Genetic lack of histamine upregulates dopamine neurotransmission and alters rotational behavior but not levodopa-induced dyskinesia in a mouse model of Parkinson’s disease

The brain histaminergic and dopaminergic systems closely interact, and some evidence also suggests significant involvement of histamine in Parkinson’s disease (PD), where dopaminergic neurons degenerate. To further investigate histamine-dopamine interactions, particularly in the context of PD, a genetic lack of histamine and a mouse model of PD and levodopa-induced dyskinesia were here combined. Dopaminergic lesions were induced in histidine decarboxylase knockout and wildtype mice by 6-hydroxydopamine injections into the medial forebrain bundle. Post-lesion motor dysfunction was studied by measuring drug-induced rotational behavior and dyskinesia. Striatal tissue from both lesioned and naïve animals was used to investigate dopaminergic, serotonergic and histaminergic biomarkers. Histamine deficiency increased amphetamine-induced rotation but did not affect levodopa-induced dyskinesia. qPCR measurements revealed increased striatal expression of D1 and D2 receptor, DARPP-32, and H3 receptor mRNA, and synaptosomal release experiments in naïve mice indicated increased dopamine release. A lack of histamine thus causes pre- and postsynaptic upregulation of striatal dopaminergic neurotransmission which may be reflected in post-lesion motor behavior. Disturbances or manipulations of the histaminergic system may thus have significant consequences for dopaminergic neurotransmission and motor behavior in both healthy and disease conditions. The findings also represent new evidence for the complex interplay between dopamine and histamine within the nigrostriatal pathway.Peer reviewe

Green economic development in Lao PDR : a Sustainability Window analysis of Green Growth Productivity and the Efficiency Gap

A novel 'Sustainability Window' (SuWi) approach is applied for simultaneous analysis of the pillars of sustainable development; social, environmental and economic, of Lao PDR. This new method employs a variety of indicators for a comprehensive and holistic analysis of sustainable development and green inclusive economy. The analysis is grounded in the assumption that economic development is required for social development, but that simultaneously development needs to be guarded or limited to protect the environment that underpins it. As all three dimensions of sustainable development are interlinked, a comprehensive analysis requires an analytical approach that is simultaneous. The analyses provide information on minimum levels of economic development that are needed to fulfil social sustainability criteria, in tandem with the maximum economic development that avoids breaching environmental sustainability criteria. If actual economic growth lies between these minima and maxima, we can interpret that development is more sustainable with respect to the relationships embodied by the selected social and environmental indicators. The main source of data is the database of the Sustainable Society Index (SSI) developed by the Sustainable Society Foundation (SSF). The indicators used by SSI have been chosen for the Sustainability Window analysis as they can be used to assess both 'weak' and 'strong' interpretations of sustainability. Weak sustainability is defined operationally as no increase in the environmental or carbon emissions intensity of the economy, while strong sustainability is defined as no increase in absolute emissions. Further, a novel Environmental Efficiency Gap analysis has been included in the Sustainability Window. This provides information about the necessary improvement in GDP production efficiency with respect to environmental emissions. Sustainability Window combined with Environmental Efficiency Gap analysis, provides critical knowledge for planners and decision makers. It provides strategic indications of how to aim for social and environmental sustainability through economic investment and growth targets. These new methods can be used in transdisciplinary research of sustainable development and can also assist in national and regional comparisons. In the case of Lao PDR, the analysis needs to be broadened for more fundamental understanding of the gaps and weaknesses. SuWi can be used to assess the sustainable development needed to address the Sustainable Development Goals by 2030. The SuWi does not provide direct policy recommendations as such, but helps to inform decision makers about the direction of development pathways towards these key goals. (C) 2018 The Authors. Published by Elsevier Ltd.Peer reviewe

Short photoperiod-induced decrease of histamine H3 receptors facilitates activation of hypothalamic neurons in the Siberian Hamster

Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short inter-like photoperiod, which induces physiological adaptation to winter in the Siberian hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electro physiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod

GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis

The Parkinson’s disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1-/-), using CRISPR/Cas technology. gch1-/- zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 dpf, movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-Dopa treatment of gch1-/- larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1-/- larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphological and functional evidence of microglial activation in gch1-/-. The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for GWAS risk factors and further emphasises the important role of inflammation in the pathogenesis of PD

Temporomandibular joint dysfunction and orthognathic surgery: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Relations between maxillo-mandibular deformities and TMJ disorders have been the object of different studies in medical literature and there are various opinions concerning the alteration of TMJ dysfunction after orthognathic surgery. The purpose of the present study was to evaluate TMJ disorders changes before and after orthognathic surgery, and to assess the risk of creating new TMJ symptoms on asymptomatic patients.</p> <p>Methods</p> <p>A questionnaire was sent to 176 patients operated at the Maxillo-Facial Service of the Lille's 2 Universitary Hospital Center (Chairman Pr Joël Ferri) from 01.01.2006 to 01.01.2008. 57 patients (35 females and 22 males), age range from 16 to 65 years old, filled the questionnaire. The prevalence and the results on pain, sounds, clicking, joint locking, limited mouth opening, and tenseness were evaluated comparing different subgroups of patients.</p> <p>Results</p> <p>TMJ symptoms were significantly reduced after treatment for patients with pre-operative symptoms. The overall subjective treatment outcome was: improvement for 80.0% of patients, no change for 16.4% of patients, and an increase of symptoms for 3.6% of them. Thus, most patients were very satisfied with the results. However the appearance of new onset of TMJ symptoms is common. There was no statistical difference in the prevalence of preoperative TMJ symptoms and on postoperative results in class II compared to class III patients.</p> <p>Conclusions</p> <p>These observations demonstrate that: there is a high prevalence of TMJ disorders in dysgnathic patients; most of patients with preoperative TMJ signs and symptoms can improve TMJ dysfunction and pain levels can be reduced by orthognathic treatment; a percentage of dysgnathic patients who were preoperatively asymptomatic can develop TMJ disorders after surgery but this risk is low.</p

HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPs (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries.Peer reviewe

Three-Dimensional Neurophenotyping of Adult Zebrafish Behavior

The use of adult zebrafish (Danio rerio) in neurobehavioral research is rapidly expanding. The present large-scale study applied the newest video-tracking and data-mining technologies to further examine zebrafish anxiety-like phenotypes. Here, we generated temporal and spatial three-dimensional (3D) reconstructions of zebrafish locomotion, globally assessed behavioral profiles evoked by several anxiogenic and anxiolytic manipulations, mapped individual endpoints to 3D reconstructions, and performed cluster analysis to reconfirm behavioral correlates of high- and low-anxiety states. The application of 3D swim path reconstructions consolidates behavioral data (while increasing data density) and provides a novel way to examine and represent zebrafish behavior. It also enables rapid optimization of video tracking settings to improve quantification of automated parameters, and suggests that spatiotemporal organization of zebrafish swimming activity can be affected by various experimental manipulations in a manner predicted by their anxiolytic or anxiogenic nature. Our approach markedly enhances the power of zebrafish behavioral analyses, providing innovative framework for high-throughput 3D phenotyping of adult zebrafish behavior

GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis

The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1–/–), using CRISPR/Cas technology. gch1–/– zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gch1–/– larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1–/– larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gch1–/–. The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD