Oxytocin in Early-Life-Stress-Related Neuropsychiatric Disorders: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Zhenzhen Quan.

Early-life stress during critical periods of brain development can have long-term effects on physical and mental health. Oxytocin is a critical social regulator and anti-inflammatory hormone that modulates stress-related functions and social behaviors and alleviates diseases. Oxytocin-related neural systems show high plasticity in early postpartum and adolescent periods. Early-life stress can influence the oxytocin system long term by altering the expression and signaling of oxytocin receptors. Deficits in social behavior, emotional control, and stress responses may result, thus increasing the risk of anxiety, depression, and other stress-related neuropsychiatric diseases. Oxytocin is regarded as an important target for the treatment of stress-related neuropsychiatric disorders. 

  • early-life stress
  • oxytocin
  • neural circuit
  • neuropsychiatric disorders

1. Introduction

Stress refers to an organism’s insufficient physiological response to any mental, emotional, or physical pressure, whether real or imagined [1,2][1][2]. While stress can positively impact behavior and brain health, chronic stress can also have substantial and persistent negative effects. Various forms of stress imposed at different life stages can affect individuals, such as early-life stress (ELS) and adult stress. ELS encompasses adverse experiences of the neonatal period, early and late childhood, and adolescence (e.g., abuse, neglect, loss of parental care, hunger, extreme poverty, and family/community/school violence). ELS also includes adverse fetal exposure, such as maternal malnutrition, stressful maternal living circumstances, increased maternal anxiety, and extreme adverse experiences [3,4][3][4].
Early-life stress can create mental health issues; people who experienced childhood abuse are more prone to develop depression, anxiety, post-traumatic stress disorder (PTSD), substance use disorders, and aggressive behavior as adults [6,7][5][6]. Similar to humans, animals exposed to ELS display behavioral abnormalities and are prone to depression and anxiety in adulthood. Therefore, it is essential to understand the mechanisms by which ELS contributes to a variety of neuropsychiatric diseases in order to improve human health. In early life, the developing brain is extremely plastic, and neural circuit development during this period is influenced by life experiences, particularly negative stimuli [8][7]. The stress response comprises a series of neural events in the hypothalamus–pituitary–adrenal (HPA) axis that trigger a neuroendocrine cascade when activated. The paraventricular nucleus releases corticotropin-releasing factor, which promotes the secretion of adrenocorticotropic hormone from the anterior pituitary, which, in turn, stimulates the production and release of glucocorticoids from the adrenal cortex. Along with this “classical” neuroendocrine response to stress, the posterior pituitary secretes oxytocin from the periphery [9,10][8][9]. Finding neural circuits underlying stress-induced oxytocin malfunction may inform the process by which ELS develops. Glial cells, which actively regulate synaptic development, pruning, neurovascular connection, and phagocytosis, are essential for the construction of neural circuits during this time [14][10].

2. The Properties of Oxytocin

Oxytocin is a neuropeptide hormone primarily synthesized in the brain by the parvocellular neurons (parvOT) of the paraventricular nucleus (PVN) and the magnocellular neurons (magnOT) of both the PVN and supraoptic nucleus (SON) [15,16,17,18][11][12][13][14]. The magnOT neurons primarily innervate the forebrain and release oxytocin through the posterior pituitary gland into the bloodstream to supply the body. The parvOT neurons release less oxytocin, mainly to brainstem nuclei, the spinal cord and amygdala, stria bed nucleus, nucleus accumbens (NAc), magnOT neurons of the SON, and other regions [19,20,21][15][16][17]. The oxytocin gene encodes the structural precursor to oxytocin and is expressed in the mammalian hypothalamus; oxytocin is stored in large, dense-core vesicles [22,23][18][19]. The axonal projections of PVN and SON pass through the median eminence and innervate the posterior pituitary lobe, thereby releasing OXT into circulation or through volume transfer to nerve tissue to regulate physiology [24][20]. Oxytocin works through its receptor, OXTR [29[21][22],30], which belongs to the GPCR family and can activate several different G-protein-induced signaling cascades [31,32][23][24]. OXTR activation has been associated with two separate intracellular signaling cascades with dependence on either: Gαi/o or Gαq [28,32][24][25]. OXTR-expressing neurons have different functionality in different brain regions: social reward in the ventral tegmental area (VTA) [33][26], social recognition in the anterior olfactory nucleus (AON) [34][27], and social memory in the hippocampal CA2 region [35][28]. OXTRs are distributed in neurons, astrocytes, and microglia [32,36][24][29]. Neuronal oxytocin signaling is primarily influenced by the amount of locally released oxytocin, OXTR affinity, density, local enzymatic cleavage, and the resulting concentration of oxytocin in the extracellular fluid [28][25]. Oxytocin treatment reduces inflammation and the severity of various diseases. OXTRs have been found on immune cells, including neutrophils, macrophages, and lymphocytes [47][30]. During inflammation, nuclear factor kappa-light-chain-enhancer (NF-κB) mediates increased OXTR expression in macrophages [48][31]. Oxytocin can inhibit the macrophage transition to active inflammatory cells by promoting the expression of β-arrestin 2 [47][30] and peroxisome proliferator-activated receptor gamma [49,50][32][33].

3. Oxytocin-Involved Social Behavior

3.1. Positive Social Interactions

Oxytocin signaling is mediated by release from afferent terminals to receptors present in various target regions that impact aspects of behavior. Oxytocin modulates a variety of positive social behaviors via OXTRs in many limbic and reward-related regions of the mammalian brain, such as the PFC, NAc, amygdala, lateral septum, and thalamus [54][34]. The VTA and the NAc of the limbic system of the midbrain cortex are abundant in OXTRs and are linked to dopaminergic reward motivation [33][26]. The VTA PVN neurons release oxytocin to dopamine-secreting neurons of the nerve bundles that stretch from the VTA to the NAc, thus strengthening the social abilities of these mice [33,55][26][35]. Oxytocin may also increase the excitatory drive of VTA dopamine neurons that project to the NAc, thus improving sociability and social pleasure and increasing 5-HT release in the NAc [33,56,57,58][26][36][37][38]. The potent monoamine releaser (±) 3,4-methylenedioxymethamphetamine (MDMA) has potent prosocial effects in humans. Beyond social reward behavior, oxytocin also regulates prosocial behavior and the parent-child relationship. Countless studies have shown that oxytocin signaling regulates social interactions, especially prosocial behaviors associated with altruism [60][39]. MagnOT neurons have long-distance axonal projections to forebrain regions, including the PFC, AON, NAc, lateral septum, hippocampus, and medial and central amygdala, which are found only in higher vertebrates such as mammals and reptiles. These co-evolved regions are implicated in complex social and emotional behaviors [28][25]. In social mammals, OXT mediates prosocial behaviors such as mate preference, social approval and proximity, and parental care, and this effect is more pronounced in monogamous mating systems [61][40]. Social monogamy is a mating system characterized by sharing of territory among partners, mutual care, and preferential mating [62][41]. Neurobiological research on animal social bonds has focused on “social monogamous” species because they have strong long-term bonds, and the formation of this social bond seems to involve oxytocin [63][42]. The density of OXTR is higher in the NAc, mPFC, and amygdala of monogamous meadow voles than in non-monogamous montane (Microtus montanus) and meadow (Microtus pennsylvanicus) voles [62,64][41][43]. OXTR mRNA expression is present in the NAc of humans but absent from non-monogamous rhesus monkeys [62,65,66][41][44][45], and oxytocin is activated in the ACC and amygdala when rats engage in helping behaviors [67][46]. Oxytocin has a crucial role in complex social behaviors such as generosity, empathy, and collaboration [78][47]. Wild-type zebrafish freeze when observing a conspecific in pain in an isolated tank, whereas mutant zebrafish lineages lacking OXT or OXTR or do not exhibit these fear responses, indicating that oxytocin is necessary and sufficient for social fear contagion in zebrafish [79][48]. Interest in the role of oxytocin in social cognition and emotional processing increased after a study found that an oxytocin nasal spray promotes trust and play in social situations [80][49]. Complex social behaviors are closely connected with analgesia, and the role of oxytocin in analgesia and fear is noteworthy. The lactation-induced and oxytocin-dependent lack of social dread is blocked by chemogenetic suppression of DREADD-expressing OXT+ neurons that project to the lateral septum in breastfeeding mice [81][50]. The freezing caused by conventional fear training is reduced by oxytocin in the central amygdala (instead of a maternal context) [21][17]. The lateral portion of the central amygdala (CeL) receives lateral branch axons from magnOT neurons in the PVN and accessory nuclei, and these neurons create glutamatergic synapses with OXTR-expressing GABAergic neurons (Figure 21) [21][17].
Figure 21. In stressful situations, disruption of oxytocin causes changes in the hippocampus and amygdala. Oxytocin levels rise in the PVN under acute stress conditions, and magnOT neurons decrease activity in the PVN of ELS mice. Oxytocin released from the PVN can modulate inhibitory interneurons in the hippocampus and magnOT in the PVN project to CeL and form glutamatergic synapses with OXTR-expressing GABAergic neurons. OXTR-expressing neurons in the CeL can project to the CeM. HIP—hippocampus; CeL—lateral portion of the central amygdala; CeM—medial part of the central amygdala; AC—accessory nuclei. Up arrow: increase; Down arrow: decrease.
Stressful situations and corticosterone infusion increase oxytocin and OXTR binding in the ventral hippocampus [83][51], and oxytocin affects inhibitory interneurons to modify the functional activity of excitatory networks in the hippocampus (Figure 21) [84][52]. Oxytocin can increase the firing of inhibitory PV+ hippocampal interneurons and enhance spike transmission in hippocampal pyramidal neurons through the modulation of fast-spiking interneurons [85][53]. High-frequency (50 Hz, blue light) stimulation of channelrhodopsin-2 OXT+ terminals in the CeL reduces the freezing response in fear-conditioned rats, possibly by activating local GABA neurons [21,86][17][54]. Selective blue-light activation of PVN parvocellular OXT+ neurons projecting to the spinal cord in rats inhibits nociception and promotes analgesia [87][55].

