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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 4, 2010

OCD Linked to the Immune System?

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Posted by Derek

Now here's one that I certainly didn't expect: there's a mouse model of obsessive-compulsive disorder, where the animals have a mutation in the Hoxb8 gene. These animals spend huge amounts of time repetitively grooming themselves (and their cagemates), and eventually remove so much hair that they give themselves lesions. From what I can see, they're doing the usual moves that mice do, but spending a lot more time doing them. And it doesn't seem to be something due to insensitivity to pain; the animals have some sensory alterations, but disrupting Hoxb8 in the spinal cord only doesn't lead to the grooming phenotype.

A new paper from a group at University of Utah reports that the brain signature of Hoxb8 mutation is found only in a population of microglia, one variety of the support cells that surround neurons. Hoxb8 was already known to affect the formation of blood cells, so this cohort of microglia (about 40% of the total in the mouse brain) look to be derived from the same precursors. So this study went the direct route: they did bone-marrow transplants on the mutant mice so that normal Hoxb8 cells would be produced. And over a time scale of weeks,most of the mice stopped their overgrooming. Meanwhile, the group also transplanted mutant bone marrow into normal mice, whereupon some of these mice began obsessively removing hair. (Here's the Nature News article on all this).

This seems to be the first time that anyone's linked microglia with behavior. The focus, naturally enough, has been on the neurons themselves and their connections, but it looks like we're all going to have to broaden our outlook. There are some things that need to be cleared up here, though. For one thing, it's not certain that these mice are truly an analog of human OCD - even the form of it that involves obsessive hair-pulling. Other obsessive mice types are known, and it'll be quite interesting to see what shape their microglia are in. At the same time, it would be worth going the other way, and seeing if the pharmacological agents used for OCD have any affect in the Hoxb8 mice, too.

Another thing that this study demonstrates is that at least one population of microglia are being continually renewed in the brain from the bone marrow. What the different roles are of this group versus the "resident" microglia is yet to be figured out. My mental picture of the brain has always been this protected zone, with very little allowed to cross in or out, but that's clearly incorrect.

But it looks as if we can say that someone has drawn a direct link between the immune/blood cell system and behavior in an animal model. Such things had long been suspected, but they've been very difficult to prove. Whether these mice have OCD or not, they've illustrated something new. This makes me wonder if various immunosuppressive drugs could have psychological and behavioral side effects that we haven't been picking up on - anyone who knows that field care to comment?

Comments (17) + TrackBacks (0) | Category: The Central Nervous System


COMMENTS

1. cynical1 on June 4, 2010 9:14 AM writes...

The CNS is known to be a site of very dynamic immune surveillance. Trafficking of T and B-cells in the abscence of inflamation takes place all the time. Lack of appreciation of this area has really impeded rapid advances in CNS autoimmune disease like multiple sclerosis. William Hickey at Dartmouth writes some great reviews on this area (and has done some really nice work, as well).

As for behavioral side effects of immunosuppressives, corticosteroids are the obvious ones that come to mind, hence the term ‘roid rage’. And if you’ve never been around someone taking IV steroids with PMS, count your blessings.

Permalink to Comment

2. passionlessDrone on June 4, 2010 9:36 AM writes...

Hi Derek -

Regarding an immune mediated pathway to OCD, have you seen the work by Swedo involving strep infection and consequent neural antibodies? Her team infected rodents with strep, observed OCD like behaviors, then took the antibodies from those rodents, and pushed them into fresh rodents and observed OCD.

http://www.scientificamerican.com/article.cfm?id=from-throat-to-mind

Her group has done some work with kids with strep invoked OCD and IVIG with results in some instances. (Or so they claim) This would seem to be somewhat similar to what was done here.

- pD

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3. Jamie on June 4, 2010 12:24 PM writes...

"Another thing that this study demonstrates is that at least one population of microglia are being continually renewed in the brain from the bone marrow."

The contribution of circulating cells to microglia appears to be an artifact of transplantation. This is elegantly demonstrated under physiological (and a couple of pathological) conditions using parabiosis in this paper:
http://www.ncbi.nlm.nih.gov/pubmed/18026097

I was surprised that the OCD paper didn't cite this work.

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4. Jamie on June 4, 2010 12:25 PM writes...

"Another thing that this study demonstrates is that at least one population of microglia are being continually renewed in the brain from the bone marrow."

The contribution of circulating cells to microglia under normal and a couple of pathological conditions appears to be an artifact of transplantation, which was elegantly demonstrated in this paper:
http://www.ncbi.nlm.nih.gov/pubmed/18026097

I was surprised the authors of the OCD paper didn't cite it.

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5. Jamie on June 4, 2010 12:34 PM writes...

"Another thing that this study demonstrates is that at least one population of microglia are being continually renewed in the brain from the bone marrow."

The contribution of circulating cells to microglia under normal and a couple of pathological conditions appears to be an artifact of transplantation, which was elegantly demonstrated in this paper:
http://www.ncbi.nlm.nih.gov/pubmed/18026097

I was surprised that the OCD group didn't cite this work.

