Oxytocin and Stress: Neural Mechanisms, Stress-Related Disorders, and Therapeutic Approaches

doi:10.1016/j.neuroscience.2019.07.046

Neuroscience

Volume 417, 1 October 2019, Pages 1-10

https://doi.org/10.1016/j.neuroscience.2019.07.046 Get rights and content

Highlights

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OT exerts antistress effects by modulation of neural circuits in hippocampus, amygdala and prefrontal cortex.
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Changes in the dynamic of OT-OTR system are involved in stress-related disorders.
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Intranasal administration of OT has therapeutic potential in the treatment of stress-related disorders.

Abstract

Clinical reports show that oxytocin (OT) is related to stress-related disorders such as depression, anxiety disorder, and post-traumatic stress disorder. Two key structures in the brain should be paid special attention with regard to stress regulation, namely, the hypothalamus and the hippocampus. The former is the region for central command for most, if not all, of the major endocrine systems, and the latter takes a key position in the regulation of mood and anxiety. There are extensive neural projections between the two structures, and both are functionally intertwined. The hypothalamus projects OTergic neurons to the hippocampus, and the latter possesses high levels of OT receptors. The hippocampus also regulates the secretion of glucocorticoids, a major group of stress hormones. Excessive levels of glucocorticoids in chronic stress cause atrophy of the hippocampus, whereas OT has been shown to protect hippocampal neurons from the toxic effects of glucocorticoids. In this article, we discuss how neural and endocrine mechanisms interplay in stress regulation, with an emphasis on the role of OT, as well as its therapeutic potential in the treatment of stress-related disorders.

Section snippets

INTRODUCTION

Oxytocin (OT) is produced in magnocellular and parvocellular neurons in the paraventricular nucleus (PVN) and the supraoptic nucleus of the hypothalamus and then carried by axonal transport to the posterior pituitary, where it is stored until secretion into the blood. Circulating OT stimulates uterine contraction during the process of labor and promotes lactation by acting on OT receptors (OTR) (Gimpl and Fahrenholz, 2001). OTR is expressed in many regions of the brain, including hypothalamus,

RELEVANCE OF THE OT-OTR SYSTEM IN THE CONTEXT OF STRESS PHYSIOLOGY

Physiological responses to stress involve complex interactions of multiple brain structures that perceive and encode valence-related contextual information and express it into emotional and physical effects at an individual level by channeling central commands to the final effectors. Yet, a comprehensive understanding of how they work together remains incomplete. In this review, we focus on three brain regions, namely, the hippocampus, amygdala, and prefrontal cortex (PFC) and discuss how the

HIPPOCAMPUS

The most well-known functions of the hippocampus are learning and memory, and awareness of space. The hippocampus is also known to modulate the sensitivity of the hypothalamus-pituitary-adrenocortical (HPA) axis, thereby regulating the stress response (Windle et al., 1997). Hippocampal dysfunction and dysregulation of the HPA axis are implicated in the pathogenesis of mood and anxiety disorders. Smaller hippocampal volumes were observed in stress-induced memory deficits and depressed adolescent

AMYGDALA

The amygdala is a key component of the neural network responsible for the expression of innate and learned fear (Davis and Whalen, 2001, Pape and Paré, 2010). Fear responses are evolutionarily protective in nature; however, excessive and inappropriate fear expression may be involved in the development of anxiety disorders such as post-traumatic stress disorder, panic disorder, and phobia. The abnormality in the amygdala function has been implicated in anxiety and depressive disorders in both

PREFRONTAL CORTEX

The PFC plays an important role in stress appraisal and adaptation as a key player in the corticolimbic circuitry, which underpins fear conditioning and extinction (Maren, 2001, Marek et al., 2013). The infralimbic region of the PFC sends out projection fibers to innervate principal neurons in the basolateral amygdala (BLA) (Strobel et al., 2015) and inhibits conditioned fear through a feedforward inhibition of central amygdala neurons through the excitation of intercalated cells (Berretta et

OT AND STRESS-RELATED DISORDERS

The prevalence of stress-related disorders such as depression and anxiety disorder has increased in developed countries. In clinical reports, blood OT concentrations are correlated to stress-related disorders such as depression, anxiety disorders, and post-traumatic stress disorder (PTSD) (Matsuzaki et al., 2012, Frijling, 2017).

Major depressive disorders are among the leading causes of disability worldwide. The Global Burden of Disease study estimated that unipolar depressive disorders would

THERAPEUTIC APPLICATIONS OF OT FOR STRESS-RELATED DISORDERS

Although antidepressant drugs and OT are pharmacodynamically different, they share many molecular mechanisms and pathways, which produce positive effects on the brain health. It has been known that the CREB/BDNF pathway is involved in neurogenesis and neuroplasticity. Stress inhibits phosphorylation of CREB in the hippocampus. Phosphorylation of CREB promotes neurogenesis in the hippocampus and neuroplasticity. CREB regulates the expression of brain-derived neurotrophic factor (BDNF) (D'Sa and

Acknowledgments

The corresponding author currently works at Nagasaki International University.

