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Research Article

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

Maximiliano Rapanelli, Luciana Frick, View ORCID ProfileHaruhiko Bito, and View ORCID ProfileChristopher Pittenger
  1. aDepartment of Psychiatry, Yale University hool of Medicine, New Haven, CT 06510;
  2. bDepartment of Neurochemistry, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan;
  3. cDepartment of Psychology, Child Study Center, and Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06519

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PNAS June 20, 2017 114 (25) 6599-6604; first published June 5, 2017; https://doi.org/10.1073/pnas.1704547114
Maximiliano Rapanelli
aDepartment of Psychiatry, Yale University hool of Medicine, New Haven, CT 06510;
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Luciana Frick
aDepartment of Psychiatry, Yale University hool of Medicine, New Haven, CT 06510;
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Haruhiko Bito
bDepartment of Neurochemistry, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan;
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Christopher Pittenger
aDepartment of Psychiatry, Yale University hool of Medicine, New Haven, CT 06510;
cDepartment of Psychology, Child Study Center, and Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06519
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  • ORCID record for Christopher Pittenger
  • For correspondence: christopher.pittenger@yale.edu
  1. Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 11, 2017 (received for review March 19, 2017)

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Significance

Dysregulation of brain histamine (HA) is a rare cause of Tourette syndrome and related conditions, but the associated pathophysiological mechanisms remain obscure. We show that repetitive behavioral pathology in mice derives from deficiency of neurotransmitter HA (rather than HA from other sources), acting in the dorsal striatum. These data provide a functional dissection of acute HA modulation in the brain and elucidate the anatomical correlates of pathological dysregulation when neuronal HA is disrupted.

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.

  • histamine
  • basal ganglia
  • grooming
  • striatum
  • Tourette syndrome

Footnotes

  • ↵1M.R. and L.F. contributed equally to this work.

  • ↵2Present address: Department of Physiology & Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo–State University of New York, Buffalo, NY 14214.

  • ↵3Present address: Hunter James Kelly Research Institute, Jacobs School of Medicine & Biomedical Sciences, New York State Center of Excellence, University at Buffalo–State University of New York, Buffalo, NY 14203.

  • ↵4To whom correspondence should be addressed. Email: christopher.pittenger{at}yale.edu.
  • Author contributions: M.R., L.F., and C.P. designed research; M.R., L.F., and C.P. performed research; H.B. contributed new reagents/analytic tools; M.R., L.F., and C.P. analyzed data; and M.R., L.F., H.B., and C.P. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1704547114/-/DCSupplemental.

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Histamine modulation of the basal ganglia
Maximiliano Rapanelli, Luciana Frick, Haruhiko Bito, Christopher Pittenger
Proceedings of the National Academy of Sciences Jun 2017, 114 (25) 6599-6604; DOI: 10.1073/pnas.1704547114

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Histamine modulation of the basal ganglia
Maximiliano Rapanelli, Luciana Frick, Haruhiko Bito, Christopher Pittenger
Proceedings of the National Academy of Sciences Jun 2017, 114 (25) 6599-6604; DOI: 10.1073/pnas.1704547114
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Proceedings of the National Academy of Sciences: 114 (25)
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