‍‍‍‍‍‍The Love Hormone Is Two-Faced!

Oxytocin.jpg
Structural diagram of Oxytocin, Sci-News.com‍‍‍‍‍

Noura Abdul Rahman z3416112
Marya Alzayer z3421831
Alexandra Gratsis z3416880
Ronald Szeto z3411478

Media Item:
http://www.australasianscience.com.au/news/july-2013/love-hormone-two-faced.html


Introduction

The article "The love hormone is two-faced”, published on the website for Australasian Science magazine, focuses on the innovative research completed by Northwestern University. The article talks about a new discovery concerning the hormone oxytocin, where the author focuses on the misleading facts of oxytocin and its association with fear and anxiety.

Oxytocin has long been known as the “love hormone”, as scientific studies have shown that it promotes feelings of love, social bonding and well-being, and increases positive social emotions such as trust and altruism. Oxytocin administered intranasally in humans has shown evidence of increased trust and reduced anxiety, and the hormone has also been tested as an anti-anxiety drug in mice, so scientists were surprised to find that oxytocin strengthens negative social memory, future anxiety and emotional pain. Although still in the early stages of development as a treatment, oxytocin's ability to increase trust and enhance emotional empathy suggests considerable potential in neuropsychiatry. There are multiple theories for oxytocin's effect (e.g., the anxiety-reduction hypothesis), with varying implications for it's use as a therapeutic agent. For example, it may be beneficial by increasing attention to social information in patients with deficits in this domain (e.g., autism), yet may be detrimental in patients already hypersensitive to social cues (e.g., borderline personality disorder). More studies are required to more clearly delineate the impact of both context and individual differences to oxytocin's effects.

We decided to research this topic because it was tempting and interesting to understand the way oxytocin functions and plays two contrasting roles. Oxytocin has been studied as a way to combat fear and anxiety, and also as a potential treatment for autism. However, researchers have discovered oxytocin's dual role in triggering and reducing anxiety, which is interesting as it means they can enhance oxytocin treatments to improve well-being instead of triggering negative reactions. It was also useful researching this topic as it relates to concepts studied in our neuroscience course, reinforcing our knowledge in hormones, pathways undertaken by hormones and neuroplasticity.



Neuroscientific Context


Background


In some mammalian species, nulliparous females show aversion to infants. Such females are frequently aggressive to pups, and even kill them. The onset of maternal behaviour begins when they start having their own pups. How does the brain switch from avoidant/aggressive to caring?

Vasotocin is found in reptiles and is important for maternal behaviour. The graph below shows that vasotocin increased during nesting in sea turtles.

seaturtle.png
Vasotocin increases during nesting in sea turtles

Figler et al. (1989)

Vasotocin evolved into two hormones, oxytocin and vasopressin. They are important for mammalian reproductive behaviour and attachment behaviour. Systematic name of oxytocin is Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2.

Parent-infant relationship

Pedersen et al. (1982) showed that maternal behaviour can be increased by giving oxytocin to nulliparous rats. Vice versa, blocking oxytocin in the female rat brain prevented maternal behaviour to occur (Pedersen et al. 1994).

maternal behaviour.png
Effect of oxytocin on maternal behaviour in female rats

Pedersen et al. (1982)

Adult relationship

Human adult couples are usually monogamous. However only 5% of all mammals are monogamous, the rest are polygamous. So is there a brain mechanism for monogamy?

We can find this out by studying two species of voles.
  1. Prairie voles: form lifelong monogamous bond
  2. Montane voles: polygamous

Insel and Young (2001) showed that monogamous bond could be blocked by inhibiting oxytocin in female voles. Male and female voles were allowed to mate and the female was later given the option to spend time with her partner, or with a stranger male, or in a chamber alone.

1. Prairie voles: spent most time with her partner, spent little time with stanger and alone
2. Montane voles: spent most time herself, no preference between her partner nor stranger

However this can be changed by blocking oxytocin in the female prairie vole brain. Prairie voles showed a preference in the stranger.

