Stimulated by Wang et al 2023.[1] KOR – ? opioid receptorCSDS – chronic social defeat stressSSDS – subthreshold social defeat stressSDS – social defeat stressAAV – adeno-associated virus key to acronyms This is a potentially important paper that describes,...
Stimulated by Wang et al 2023.[1]
Supplemental Figure 2 from Wang et al 2023 showing development of animal models of SDS.
KOR – ? opioid receptor
CSDS – chronic social defeat stress
SSDS – subthreshold social defeat stress
SDS – social defeat stress
AAV – adeno-associated virus
This is a potentially important paper that describes, for the first time, the neural circuitry involved in the link between chronic psychological stress and depression. There is no acupuncture in the research, but since we can help depressive disorders, and dynorphin (the ligand associated with KOR) is implicated in some acupuncture mechanisms, I thought it was just close enough. Plus, it is very high-quality research and Nature Communications has an impact factor of 16.6 and downloads of close to 100 million in 2022.
It came up on my searches because the research comes from Shanghai and the word acupuncture is in the affiliations of two of the authors. I guessed that would be the reason when screening my daily search results, but the journal name and CSDS caught my eye. I had not come across the term social defeat stress, although the phrase seems pretty straightforward. I have often been surprised by the ingenious models used in laboratory studies and was curious about how one creates CSDS in the lab. In real life you can see it all around you, especially in healthcare environments, and hear about it in the stories of patients, but in the lab, how do you create the same social defeat and suffering?
Well, it turns out that, of the many genetic mouse lines bred for laboratory research, male CD-1 mice are somewhat more aggressive than average, and based on the diagrams in this paper, a lot bigger than the C57BL/6 mice used as the main participants in the research. They do not appear to be bred specifically to be aggressive, rather the later lines are smaller and less aggressive than those from older lines, which are presumably somewhat closer to wild types. Having said that, CD-1 mice derive originally from mice bred in a laboratory in Switzerland and were later imported to the US. They are albino mice with no thymus, so they are somewhat immunocompromised, but that does not stop them attacking smaller colleagues of course.
In my searching around aggressive mice I came across the grasshopper mouse, which is said to be the most aggressive mouse. It lives in the southwestern deserts of US and is carnivorous, surviving by killing and eating insects such as grasshoppers, hence the name, but also the bark scorpion, which is in plentiful supply according to Wikipedia.
The SDS model is created by exposure of each of the test mice to one of the larger, more aggressive CD-1 mice for 10 minutes, followed by 24 hours being housed in the same enclosure, but separated by a perforated plexiglass partition. This was repeated daily for 10 days to create the CSDS model.
So, now we have a model for chronic social defeat stress leading to depressive behaviours – the latter being measured in all the usual ways in a laboratories eg social activity, tail suspension, forced swimming, sucrose preference, locomotor activity. Now we need to understand how the relationship between the two things, which is encoded in neural circuitry, can be assessed in vivo.
I’m afraid the methods get rather complex… They involve the use of numerous different AAVs injected into specific regions of the brain with genomes encoding for a variety of sophisticated receptors. GCaMP is a fusion of a green fluorescent protein with calmodulin and M13 (a peptide sequence from myosin light chin kinase). It fluoresces when bound to calcium ions and can be used to monitor neural activity in vivo.
By contrast, DREADDs (designer receptors exclusively activated by designer drugs) such as hM3Dq and hM3Di are modified muscarinic acetylcholine receptors that can be controlled by synthetic (otherwise inert) ligands to either activate or inhibit the neurones infected by their AAV transporter vectors.
It gets more complicated than this, but that should be enough to persuade the reader that we can now dissect the inner workings of complex brain circuits with a view to develop treatments that might mitigate the negative effects of CSDS.
The authors indicate that they are aiming at providing data to drive drug development, but mere molecular switches (drugs) are hopelessly simplistic in comparison with the neural circuits these researchers have uncovered. Treatments that resemble the methods they used to illuminate these neural mechanisms might be more convincing, but that would mean we had to consider the use of genetically modified viruses injected into the brains of our patients. Or perhaps treatments with homeostatic actions, such as acupuncture, might be a better bet while we await ethically palatable interventions using targeted genetic engineering.
References
1 Wang Y-J, Zan G-Y, Xu C, et al. The claustrum-prelimbic cortex circuit through dynorphin/?-opioid receptor signaling underlies depression-like behaviors associated with social stress etiology. Nat Commun. 2023;14:7903.