The paper is Singer et. al.'s Conditional ablation and recovery of forebrain neurogenesis in the mouse. Via some cunning genetic engineering, the authors created mice with a gene for a protein called herpes simplex virus thymidine kinase. As the name suggests, this is a protein normally found in, er, herpes. Ganciclovir is a drug which can be used to treat herpes and related viral infections. And, as you might expect, cells engineered to express the herpes protein die when exposed to ganciclovir.The authors engineered mice which expressed herpes simplex virus thymidine kinase, but only in neural progenitor cells. These are the cells which eventually become new neurones in the adult brain. They found that injections of gancyclovir devasasted the production of new neurones in the engineered mice. (It had no effect on normal mice, of course, because their brain cells weren't half mouse, half herpes). That's not all that surprising.
However, they also found that gancyclovir treatment had no effect on the ability of 28 days treatment imipramine, an antidepressant, to affect the mice's behaviour. (The measure of antidepressant action was the Tail Suspension Test). That's a result, because a lot of people are interested in the theory that antidepressants work by boosting neurogenesis in the hippocampus. If that were true, blocking neurogenesis should also block the effects of antidepressants.Some rather exciting experiments found that it does, most famously the much-cited Santarelli et al (2003). But a growing number of other studies, such as this one, have not confirmed this finding. This doesn't mean that Santarelli et al were wrong, but it does suggest that there's more to antidepressants than neurogenesis. The seemingly-contradictory findings of the various studies might be due to important differences in the methods used. For example, the authors of this paper say that Santarelli et al's way of blocking neurogenesis - using x-rays - may have also caused inflammation and blocked the formation of non-neural cells, such as those which go to make up blood-vessels.
Of course, it's easy enough for us to speculate along such lines - rather harder to work out what exactly is going on. With any luck, the next few years will see more progress on this important topic.
Singer, B., Jutkiewicz, E., Fuller, C., Lichtenwalner, R., Zhang, H., Velander, A., Li, X., Gnegy, M., Burant, C., & Parent, J. (2009). Conditional ablation and recovery of forebrain neurogenesis in the mouse The Journal of Comparative Neurology, 514 (6), 567-582 DOI: 10.1002/cne.22052
8 comments:
"a lot of people are interested in the theory that antidepressants work by boosting neurogenesis in the hippocampus. If that were true, blocking neurogenesis should also block the effects of antidepressants."That, of course, assumes that animal models are good models for human diseases. In particular, since we know that antidepressants have potent monoaminergic effects anyway, it simply shows that behavioural effects of antidepressants in mice are not due to neurogenesis - but I doubt many people thought that anyway.
I don't know. I think a lot of people did think that. See for example Castren's much-cited paper "Is Mood Chemistry?" (his answer - no).
Seems to me that, apart from Santerelli et al, there wasn't much literature with that as a basis (certainly Castren doesn't cite anything else).
So even if it proves that neurogenesis is not necessary for behavioural effects of antidepressants in rodents that won't necessarily have much impact on the neurogenesis theory - that will continue to stand (or more likely fall) on the inherent implausibility and lack of evidence in humans.
I agree that that's how it should be but I'm not sure everyone is so mindful of the difference between mice and men. I think there are people - basic scientists especially - who will assume that the neurogenesis theory is true for humans if it remains a good explanation for the animal evidence.
Oh, and to be fair to the neurogenesis crowd, there is some (circumstantial) human evidence. Namely the whole cortisol-shrinks-your-hippocampus story. The finding that depressed people have smaller hippocampi on MRI scans is pretty robust. As is the fact that high dose corticosteroids can cause mood disturbance and also shrink the hippocampus.
so the neurogenesis theory has at least some human evidence behind it. Although not enough.
High dose steroids have a tendency to produce euphoria and psychosis acutely - so that doesn't really fit with neurogenesis - and, of course, the evidence that depression is primarily an HPA axis disorder is still lacking.
As for imaging evidence of reduced hippocampal volume - I remain unconvinced that it is 'robust' - it is suggestive (there was a meta-analysis a few years ago that showed massive heterogeneity but an overall significant reduction - I'm not aware of any more recent meta-analyses).
I have to confess I'm not a massive fan of animal models of psychiatric disease - I've seen so many 'models' that have ended up being applied to pretty much every major diagnosis (schizophrenia, depression, anxiety) depending on the results.
Animal studies are definitely of benefit for basic pharmacology, but I'm less convinced of the relevance beyond that.
im currently doing an animal model of GVHD, an immunesuppresive model, I feel the same with pj, there are too many differency and variery with human and animals.
now I am more interested in the natural drugs, just wonder if there's a way to study natual drugs without ever concentrating all the elements and drug targets? because human body is sooooo complex
Post a Comment