Conclusion

Oxytocin is important for attachment behaviour in mammals, including humans.
There are shared brain mechanisms for different kinds of attachment and love (eg. romantic attachment, filial attachment).
Although the frequency and type of parental behaviours differ between species, the brain mechanisms for attachment are shared across mammalian species, including humans, indicating that they have been conserved across evolutionary history.


‍‍‍‍‍Fear pathways used by Oxytocin in the lateral septum


Synthesis of Oxytocin

Oxytocin is secreted by the magnocellular neurosecretory cells in the hypothalamus. The hormones travel to and are stored in the posterior lobe of the pituitary gland. Oxytocin is released into the blood stream when needed.


Lateral Septum

The limbic system is above the thalamus and hypothalamus. Limbic means border, it is located around the edge of the center of the brain. The limbic system includes the hippocampus, amygdala, cingulated gyrus and septum. It regulates our emotion and motivation.

The lateral septum is connected to numerous regions, such as the limbic system and thalamus. The amygdala is the single most important part of the brain for expression of fear. Animals and humans with a damaged amygdala will no longer show signs of fear when conditioned with fear stimuli. The hippocampus is important in the formation of memory, as it provides explicit memory of learned danger and aversive experience. Patients with a damaged hippocampus fail to consolidate new memories into brain. The lateral septum itself has the highest level of oxytocin receptors in the brain across different species, including humans. Therefore stimulation of the lateral septum can influence fear memory and stress response (Singewald et al. 2011).

amygdala pathway.png
Input and output of amygdala

(Singewald et al. 2011)

Pathways of triggering ERK molecule by Oxytocin


How do we form memory?

Synaptic plasticity is the idea that synapses have a plastic property. They are changeable, either in shape or function over a period of time that could last few seconds, few hours or even for a lifetime. We never forget what we experience and learn and it is done by long term potentiaiton (LTP) in the hippocampus. LTP is the long lasting enhancement in the strength of synapses by inserting new receptors (AMPA receptors). There are two stages on LTP, early LTP (E-LTP) and late LTP (L-LTP). E-LTP is the initiation of LTP and L-LTP is self sustaining of LTP.


Role of extracellular signal-regulated kinases (ERK) in LTP

Adams and Sweatt (2002) said there are several protein kinases essential for LTP to occur for example CaM-KII, PKA, PKC, ERK. In E-LTP, Ca2+ ions influx through NMDA receptors activates CaM-KII and other calcium activated enzymes (PKA & PKC). PKA and PKC lead to activation of ERK. In order for L-LTP to occur, gene transcription and protein synthesis must happen. It is ERK and other proteins (eg. PKM-zeta) that regulate the two processes.


Conclusion

An increased amount of oxytocin influences the lateral septum, which is connected to the hippocampus. After several hours, L-LTP occurs in the hippocampus. ERK is triggered due to influences from the lateral septum and changes LTP which lead to strengthening bad memories. However the septum is also connected with the amygdala. Therefore it also increases fear and anxiety response in stressful situations.‍‍‍‍‍


‍‍‍‍‍The dual role of Oxytocin


Although oxytocin has long been considered beneficial to mental health due to its anxiolytic, prosocial and anti-stress effects, evidence for anxiogenic actions of oxytocin in humans has recently emerged. Moreover, the established view that oxytocin reduces fear and anxiety has been challenged, as humans given oxytocin intranasally exhibit increased recollection of aversive events (Bartz et al., 2010; cited in Guzman et al., 2013).


Strengthens the memory of negative social interactions

In line with the hypothesized role of the lateral septum and ERK molecule in influencing fear responses, Guzman et al. (2013) used region-specific manipulations of the mouse oxytocin receptor (Oxtr) gene and identified the lateral septum as the brain region mediating fear-enhancing effects of Oxtr. These effects occur after social defeat and require Oxtr specifically coupled to the ERK pathway.