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Cited by (56)

Group differences in OXT methylation between patients with Major Depressive Disorder and healthy controls: A pre-registered replication study
2024, Psychiatry Research
Depression is linked to stress which leaves traces in the epigenetic signature of genes. The oxytocin system is implicated in allostatic processes promoting adaption to environmental stressors. Interactions of the oxytocin system with the environment, e.g., methylation of the gene coding for oxytocin (OXT), are candidates for the investigation of the biological underpinnings of depression. Recently, we found hypomethylation of OXT in patients with Major Depressive Disorder (MDD) compared to healthy controls (HC). Since the replicability of findings is a key point of criticism in (epi‑)genetic research, we aimed to confirm our previous findings in a pre-registered study (data was stored in a database prior to pre-registration) within a new sample of n = 85 patients with MDD and n = 85 HC. We investigated OXT DNA-methylation in peripheral blood samples, stressful life events and depression severity. In accordance with our previous study, we found hypomethylation of OXT in patients with MDD compared to HC. Methylation was not associated with stressful life events. Patients reported significantly more stressful life events compared to HC. Our study revealed that hypomethylation of OXT can be demonstrated in a reproducible fashion and provides further evidence for the involvement of the oxytocin system in depression.
Oxytocin as a transdiagnostic biomarker of well-being in severe mental illness during the Covid-19 pandemic
2024, Journal of Psychiatric Research
Individuals with severe mental illness (SMI) have been found to suffer a greater decline in psychological well-being compared to the general population in times of stress. The present study aimed to examine clinical and endocrine resilience factors of psychological well-being in SMI patients during the Covid-19 pandemic. Methods: After Covid-19 crisis outburst in Israel 112 participants, 69 outpatients, and 43 inpatients and day treatment patients were recruited. Outpatients signed an online informed consent and filled in questionnaires regarding their level of mental health symptoms (OQ-45), fear of Covid-19 (FCV), and psychological well-being (PWB). Inpatients answered the same questionnaires and in addition, went through a positive social interaction paradigm while providing three saliva samples to measure their s-IgA and oxytocin (OT) levels. Results: A strong negative correlation was found in the whole sample between reported mental health symptoms, fear of Covid-19, and well-being. Hierarchical regression did not find additional contribution of the fear of the pandemic in predicting well-being beyond the impact of symptomatology. For inpatients (N = 39) only, hierarchical regression found that oxytocin, but not s-IgA could explain 5% of the variance of well-being (R² = 0.05) in individuals with SMI regardless of their mental health symptoms (R² = 0.46) and their marital status (R² = 0.21). Conclusions: OT is suggested as a possible independent biological resilience factor of well-being in times of major stress among SMI patients. It is still unknown whether OT is a mediator that contributes to well-being or a biological marker that indicates the degree of beneficial social interactions.
Oxytocin as neuro-hormone and neuro-regulator exert neuroprotective properties: A mechanistic graphical review
2023, Neuropeptides
Neurodegeneration is progressive cell loss in specific neuronal populations, often resulting in clinical consequences with significant medical, societal, and economic implications. Because of its antioxidant, anti-inflammatory, and anti-apoptotic properties, oxytocin has been proposed as a potential neuroprotective and neurobehavioral therapeutic agent, including modulating mood disturbances and cognitive enchantment.
Literature searches were conducted using the following databases Web of Science, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, and Cochrane from January 2000 to February 2023 for articles dealing with oxytocin neuroprotective properties in preventing or treating neurodegenerative disorders and diseases with a focus on oxidative stress, inflammation, and apoptosis/cell death.
The neuroprotective effects of oxytocin appears to be mediated by its anti-inflammatory properties, inhibition of neuro inflammation, activation of several antioxidant enzymes, inhibition of oxidative stress and free radical formation, activation of free radical scavengers, prevent of mitochondrial dysfunction, and inhibition of apoptosis.
Oxytocin acts as a neuroprotective agent by preventing neuro-apoptosis, neuro-inflammation, and neuronal oxidative stress, and by restoring mitochondrial function.
Sex and hormonal status influence the anxiolytic-like effect of oxytocin in mice
2023, Neurobiology of Stress
Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.
Prenatal Stress and the Developing Brain: Postnatal Environments Promoting Resilience
2023, Biological Psychiatry
Heightened maternal stress during pregnancy is associated with atypical brain development and an elevated risk for psychopathology in offspring. Supportive environments during early postnatal life may promote brain development and reverse atypical developmental trajectories induced by prenatal stress. We reviewed studies focused on the role of key early environmental factors in moderating associations between prenatal stress exposure and infant brain and neurocognitive outcomes. Specifically, we focused on the associations between parental caregiving quality, environmental enrichment, social support, and socioeconomic status with infant brain and neurocognitive outcomes. We examined the evidence that these factors may moderate the effects of prenatal stress on the developing brain. Complementing findings from translational models, human research suggests that high-quality early postnatal environments are associated with indices of infant neurodevelopment that have also been associated with prenatal stress, such as hippocampal volume and frontolimbic connectivity. Human studies also suggest that maternal sensitivity and higher socioeconomic status may attenuate the effects of prenatal stress on established neurocognitive and neuroendocrine mediators of risk for psychopathology, such as hypothalamic-pituitary-adrenal axis functioning. Biological pathways that may underlie the effects of positive early environments on the infant brain, including the epigenome, oxytocin, and inflammation, are also discussed. Future research in humans should examine resilience-promoting processes in relation to infant brain development using large sample sizes and longitudinal designs. The findings from this review could be incorporated into clinical models of risk and resilience during the perinatal period and used to design more effective early programs that reduce risk for psychopathology.
Breastfeeding and maternal attachment: The moderating roles of maternal stress and child behavior
2023, Journal of Pediatric Nursing
Citation Excerpt :
A possible explanation in our study is that maternal stress may be related to the child, indicating a greater emotional involvement of the mother with the child. From a more biological point of view, another possible explanation is the release of oxytocin that occurs with stress (Matsushita et al., 2020). This hormone has relaxing effects and is known to promote mother–child attachment beyond the immediate postpartum period (Mitra, 2021; Riem et al., 2016).
This study examined the effect of breastfeeding on maternal attachment, and explored the moderating role of maternal stress and child behavior in this relationship, in a sample of Spanish mothers with children aged between 2 and 7 years.
A total of 432 mothers participated in a cross-sectional online survey. A three-way interaction model was used to test the moderating role of maternal stress and child behavioral problems in the relationship between breastfeeding and maternal attachment.
The full model accounted for 19% of the variance of maternal attachment. Breastfeeding was significantly associated with mother-rated attachment, and the moderated moderation analysis confirmed the moderating effects of maternal stress and child behavior on the relationship between breastfeeding and maternal attachment.
This study adds to the existing literature that supports the contribution that breastfeeding makes in enhancing maternal attachment, and may help to clarify the role of breastfeeding in shaping maternal attachment. Our findings suggest that breastfeeding is a factor in enhancing maternal attachment, and also identify maternal stress and child behavior as moderators of this relationship.
Understanding the mechanisms by which breastfeeding affects maternal attachment will help generate recommendations to improve breastfeeding and maternal attachment.