3.2. Negative Social Interactions

Oxytocin can also produce negative behaviors such as aggression [89][56], and such effects are susceptible to individual and sex-specific influences. The OXT+ PVN–CeL projection helps to distinguish between positive and negative emotional states [92][57]. Inhibition of OXT+ projections to the CeL suppresses fear-subsiding behavior [93][58]. Oxytocin in the lateral septum of female mice can promote aggressive behavior in a manner that depends on environmental factors [94][59]. Oxytocin administration into the BNST causes unstressed mice to display social anxiety behaviors.

3.3. Sexual Dimorphism of Oxytocinin Social Behavior

Sexually dimorphic behaviors may result from sex-specific patterns of activity in the social-behavior-related brain areas. Sexual dimorphism should be considered when investigating the oxytocin system because OXTR expression is regulated by sex hormones, though there are no evident neuroanatomical differences in the distribution of OXT and OXTR expression. There have been reports describing sex-differentiated OXT+ fibers in the MPOAi of Mongolian gerbils, where females have a higher OXT+ cell density than males [96[60][61][62][63],97,98,99], and this sex difference may result from differences in axonal transport or behavioral response speed. The OXTR+ mPFC interneurons have obvious sexual dimorphism in social behavior; activation of these neurons causes anxiety in males but promotes social behavior in females [100,101][64][65].