Coupling of lateral septal Oxtr to Erk.png
Coupling of lateral septal Oxtr to Erk-1/2 signaling



(a) Immunofluorescence with antibodies to GFP and to pErk-1/2 (top), pCREB (middle) or pPKC (bottom) in the lateral septum of heterozygous Venus+/− Oxtr ‘reporter’ mice. b) Quantification of pErk-1/2 in Venus-positive neurons of Venus Oxtr reporter mice 6 h after social defeat (‘SD6’ group) or in naive controls. Percentage of pErk-1/2 is significantly greater in mice that underwent SD when compared to mice that lack the Oxtr gene. (c) Freezing in mice treated with U0126 or vehicle after social defeat (SD) or non-stressed (NS) condition, (Guzman et al., 2013).


In their experiment, three groups of mice were individually placed in cages with aggressive mice and experienced social defeat. One group was missing its oxytocin receptors. The second group had an increased number of receptors whereas the third control group had a normal number of receptors. Guzman and colleagues (2013) found that mice with no oxytocin receptors didn't appear to remember the aggressive mice and showed no fear when returned to the cages. Conversely, when mice with increased oxytocin receptors were reintroduced to the aggressive mice, they showed an intense fear reaction and avoided them, suggesting that oxytocin is essential for strengthening bad memories.


Increases fear and anxiety in future stressful situations

Again, the three groups of mice were exposed to the stressful experience of social defeat in the cages of other more aggressive mice. Then they were put in a box in which they received a brief electric shock. 24 hours later, the mice were returned to the same box but did not receive a shock.

The mice missing their oxytocin receptors did not show any enhanced fear when they re-entered the box in which they received the shock. The second group, which had extra oxytocin receptors showed greater fear in the box. The third control group exhibited an average fear response.
Radulovic, the senior author of the study, stated that "this experiment shows that after a negative social experience, oxytocin triggers anxiety and fear in a new stressful situation".

On the contrary, other studies showed that oxytocin exerts its effects in modulating anxiety, increasing trust and reducing fear through specific oxytocin receptors found within the amygdala central to neurological pathways that mediate fear, trust and social recognition (Huber et al., 2005; cited in IsHak et al., 2011). It excites the GABAergic neurons in the amygdala and also inhibits neurons excited by vasopressin in response to fear. Amygdala hyperactivation leads to impairment in emotional and mental state and is a key symptom domain in many neuropsychiatric disorders.

Kirsch and colleagues (2005) reported that in healthy males, oxytocin infusion reduced amygdala activation after exposure to stress as seen on functional MRI. These results were also accompanied by a reduction in sympathetic behavioral manifestations of fear in response to angry and fearful facial expressions (cited in Ishak et al, 2011).

Similarly, animal studies suggest that subcutaneous administration of low dose oxytocin has an anxiolytic effect very similar to clinically used short acting benzodiazepines (Uvnas-Moberg et al., 1994; cited in IsHak et al., 2011). Moreover, when animals are treated with oxytocin, they show decrease in plasma corticosterone levels as well as a decrease in anxiety behavior in response to stress as compared to controls (Windle et al., 1997; cited in Ishak et al 2011).


May impede trust and pro-social behavior

Oxytocin administration is associated with increased trust, according to Kosfeld’s et al. (2005) findings based on a test experiment that required financial investment. Male volunteers who received intranasal oxytocin 50 minutes prior to the test showed increased levels of trust as shown by significantly higher MU (money transfer amount units) per investor compared to placebo. Oxytocin test subjects when participated in a similar experiment but one that assessed level of risk taking exhibited identical money transfer rates to the placebo group, suggesting the increased trust is unrelated to increased risk taking.
trust experiment.png
Effect of oxytocin on trust in humans

Kosfeld et al. (2005)
The filled bars represent participants with oxytocin. Empty bars represent participants with a placebo.

Opposing to these findings, another study conducted by Bartz et al. (2011), who investigated the effects of intranasal oxytocin on trust and cooperation in borderline personality disorder (BPD), a disorder marked by interpersonal instability and difficulties with cooperation, hypothesized that no significant increase in trust and/or pro-social behavior in their healthy controls participants was observed, suggesting that oxytocin does not uniformly facilitate trust and pro-social behavior in humans.

OXT & BPD.png
Effect of oxytocin on trust & cooperation in BPD VS controls

Partner strategy expectations (‘trust’) & strategic response to partner hypothetical cooperation following oxytocin or placebo for healthy control and BPD participants, (Bartz et al., 2011).