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ReviewOxytocin and Stress: Neural Mechanisms, Stress-Related Disorders, and Therapeutic Approaches

Highlights

Abstract

Section snippets

INTRODUCTION

RELEVANCE OF THE OT-OTR SYSTEM IN THE CONTEXT OF STRESS PHYSIOLOGY

HIPPOCAMPUS

AMYGDALA

PREFRONTAL CORTEX

OT AND STRESS-RELATED DISORDERS

THERAPEUTIC APPLICATIONS OF OT FOR STRESS-RELATED DISORDERS

Acknowledgments

Life Sci

Neuroscience

Neuroscience

Neuron

Neuron

J Psychiatr Res

Psychoneuroendocrinology

Neuron

Psychoneuroendocrinology

Neuroscience

Neuron

Neuropharmacology

Neuron

Cell Rep

Neuron

Neuroscience

Biol Psychiatry

Cell Rep

Cell

Psychoneuroendocrinology

Brain Res

Int J Psychophysiol

Eur Neuropsychopharmacol

Neuropharmacology

Psychoneuroendocrinology

Neuroscience

Cell

Psychoneuroendocrinology

Brain Res

Neuropharmacology

Biol Psychiatry

Front Neuroendocrinol

Neuroscience

Psychoneuroendocrinology

Biol Psychiatry

Neurosci Lett

Ageing Res Rev

Prefrontal/amygdalar system determines stress coping behavior through 5-HT/GABA connection

Neuropsychopharmacology

State-dependent changes in hippocampal grey matter in depression

Mol Psychiatry

Expression and region-specific regulation of the oxytocin receptor gene in rat brain

Endocrinology

Encoding of conditioned fear in central amygdala inhibitory circuits

Nature

Effects of oxytocin on attention to emotional faces in healthy volunteers and highly socially anxious males

Int J Neuropsychopharmacol

Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses

J Neuroendocrinol

The amygdala: vigilance and emotion

Mol Psychiatry

Stress and the brain: from adaptation to disease

Nat Rev Neurosci

Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls

J Clin Endocrinol Metab

Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder

Neuropsychopharmacology

The effect of oxytocin on attention to angry and happy faces in chronic depression

BMC Psychiatry

Antidepressants and neuroplasticity

Bipolar Disord

Separation anxiety, attachment and inter-personal representations: disentangling the role of oxytocin in the perinatal period

PLoS One

Review
Oxytocin and Stress: Neural Mechanisms, Stress-Related Disorders, and Therapeutic Approaches