Barbering, Trichotillomania, and Imprinted Gene Expression in the Brain

By Bernard Crespi

“You know, sometimes I feel well and vital in the world, and sometimes I just feel so distressed I want to pull my hair out by the roots”  – Sharon Stone

Imprinted genes are, or perhaps should be, of special interest in evolutionary approaches to medicine because they are expected from theory to be involved in genomic conflicts that potentiate and structure distress, pathology, and disease (Haig 1993; Crespi 2010).  A paper just published in Nature (Garfield et al. 2011) describes new data on the effects of one brain-expressed imprinted gene, Grb10, claiming that it represents “the first example of an imprinted gene that regulates social behaviour”. Does it?  Their claim is based on a mouse gene knock-out model, whereby they genetically-engineered a mouse strain to not express Grb10 in the brain.  Normally, mice express this gene, in brain, only in subcortical structures and only from the paternally-inherited chromosome – so the mice have been made more ‘maternal-gene’ as regards expression and effects from Grb10.

How does the behavior of mice knocked-out in brain for Grb10 differ from normal?  Garfield et al. (2011) subjected knockouts and normals to a suite of tests, and found two main differences.  First, Grb10-knockouts exhibited a strikingly-higher incidence of ‘barbering’, a behavior whereby one mouse (the barber) bites and pulls whiskers from other mice (the barbees, shall we say). Garfield et al. (2011) construe this behavior as reflecting social dominance of the knockouts.  Second, the knockout mice are less likely to back down when faced with an unfamiliar male mouse, in a long narrow tube.  This behavior is also interpreted by the authors as indicating social dominance of the Grb10-deficients.

The paper is a tour de force as regards neurogenetic methods.  However, there are a number of considerations that should be clarified with regard to the conclusion that this gene ‘regulates social behavior’.

First, there is no strong evidence that mouse ‘barbering’ represents a dominance behavior, or even a normal social behavior.  Indeed, the most recent comprehensive review of barbering (Dufour and Garner 2010) flatly states that ‘barbering is not a dominance behavior’ (page 215).  What is it, then?  According to these authors, it appears to be a pathological stereotypy of no adaptive function, brought on by laboratory housing conditions.  What’s interesting though, is that Dufour and Garner explain in some detail how barbering in mice appears quite similar to a condition in humans known as ‘trichotillomania’ – habitual, compulsive hair-pulling. Trichotillomania appears to occur differentially often among human psychiatric patients with obsessive-compulsive disorder, schizophrenia, depression, borderline personality disorder, or intellectual disability (Shah et al. 2010); it reaches a notably-high incidence (about 16%) in Prader-Willi syndrome, an imprinted-gene disorder involving bias towards maternal gene expression in the hypothalamus and very high rates of affective psychosis  (Wigren and Hansen 2003; Webb et al. 2008).  These findings are of notable interest given the subcortical expression of (paternally-expressed) Grb10 in brain, which suggests that subcortical losses of paternal gene expression may be associated with some psychotic and affective conditions.  Why is this important? Further studies of Grb10 knock-out mice may lead to important insights into the neurological, epigenetic and genetic bases of trichotillomania in particular and psychotic-affective conditions (and obsessive-compulsive disorder) more generally.  For example, can excessive barbering, like trichotillomania, be treated effectively with the antipsychotic haloperidol (Van Ameringen et al. 1999)?

See www.mybrainnotes.com/bdd-trichotillomania-skin-picking.html for a fascinating discussion of trichotillomania in relation to normal grooming in primates, in mice, and human neurobiology and psychiatric disorders.

Second, it is not clear that the ‘tube test’ used to evaluate ‘social dominance’ actually represents an ecologically or behaviorally meaningful assay of dominance, in the context of normal mouse social interactions.  Has this test been validated with independent measures of dominance in mice?  How ‘social’ are reactions to unfamiliar mice in tubes? Aren’t imprinted genes expected to affect mainly kinship-related interactions, in any case?  Of course behavioral assays can be difficult to interpret in mice – but all the more reason to evaluate their meaning, to the mice themselves, with convergent behavioral, neurological and pharmacological evidence.

Understanding the behavioral significance of Grb10 imprinting in the brain will require considerable further work that takes closer account of both natural and pathological mouse behavior. No need to pull our hair out about it – but yes, there is a need to account very carefully for the evolved adaptations of mice, and imprinted genes, in devising and interpreting tests that assay behavior.

References

Crespi BJ. 2010. The origins and evolution of genetic disease risk in modern humans.

Ann N Y Acad Sci. 1206:80-109.

Dufour BD and Garner JP. An ethological analysis of barbering behavior. 2010.  pp. 184-225

In Neurobiology of Grooming Behavior, edited by Allan V. Kalueff, Justin L. La Porte, Carisa L. Bergner.  Cambridge Univ. Press.  Available via Google Books.

Garfield AS, M Cowley, FM Smith et al. 2011. Distinct physiological and behavioural functions for parental alleles of imprinted Grb10  Nature 469:534-540.

Haig D. 1993. Genetic conflicts in human pregnancy. Q Rev Biol. 68:495-532.

Shah R, M. Somaiya and S Grover 2010. Trichotillomania comorbid with schizophrenia

German Journal of Psychiatry 13:154-156. www.gjpsy.uni-goettingen.de/gjp-article-shah-tricho.pdf

Van Ameringen M, Mancini C, Oakman JM, Farvolden P. 1999. The potential role of haloperidol in the treatment of trichotillomania. J Affect Disord. 56:219-226.

Webb T, Maina EN, Soni S, Whittington J, Boer H, Clarke D, Holland A. 2008. In search of the psychosis gene in people with Prader-Willi syndrome. Am J Med Genet A. 46:843-853.

Wigren M, Hansen S. 2003. Rituals and compulsivity in Prader-Willi syndrome: profile and stability.

J Intellect Disabil Res. 47:428-38.