Chronic stress can cause depression in some individuals, but leaves others untouched. Engagement of a molecular pathway controlling the production of tiny RNA snippets might help to explain the difference. See Article p.51
Stress and adversity can put the balance of our lives at risk — the death of a loved one, loss of a job or other financial or personal problems can have detrimental effects on the human psyche. Although some people become depressed in such circumstances, others are more resilient and can successfully cope with difficult experiences. Resilience was first documented in the 1970s, but the molecular underpinnings of this phenomenon are still mostly elusive1. In this issue, Dias et al.2 (page 51) report that behavioural resilience in mice is promoted by the β-catenin protein, through control of the enzyme Dicer1.
Research over the past decade shows that a complex interplay between genetic and environmental factors underlies mood disorders, and points to some key molecular pathways involved in such conditions3. This work has also led to the development of antidepressants, but such drugs are effective in only about two-thirds of people with depression4. A better understanding of the molecular pathways active in resilient individuals could inform us of alternative treatment strategies5.
β-Catenin controls brain function6, and molecules regulating β-catenin activity have been implicated in depression7. Dias and colleagues analysed the role of β-catenin in resilience, using a well-established mouse model of depression — chronic social defeat stress (CSDS)8. Briefly, male mice are repeatedly exposed to males from a physically superior strain. The encounter regularly ends with the defeat of the test mice. Although the fights do not usually result in severe physical injury, the repeated defeat leaves psychological scars that ultimately manifest in depressive behaviour. For example, mice that have experienced CSDS will largely avoid social contact, a symptom also observed in people with depression9.
The authors focused on a specific brain region, the nucleus accumbens (NAc), which is part of the forebrain. Although the NAc is primarily known for its role in addiction10, earlier work from the same group suggests that it is also involved in depression7. When Dias and co-workers artificially increased the amount of β-catenin in the NAc, the social behaviour of mice that had experienced CSDS became indistinguishable from that of the controls, suggesting that β-catenin promotes resilience. Conversely, blocking β-catenin resulted in depressive behaviour in mice that had experienced a stress dose that normally does not cause depression. Together, these experiments point to a pivotal role for β-catenin in stress resilience. Further investigation revealed that this action of β-catenin took place in only one type of neuron in the NAc, the D2-type medium spiny neurons, which are inactive in 'depressed' mice, but activated in those that show resilience.
These straightforward findings became more complicated when the authors tried to address exactly how β-catenin mediates pro-resilient behaviour. β-Catenin provides a classic example of 'protein moonlighting', a phenomenon in which a protein performs more than one function. It was originally identified as a component of a cell-adhesion complex11 that, among other roles, regulates plasticity in mammalian neurons. But β-catenin also has a nuclear function as an intracellular signal transducer, relaying information from a class of extracellular signalling molecules, Wnts, to regulate gene expression in the nucleus12. Dias et al. provide strong evidence that it is the nuclear function of β-catenin that is involved in resilience.
To gain insight into the genes regulated by β-catenin, the researchers created a genome-wide map of genetic regions bound by the protein. One of the most highly ranking genes to surface from this analysis was Dicer1, which encodes an enzyme that is crucial for the generation of various small regulatory RNAs13 — molecules that do not code for proteins themselves, but rather control protein production. The best-studied family of such RNAs, microRNAs (miRNAs), fulfil various functions in neurons14. Through a series of genetic experiments, the authors convincingly show that the pro-resilient effects of β-catenin are absent if Dicer1 is genetically removed.
Dias et al. propose a model whereby β-catenin-dependent regulation of small RNAs — in particular miRNAs — underlies behavioural resilience to stress (Fig. 1). The potential link between β-catenin and miRNAs is perhaps the most exciting aspect of this study. Because each miRNA can regulate the production of hundreds of proteins, β-catenin could in this way control the expression of a plethora of 'anti-resilience' proteins that counteract resilience. However, several caveats remain to be addressed.
Dicer1 protein is necessary for the expression of most miRNAs, but only a few miRNAs were robustly affected by β-catenin manipulation. Could this mean that other targets of Dicer1 are involved in resilience? A growing body of work13 indicates that Dicer1 is responsible for the production of other classes of small RNA (such as small interfering RNAs) and that it is also involved in small-RNA-independent processes. Comparing Dias and colleagues' results with those from other mice with reduced miRNA processing — for example, mice with mutations in the Dgcr8 gene15— should help to clarify the role of miRNAs in resilience. Even if miRNAs are the crucial effectors of resilience, identifying the physiologically relevant ones among the nearly 1,000 miRNA species seems to be a long shot. Nevertheless, Dias et al. provide some promising leads for follow-up experiments.
What is the relevance of these findings for humans? The β-catenin pathway is not unknown territory for therapeutic depression research. Several proteins that control β-catenin activity are altered in people with depression, including the kinase enzyme GSK3, which is a target of the antidepressant drug lithium4. It will now be necessary to determine if the β-catenin-regulated miRNAs presented in the current study are also affected in the brains of people with depression.
Dias and colleagues' research underscores the importance of small-RNA regulation in neuropsychiatric conditions. Assuming that effective and safe delivery of RNA into the human brain can be accomplished in the future, boosting the expression of selected small RNAs could become a viable strategy for building a protective shield that prevents stress from throwing our minds off balance.
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Astrocytic GABAB Receptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF
Neuroscience Bulletin (2020)