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Decoding Stress Resilience

Periodic Reporting for period 1 - DE-STRESS (Decoding Stress Resilience)

Reporting period: 2016-07-01 to 2018-06-30

• What is the problem/issue being addressed?

Stress-induced psychopathologies such as depression are the most prevalent mental health disorders worldwide and impose a significant burden on society. A conventional approach to developing therapeutic strategies in this context is to create preclinical models which incorporate acute or chronic stress exposure. Such paradigms enable the discovery of causative links between stress, its effects on the central nervous system and the onset of behaviours in the model which are clinically relevant. These links, in turn, form the basis for developing novel therapeutics. However, as evidenced by several recent reports, this drug discovery scheme has, to date, yielded only modestly efficacious antidepressants and a significant proportion of patients are treatment-resistant. Against this background, over the last two to three decades our perspective of stress as a risk factor with a predetermined detrimental outcome has shifted significantly to one where stress induces a spectrum of phenotypes and at opposing ends lie individuals who are stress-resilient and stress-susceptible. Accordingly, the experimental aims of the project undertaken was to use a preclinical paradigm to identify mediators of stress-resilience and study their functional roles.

• Why is it important for society?

From a therapeutic standpoint, identifying the central and peripheral processes which underlie the former could form the basis for therapeutic strategies which not only treat stress-induced psychopathologies but also build resilience against future stress exposure.

• What are the overall objectives?

The first objective of the project was to develop a preclinical paradigm which could be used to examine physiological, neurobiological and behavioural phenotypes of stress-susceptibility and stress-resilience.

The second aim of the project was to use orthogonal techniques to identify central and peripheral mediators of stress resilience. The specific focus of the project was a brain region called the bed nucleus of the stria terminalis (BNST) and changes in gene expression within this structure.

The third and final objective was to examine the functional roles of the identified mediators of resilience and susceptibility.
July 2016 – August 2016: Experiments planned in consultation with Professor Cryan, lab manager(s) and other colleagues.

September 2016: Preclinical experiments commenced
- Setting up of experimental paradigm
- Collection and analysis of samples
- Data analysis

Main results achieved so far:
-Chronic psychosocial defeat stress induced divergent behavioural phenotypes of social avoidance - stress-susceptible - and normal social behaviour - stress-resilience. We obtained an approximately equal proportion of both mice.
-Stress-resilience was negatively correlated with levels of the stress hormone, corticosterone, and weight of adrenal glands.
-In the prefrontal cortex, expression of cortictropin release factor (Crf) mRNA was higher in stress-susceptible mice compared to controls and stress-resilient mice. Expression was also lower in stress-resilient mice compared to controls.
-In the amygdala, expression of glucocorticoid receptor (Gr) and mineralocorticoid receptor (Mr) mRNA was lower in stress-resilient mice than stress-susceptible mice.
-In the hippocampus, expression of Crf receptor 1 (Crfr1) was higher in stressed mice but most significantly in stress-resilient mice.
-We observed no changes in gene expression, including PACAP, in the BNST.
-Stress had no effect on alpha- or beta-diversity of the gut microbiome. However, baseline microbiome composition covaried with several post-stress outcomes.

Exploitation/Dissemination:
Research findings have presented at conferences as posters and oral presentations in Europe and in the US.
Gururajan A, Lyte J, Da Silva APV, Becker T, O’Connor R, Boehme M, van de Wouw M, Moloney G, Dinan TG, Cryan JF (2017). Molecular mediators of stress resilience. (Poster) 1st Munich Winter Conference on Stress, Garmisch-Partenkirchen, Germany.
Gururajan A, Lyte J, Da Silva APV, Mercx B, Becker T, O’Connor R, Boehme M, van de Wouw M, Moloney G, Dinan TG, Cryan JF (2017). Neuromolecular mediators of resilience to chronic stress in the bed nucleus of the stria terminalis of the mouse. (Poster) Society for Neuroscience Conference, Washington DC, USA.
Gururajan A, Lyte J, Da Silva APV, Becker T, O’Connor R, Boehme M, van de Wouw M, Moloney G, Dinan TG, Cryan JF (2018). Stress Resilience: A state of Mind or A State of Gut? (Symposium) International Behavioural Neuroscience Society, Florida, USA.

I have published one review to date, with one more in preparation:
Gururajan A, Dinan TG, Cryan JF (2017). True grit: the role of neuronal microRNAs as mediators of stress resilience. Current Opinion in Behavioural Sciences, 14:9-18.
Gururajan A, Reif A, Cryan JF, Slattery DA. Models to Mechanisms: Drug Discovery for Depression. In preparation and to be submitted to Nature Reviews Neuroscience.

I have two original research articles are in preparation:
Gururajan A, Boehme M, Becker T, Van de Wouw M, O’Connor R, Moloney GM, Bastiaansen T, Lyte JM, Da Silva APV, Mercx B, Dinan TG, Cryan JF. Central & Peripheral Signatures of Stress Resilience in Mice. In preparation, to be submitted to Neurobiology of Stress.
Gururajan A, Bastiaansen T, Lyte JM, Wiley N, Moloney GM, Stanton C, Dinan TG, Cryan JF. Ecological networks in the mouse gut microbiome as predictors and mediators of stress resilience. In preparation, to be submitted to Microbiome.

I have been able to communicate my research findings at the following public forums:
Brain Awareness Week, UCC (2016) – Public lecture on Stress & Stress Resilience.
Adolescent Mental Health (2016) – Lecture to Health Service Executive (HSE, Ireland) Occupational Therapists.
The Science of Stress Resilience (2016) – Public lecture for Cork Science Festival.
‘It’s your RNA, not your DNA, that counts!’ (2018) – Pint of Science, Cork.

I have also written a piece for the Irish national broadcaster’s academic website, RTE Brainstorm.
Why do some people respond better to stress than others? (https://www.rte.ie/eile/brainstorm/2018/0110/932312-why-do-some-people-respond-better-to-stress-than-others/)
The outcomes of this project have progressed the field beyond the state of the art particularly in terms of the orthogonal techniques used to simultaneously identify central and peripheral mediators of stress resilience in the same mouse model. The results have shown firstly (i) a critical role for corticotrophin release factor in the prefrontal cortex in mediating stress-resilience and (ii) the presence/absence of specific gut microbial species at baseline can potentially predict stress-response. The potential impacts of the study carried out are significant. Based on the data, developing therapeutic strategies which boost resiliency in response to or in anticipation of stress exposure could potentially stave off risk of psychiatric sequelae. These strategies could take the form of pharmacological, non-pharmacological and psychobiotic based therapies which reinforce integrity of the stress-response and recovery systems in the brain and the gut. The longer-term outcomes are anticipated to be a reduced prevalence of stress-induced disorders and a more healthy and productive society.