous studies have identified oxytocinergic dysfunction in people with schizophrenia, and single-nucleotide polymorphisms in the
OXT gene contribute to schizophrenia vulnerability
[102]. Thus, there has been growing interest in the use of oxytocin as a treatment for schizophrenia
[100].
Social cognitive dysfunction leads to exacerbated delusions, anhedonia, diminished motivation, and disengagement from social interactions, which further leads to comorbid depression
[103][104][105]. Mice with knock-outs of either
OXT [106][107][108] or
OXTR [90][104] have deficits in social recognition, and oxytocin supplementation to the preoptic region rescues these deficits
[107][109].
5.3. Social Anxiety Disorders
Social anxiety disorder (SAD) is characterized by social fear, avoidance, cognitive dysfunction, and life interference, and oxytocin inhibits the amygdala’s response to fear signals, slows maladaptive cognition toward exposed tasks and reduces negative self-evaluation after social stress. In healthy subjects, intranasal administration of synthetic OXT reduces anxiety levels and broadly promotes human social behavior
[110].
6. Conclusions
Early-life stress contributes to many social disorders by altering OXT and OXTR expression in adulthood. Complex social interactions and behaviors are governed by many neural circuits and neuromodulators, and oxytocin plays a crucial role in the mother–infant relationship and stress-induced neuropsychiatric disorders. The impact of oxytocin administration depends on patient gender, brain region, dosage, and experimental paradigms for ELS. Oxytocin is mainly being considered for the treatment of ASD; studies of oxytocin treatment for stress-related neuropsychiatric disorders have produced inconsistent results, but further study of this inconsistency is warranted. Oxytocin signaling may play a more limited role than previously thought in attachment behaviors that may be too essential to rely on simplistic regulation, and other regulatory pathways may compensate for defective oxytocin signaling. This may also explain the mixed results of oxytocin treatment for stress-related neuropsychiatric disorders.