Conclusion


Oxytocin administered intranasally has shown clear evidence of enhancing interpersonal and individual well-being. Thus, it might have more applications in the treatment of social deficits, repetitive behaviour, fear reduction, and trust problems, which are all potential targets for intervention with exogenous oxytocin.

However the idea that oxytocin reduces fear and anxiety in the individual has been challenged. The growing interest in the commercial use of oxytocin as a nasal spray has prompted further studies to report that it does not necessarily improve pro-social behaviour and might even possess an underlying dark side.

It could be possible for future research to investigate optimising oxytocin treatments due to its recently discovered dual role of both triggering and reducing anxiety, depending on the conditions of the social situation. This knowledge on the possible negative effects of oxytocin, could lead to advancements in treatments for anxiety conditions such as PTSD, social anxiety and fear disorders.



Critical Analysis


The media item, "The love hormone is two-faced" is an article that was published on the website for the Australasian Science Magazine. Australasian Science is a monthly science magazine published in Australia, which boasts an experienced team of science journalists in Australia, as well as publishing a range of articles written by scientists about their own work. The article focuses on the study 'Fear-enhancing effects of septal oxytocin receptors' undertaken by the Department of Psychiatry and Behavioural Sciences, Northwestern University, Chicago.

The guidelines for submissions on the website states that submissions should be written in 'plain and simple language' and authors should explain 'the significance of their work to the general public', as the website has a wide local audience. The author has achieved this as the neurological context is highly simplified by using basic scientific concepts to appeal to the general public who have little scientific knowledge, as well as communicating the general methods and results of the study without delving too much into the details.

The author initially captures the general audiences attention and interest through, 'The love hormone is two-faced'; a seemingly controversial title about the so called 'love hormone'. They have also used language in an attempt to engage the audience with phrases such as, 'the warm, fuzzy hormone' and 'darker identity for the hormone', as well as using relatable situations that may appeal to the general public such as 'being bullied at school' or being 'tormented by a boss', to inform the audience that oxytocin may be the reason that these situations can have long lasting negative effects by triggering fear and anxiety in them.

Whilst the aim of the article is to present the findings of this study, it focuses entirely on the negative effects of oxytocin that could arise from negative social situations. It states that 'the hormone actually strengthens social memory in one specific region of the brain', and continues to focus on the fear and anxiety that arises from negative situations, failing to emphasise the possible dual action of oxytocin as there have been countless studies before which have proven the positive and therapeutic effects of hormone. This presents a biased view on the effects of oxytocin to the general public. The article also fails to include evidence from other articles or interviews with researchers apart from those who participated in the study, focusing solely on the results of this study to state that oxytocin is the cause of emotional pain.


‍‍‍‍‍Appendix


Making a final decision on our project’s topic was not as easy as we thought! With so many to choose from, we were interested in more than one journal article. Yet, we were not confident about the quality and relevance of each of them.

“Learning under stress” was our first choice based on its relevance, as we believed, to one of the Neuroscience areas that we were studying about at that time- i.e. stress. This topic was “definitely interesting” according to Dr. Vickery. However, he asked us to search for another media item as he thought that the one we found was a bit sparse and has no enough information to analyse.

Because we were not able to find an appropriate alternative media item related to the same topic that we primarily decided on, we ended up searching for a different one. On the day of our scheduled meeting, we came across fascinating fields and even some unusual and controversial topics of neuroscience. We used internet search engines to identify neuroscience journals that offer a wide range of issues to select from. After more than one hour and a half of research and discussion among all group members, we could finally agree on our current topic “The love hormone is two-faced”, which was approved by Dr. Vickery. Our search tools for the resources used were mainly library databases, which provided us with numerous peer-reviewed articles that were chosen for their academic integrity and significance.

Investigating the potential dark side of oxytocin was of particular interest for us especially that it has recently been used commercially as an anti-anxiety drug and in the treatment of social deficits and neuropsychiatric disorders such as autism and schizophrenia.