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6. Capek on June 4, 2010 1:32 PM writes...

The relationship between the immune system and OCD is very intriguing. There have been some reports about auto-immunity in OCD:

Author(s): Goodman, WK; Sajid, MW; Goodman, WK
Title: Immunology of obsessive-compulsive disorder
Source: PSYCHIATRIC CLINICS OF NORTH AMERICA, 29 (2): 445-+ JUN 2006

Relevant to comment 1, there have been very rare reports of co-morbidity of OCD and MS.

Author(s): MIGUEL, EC; STEIN, MC; RAUCH, SL; OSULLIVAN, RL; STERN, TA; JENIKE, MA
Title: OBSESSIVE-COMPULSIVE DISORDER IN PATIENTS WITH MULTIPLE-SCLEROSIS
Source: JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES, 7 (4): 507-510 FAL 1995

Author: Douzenis, A; Michalopoulou, PG; Voumvourakis, C; Typaldou, M; Michopoulos, I ; Lykouras, L
Title: Obsessive-compulsive disorder associated with parietal white matter multiple sclerosis plaques
Source: WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, 10 (6): 956-960 2009

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7. KS on June 4, 2010 8:02 PM writes...

many patients report an eyphoric effect of IVIG
And corticosteroid -nduced psychosis is long known but mechanisms have not been elucidated

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8. KS on June 4, 2010 8:08 PM writes...

Many patients report an euphoric effect of IVIG
And corticosteroid -induced psychosis is long-known but its mechanisms have not been elucidated

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9. Josh Walsh on June 6, 2010 7:38 AM writes...

extremely interesting, unfortunately i know next to nothing in that field.

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10. Anonymous BMS Researcher on June 6, 2010 6:29 PM writes...

I am beginning to suspect EVERY disease has some relationship to immunity and inflammation. My dentist even tells me flossing my teeth may reduce my risk of heart attacks by reducing the level of inflammatory cytokines in my bloodstream...

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11. Lurker on June 6, 2010 7:05 PM writes...

Interferon alfa works through stimulation of the immune system. I have always thought it was interesting that a major side effect of interferon alfa for the treatment of Hepatitis C are neuropsychiatric reactions: depression, suicidal ideations, suicide
relapse of drug dependence and drug overdose.

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12. Rich Rostrom on June 6, 2010 11:23 PM writes...

Having an animal model of any mental condition would be great, if one could verify that the condition was really there. How would one tell if a rat is schizophrenic, or a monkey is paranoid, or a mouse is mentally retarded?

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13. mad on June 7, 2010 10:25 AM writes...

@ 12 there may be no verification possible…Many of these conditions may be malfunctions of higher level cognitive processes that mice don’t have/display. We might only be studying the most basic aspect of the behavior.

Derek how to I resize font on your page its too small drives me nuts reading it!

Permalink to Comment

14. NJBiologist on June 7, 2010 5:56 PM writes...

"This seems to be the first time that anyone's linked microglia with behavior."

Actually, Michael Salter has shown that you can induce pain behavior by implanting activated microglia into the spinal cord--he's used this to do some interesting work on signalling molecules mediating neuronmicroglia communication.

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15. Anonymous on June 8, 2010 4:57 AM writes...

#13 mad: use your browser settings, for example press Ctrl-+

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16. Kyoko Mczeal on August 18, 2012 9:49 AM writes...

I genuinely enjoy reading on this internet site , it has excellent blog posts. "When a man's willing and eager, the gods join in." by Aeschylus.

Permalink to Comment

17. Boris Beckelhimer on March 29, 2014 1:07 PM writes...

The article that I am thinking about, with Scott Payne, my co-author and a technology expert and two recent students, will explore aspects of collaborative work in the digital world as students contribute work to Wikipedia. In my survey of U.S. women's history I ask students to critique an article in Wikipedia for its content, sources and tone, and for their final project, they edit significantly an established article or develop one on their own. Two of the purposes are to increase the presence of historical material on women in the encyclopedia and to teach students about the careful creation of historical knowledge, but the third and more complex purpose is to introduce them to negotiating over their production of historical knowledge. Scott helps students to understand and navigate the preliminary protocol necessary for editing "established" articles that are usually patrolled by several self-appointed editors. Our students encounter cooperation or resistance depending on their selection of topic and their intended contribution. The article will discuss the collaborations between students and the editors whose preferences and ideologies "protect" the perimeters of many Wikipedia entries. It will also explore the experience students have writing material over which they do not have complete control, for an unknown public, rather than a relatively predictable professor. And, finally, there is the question of evaluating the significance of contributing to an encyclopedia that is by nature subject to the pressures of popular opinion and memory (see essay 21). What is gained and what is lost in the exchanges over content and tone that can precede the editing of entries with material that can be viewed ideologically? What do we learn about our history?Martha Saxton

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