4. Effects of ELS on the Oxytocin System and Central Nervous System

ELS is a stress-induced deficit in social behavior that is closely related to limbic abnormalities that cause chronic activation of physiologic stress responses [56][36]. The term “early life” is frequently used to characterize several developmental periods, such as prenatal, early postnatal (until weaning on postnatal day 21), and puberty (postnatal day 25–35 in rodents). Experience shapes neural circuits during crucial periods of development, allowing individuals to adapt their behaviors to their surroundings in a unique way [102][66]. During this period, the nervous system is extremely sensitive to specific environmental stimuli [103][67], and this sensitivity is necessary for the normal formation of neural circuits and biological learning. In humans, the effects of ELS are similar to those in children born to mothers who experience adverse living circumstances during pregnancy, children in orphanages, and children who are abused in childhood. ELS can be studied more easily by observing animal models, and there are many ELS mouse models; common models include maternal separation/maternal deprivation and limited bedding and nesting. Maternal separation is widely used to simulate ELS through repeated separations from the mother over prolonged periods. Maternal separation can induce depression-like and anxiety-like behaviors in rodents [106,107][68][69]. The ELS pups will activate the HPA axis after long-term separation from their mothers, causing corticosterone levels to rise, and these inflammation episodes may develop over time into chronic inflammation [108][70].

4.1. Effects of ELS on the Oxytocin System

The oxytocin system is crucial to social behavior, and its disturbance can have far-reaching implications. In prairie voles, it has been demonstrated that increased parental care causes hypomethylation of the oxytocin receptor gene [111][71]. Female rats raised by attentive mothers who frequently licked or groomed their paws showed significant OXTR binding [112][72]. During development, slow, gentle stroking can elicit pleasurable sensations and social rewards by activating C-tactile fibers [113][73]. This stroking also acutely activates hypothalamic OXT+ neurons and promotes OXT release, and parental care modulates hypothalamic oxytocin concentrations in rat pups [114][74]. Deprivation of touch and social interaction can lead to irreversible deficits in emotional, social, and cognitive behavior [115][75].

4.2. Abnormalities in Oxytocin System Altered by ELS Correlated with Glial Cells

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 [129][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 [130][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 [131][78]. While astrocyte calcium transients can last anywhere from minutes to hours, neuronal electrical activity lasts only a few milliseconds [131][78]. Optogenetic photostimulation of CeA axon terminals causes the release of OXT, which creates calcium transients in adjacent astrocytes [39][79]. In the hippocampus, mPFC, and ACC, ELS decreases the number of astrocytes [132,133][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 [134][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 [36][29]. Glial cells have functions beyond support; astrocytes and microglia release neuromodulators, and oligodendrocytes produce myelin that facilitates neurotransmission and neuronal oscillations [135,136,137,138][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 [142][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 [84][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 [84,144][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 [147][89]. Children with ASD have lower plasma oxytocin levels but higher precursor levels than healthy controls, suggesting that oxytocin processing may contribute to ASD [148][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 [82][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 [150][92], while a study of 16 ASD patients aged 12–19 showed that oxytocin treatment improved emotion recognition [151][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) [169][94]. In ASD animal models, microglia activation and increased peripheral and central TNF-α, IL-1β, and IL-6 have been observed [170][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 [171,172][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 [178][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 [179][99]. 

5.2. Schizophrenia

Schizophrenia is a neurodevelopmental condition with genetic predispositions and an origin connected to stress during critical periods of development [181][100]; the condition has positive symptoms (delusions, hallucinations, thinking abnormalities), negative symptoms (anhedonia, sadness, social isolation, faulty thinking), and cognitive dysfunction [182][101]. Previous studies have identified oxytocinergic dysfunction in people with schizophrenia, and single-nucleotide polymorphisms in the OXT gene contribute to schizophrenia vulnerability [183][102]. Thus, there has been growing interest in the use of oxytocin as a treatment for schizophrenia [181][100]. Social cognitive dysfunction leads to exacerbated delusions, anhedonia, diminished motivation, and disengagement from social interactions, which further leads to comorbid depression [185,186,187][103][104][105]. Mice with knock-outs of either OXT [188,189,190][106][107][108] or OXTR [148,186][90][104] have deficits in social recognition, and oxytocin supplementation to the preoptic region rescues these deficits [189,191][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 [199][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.

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