For the same reason of interest, one of our peers mentioned in his comment that he really enjoyed our topic as he has read studies showing that oxytocin has an effect on long term memories being retained during reconsolidation processes, which aids our idea that the new potential aspects of oxytocin’s role are becoming more popular not only for the scientific but also for the general community.

In their constructive comments on the draft of our project, all of our peers agreed that our article was a good choice, the critical analysis and referencing sections were well written and the general organization of the scientific context made it easier to read and understand. To help us in our final editing process, they also provided us with valuable suggestions highlighting the weaknesses and how these can be improved.

In particular, our reviewers criticized the broad range of areas covered in the scientific context as it was not all relevant to the article. They thought that it would be better to discuss fewer points but with greater details and to focus on the dark side of oxytocin as it is more related to our topic. In addition, they recommended including more information on the neurological basis behind the findings of the studies and to link the results of the previous literature with the claims of the media item. Other suggestions for improvement included restructuring the introduction, correcting some grammatical errors, not exceeding the word limit and using only one referencing style in the referencing section.

We highly appreciated all comments as we agreed with most of what was mentioned for its relevance and accuracy. As a result of taking the reviewers’ comments into consideration, several changes and edits were required and because the main issue was in regards to the non-specificity of the scientific context, we tried to focus on the dual role of oxytocin’s system, to enable us to draw a final conclusion that either supports or rejects the author’s claims, and the mechanism by which it enhances fear and recollection of aversive events. Furthermore, minor adjustments were made-i.e. grammar and structure of sentences were reviewed and references were reconsidered to follow one format as advised.

Overall, we addressed the reviewers’ comments that we received where appropriate and tried our best not to dismiss any suggestion as they were very useful and applicable.


References


Adams, P., & Sweatt, D. (2002). Molecular psychology: Roles for the erk map kinase cascade in memory. Annual Review of Pharmacology and Toxicology, 42, 135-163.

Bartz, J., Simeon, D., Hamilton, H., Kim, S., Crystal, S., Braun, A., Vicens, V., & Hollander, E. (2011). Oxytocin can hinder trust and cooperation in borderline personality disorder. Social Cognitive and Affective Neuroscience, 6 (5), 556-563.

Figler, R. A., MacKenzie, D. S., Owens, D. W., Licht, P., & Amos, M. S. (1989). Increased levels of arginine vasotocin and neurophysin during nesting in sea turtles. Gen. Comp. Endocrino, 73, 223-232.


Guzman Y.F., Tronson N.C., Jovasevic V., Sato K., Guedea A.L., Mizukami H., Nishimori K., & Radulovic J. (2013). Fear-enhancing effects of septal oxytocin receptors. Nature Neuroscience, 16, 1185–1187.

Ishak, W.W., Kahloon, M., & Fakhry, H. (2011). Oxytocin role in enhancing well-being: A literature review. Journal of Affective Disorders, 130 (1-2), 1-9.

Insel, T. R. & Young, L. J. (2001). The neurobiology of attachment. Nature Reviews Neuroscience, 2, 129-136.

Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005). Oxytocin increases trust in humans. Nature, 435, 673-676.


Pedersen, C. A., Ascher, J. A., Monroe, Y. L. & Prange, A. J. (1982). Oxytocin induces maternal behaviour in virgin female rats. Science, 216, 648-650.


Pedersen, C. A., Caldwell, J. D., Walker, C., Ayers, G. & Mason, G.A (1994). Oxytocin activates the postpartum onset of rat maternal behaviour in the ventral tegmental and medial preoptic area. Behavioural Neuroscience, 108, 1163-1171.


Singewald, G. M., Rjabokon, A., Singewald, N., & Ebner, K. (2011). The modulatory role of the lateral septum on neuroendocrine and behavioral stress responses. Neuropsychopharmacology, 36, 793-804.


OK -this looks good. Compare the article with the source to see what extra the journalist and magazine bring to the story.

Approved


Workload allocation:
Introduction : Noura
Scientific Context :
background = Noura (was done by Ronald)
pathways of oxytocin = Ronald
the dual role of oxytocin = Marya
conclusion = Alexandra+Marya
Critical Analysis: Alexandra
Appendix: Marya