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Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):6599-6604. doi: 10.1073/pnas.1704547114. Epub 2017 Jun 5.

Histamine modulation of the basal ganglia circuitry in the development of pathological grooming.

Author information

1
Department of Psychiatry, Yale University hool of Medicine, New Haven, CT 06510.
2
Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
3
Department of Psychiatry, Yale University hool of Medicine, New Haven, CT 06510; christopher.pittenger@yale.edu.
4
Department of Psychology, Child Study Center, and Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06519.

Abstract

Aberrant histaminergic function has been proposed as a cause of tic disorders. A rare mutation in the enzyme that produces histamine (HA), histidine decarboxylase (HDC), has been identified in patients with Tourette syndrome (TS). Hdc knockout mice exhibit repetitive behavioral pathology and neurochemical characteristics of TS, establishing them as a plausible model of tic pathophysiology. Where, when, and how HA deficiency produces these effects has remained unclear: whether the contribution of HA deficiency to pathogenesis is acute or developmental, and where in the brain the relevant consequences of HA deficiency occur. Here, we address these key pathophysiological questions, using anatomically and cellularly targeted manipulations in mice. We report that specific ablation or chemogenetic silencing of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus leads to markedly elevated grooming, a form of repetitive behavioral pathology, and to elevated markers of neuronal activity in both dorsal striatum and medial prefrontal cortex. Infusion of HA directly into the striatum reverses this behavioral pathology, confirming that acute HA deficiency mediates the effect. Bidirectional chemogenetic regulation reveals that dorsal striatum neurons activated after TMN silencing are both sufficient to produce repetitive behavioral pathology and necessary for the full expression of the effect. Chemogenetic activation of TMN-regulated medial prefrontal cortex neurons, in contrast, increases locomotion and not grooming. These data confirm the centrality of striatal regulation by neurotransmitter HA in the adult in the production of pathological grooming.

KEYWORDS:

Tourette syndrome; basal ganglia; grooming; histamine; striatum

PMID:
28584117
PMCID:
PMC5488951
[Available on 2017-12-20]
DOI:
10.1073/pnas.1704547114

Conflict of interest statement

The authors declare no conflict of interest.

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