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

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.

SUBMITTER: Rapanelli M

PROVIDER: S-EPMC5488951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Basal ganglia (BG) circuitry plays a crucial role in the control of movement. Degeneration of its pathways and imbalance of dopaminergic signalling goes along with movement disorders such as Parkinson's disease. In this study, we explore the interaction of degeneration in two BG pathways (the nigro-striatal and dentato-pallidal pathway) with D2 receptor signalling to elucidate an association to motor impairment and medication response. Included in the study were 24 parkinsonian patients [male, 62 years (± 9.3 SD)] compared to 24 healthy controls [male, 63 years (± 10.2 SD)]; each participant passed through three phases of the study (i) acquisition of metadata/clinical testing, (ii) genotyping and (iii) anatomical/diffusion MRI. We report a decline in nigro-striatal (p < .003) and dentato-pallidal (p < .0001) connectivity in the patients compared to controls, which is associated with increasing motor impairment (relating to nigro-striatal, r = -0.48; p < .001 and dentato-pallidal connectivity, r = -0.36; p = .035). Given, that variations of the ANKK1 Taq1 (rs 1,800,497) allele alters dopamine D2-dependent responses, all participants were genotyped respectively. By grouping patients (and controls) according to their ANKK1 genotype, we demonstrate a link between D2 receptor signalling and decline in connectivity in both investigated pathways for the A1- variant (nigro-striatal pathway: r = -0.53; p = .012, dentato-pallidal pathway: r = -0.62; p = .0012). In patients with the A1+ variant, we only found increased brain connectivity in the dentato-pallidal pathway (r = 0.71; p = .001) correlating with increasing motor impairment, suggesting a potentially compensatory function of the cerebellum. Related to medication response carriers of the A1+ variant had a better drug effect associated with stronger brain connectivity in the nigro-striatal pathway (r = 0.54; p < .02); the A1- group had a good medication response although nigro-striatal connectivity was diminished (r = -0.38; p < .05); these results underscore differences in receptor availability between both groups in the nigro-striatal pathway. No effect onto medication response was found in the dentato-pallidal pathway (p > .05). Interplay between basal ganglia connectivity and D2 receptor availability influence the clinical presentation and medication response of parkinsonian patients. Furthermore, while current models of basal-ganglia function emphasize that balanced activity in the direct and indirect pathways is required for normal movement, our data highlight a role of the cerebellum in compensating for physiological imbalances in this respect.

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

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