Prerna Jha, NIT Durgapur
“Fears are nothing more than a state of mind “~Napoleon Hill
To continue per this proverb, the stimulus due to fear is initiated in the brain, which is a distressing emotional reaction in response to a real or potential threat. These perceptions of danger and feelings of helplessness activate the brain’s alarm system, called the Fright-Flight-Freeze response. With the onset of which, the hypothalamus, pituitary, and adrenal system, forming the HPA axis perform together to send signals to the Autonomic Nervous System (ANS). These signals then start a chemical cascade that floods the body with stress hormones to adjust itself according to the stressful environment. The Amygdala complex is the pivotal region of the brain responsible for detection, regulation, and prediction of fear memory that consists of –
● Lateral Amygdala (LA) together with the lateral nucleus of the central amygdala (CeL) and the Basolateral nucleus (BLA) for acquisition and storage of fear memory.
● The medial nucleus of the central amygdala (CeM) – the main output structure to the brainstem that modulates behavioral expressions of conditioned fear responses.
The nonapeptide Oxytocin
Oxytocin is a neurotransmitter, produced in the paraventricular and supraoptic nuclei of the hypothalamus and is released to and later secreted by the posterior pituitary. It plays many important roles in our body in terms of assisting in social bonding, sexual reproduction, contractions of the uterus during parturition, milk ejection during the lactation period, and many more. Recent studies following humans and animals have shown the neuropeptide oxytocin to have anxiolytic (reduce anxiety) and antidepressant (reduce depression) properties which aid in modulating the fear response.
It was found that the oxytocin-producing neurons (OT neurons) were spread out not only in the amygdala but also in regions of the basal forebrain forming a brain neural-circuitry that was responsible for attenuating fear responses. Scientists were able to confirm that the locally released oxytocin had an inhibitory effect on the neurons of the amygdala through the neurotransmitter GABA (Gamma-aminobutyric acid) and hence regulate the stress-related behavior.
Oxytocin (OT) in fear responses
The regulation of fear responses by oxytocin is known to be concentrated in certain regions of the brain i.e., it is brain-region specific. The regulation of emotional behavior is executed as oxytocin binds to the oxytocin receptors (OTRs) belonging to the G Protein-Coupled Receptor (GPCR) family, residing mainly in the amygdala. The central nucleus of the amygdala (CeA) regulates contextual fear responses while OTR neurotransmission in the Bed Nucleus of Stria Terminalis (BNST) increases cued fear responses. Contextual and cued fear conditioning activates hypothalamic neurons differently.
With experiments carried out on rodents, it was reported that the OT neurons are activated more in case of uncertainty, i.e., contextual fear in case of an imminent threat. It is seen that the effects of oxytocin on fear responses are ostensibly contrasting as on one side it facilitates fear discrimination by reducing responses to diffuse threats, yet on other hand, it increases the ability to discriminate and predict the stimuli to be dangerous or safe. This is done by strengthening the responses to predictable threats, as is observed in CeA and basolateral axis (BLA), where oxytocin has reverse effects even within the same brain structure. Thus, with an ability to manipulate the salience of both positive and negative fear responses, it can be used to predict any upcoming environmental threats and promote defensive behaviors.
Scientists report a sexually dimorphic oxytocin-sensitive (medial prefrontal cortex) mPFC (medial prefrontal cortex) circuit where stimulation of oxytocinergic interneurons leads to the release of GABA and Corticotropin-Releasing Hormone-Binding Protein (CRHBP) which reduce the level of corticotropin-releasing factor (CRF) in the brain and hence reduce the level of anxiety in males. But in females, due to high levels of CRF in the paraventricular nucleus (PVN), CRHBP is unable to reduce the CRF levels, hence cannot reduce stress. Sex-specific oxytocin effects have also been seen where administration of intranasal oxytocin was able to reduce behavior in males but in females, was unable to alter their behavior in a stressful condition.
Oxytocin and fear extinction
It’s often not very easy to overcome the fear associated with a traumatic event that might have occurred. Sometimes even smaller aspects of stress-related events may elevate the anxiety levels to a great extent. Science calls this phenomenon conditioning.
But the good news here is that our social-bonding hormone, or oxytocin, because of its anxiolytic properties can overwrite fearful memories by reinforcing extinction. It gradually reduces the impact of those fearful experiences with time. In a study conducted on some male subjects, fear conditioning was induced in them by pairing some images shown to them with electric shocks so that whenever the subject encounters these images again, they would recall the fear associated with them. Then, half of these subjects were given an intranasal oxytocin treatment while the other half was subjected to placebos. Results revealed that the group with oxytocin supply showed higher intensity of fear extinction with their fear inhibiting areas of the brain being more active and hence took lesser time for their fear to abate.
Post-traumatic stress disorder (PTSD) is a psychiatric disorder caused due to maladaptive processing of fear memory, over-reactivity towards diffused threats, deficits in fear extinction, ultimately leading to many neurobiological and behavioral abnormalities in the brain. To date, no specific treatment has been found for PTSD due to various highly complicated attributes associated with it. Oxytocin with its role in modulating stress and anxiety-related behavior has been proposed to be a potential preventive intervention in patients with a high risk of PTSD symptoms.
With further studies carried out, it was seen that the effects of oxytocin on PTSD-affected patients were dependent on its frequency of administration. While a single dose of intranasal oxytocin treatment increased neural fear processing, early and repeated doses of it were successful in reducing the subsequent PTSD symptoms for up to six months post-trauma. Hence with these effects of intranasal oxytocin, scientists find it a probable tool for the treatment of anxiety disorders.
Conclusion and future perspectives
● Intranasal application of the neuropeptide oxytocin has emerged as an efficient tool in studies investigating the behavioral effects in social cognition and emotional regulation; in the treatment of severe trauma.
● The effects brought out are complex and, in many cases, contradicting in nature. These contradictions are brought out by varying the frequency and timing of administration and are brain region-specific and even sex-specific.
Pavlovian fear conditioning, from a neurobiological perspective, is a form of associative learning that allows us to predict aversive events by transforming threats into adaptive behaviors. It is carried out by combining a neutral stimulus with an unconditioned or aversive stimulus, which results in a conditioned response. Treatments with exogenous oxytocin being administered before fear extinction and followed by Pavlovian fear conditioning, results showed a rise in the level of fear extinction and inhibition of amygdala response. Thus, oxytocin is considered a viable psychotherapeutic for social anxiety disorders such as PTSD.
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References:
- Eckstein, M., Becker, B., Scheele, D., Scholz, C., Preckel, K., Schlaepfer, T. E., …& Hurlemann, R. (2015). Oxytocin facilitates the extinction of conditioned fear in humans. Biological psychiatry, 78(3), 194-202. https://doi.org/10.1016/j.biopsych.2014.10.015
- Wang, S. C., Lin, C. C., Chen, C. C., Tzeng, N. S., & Liu, Y. P. (2018). Effects of oxytocin on fear memory and neuroinflammation in a rodent model of posttraumatic stress disorder. International journal of molecular sciences, 19(12), 3848. https://doi.org/10.3390/ijms19123848
- Olivera-Pasilio, V., & Dabrowska, J. (2020). Oxytocin promotes accurate fear discrimination and adaptive defensive behaviors. Frontiers in Neuroscience, 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538630/
- Eckstein, M., Scheele, D., Patin, A., Preckel, K., Becker, B., Walter, A., … & Hurlemann, R. (2016). Oxytocin facilitates Pavlovian fear learning in males. Neuropsychopharmacology, 41(4), 932-939. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748433/
- Love, T. M. (2018). The impact of oxytocin on stress: the role of sex. Current opinion in behavioral sciences, 23, 136-142. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC6863168/
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