Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammat... - PubMed - NCBI

 OBJECTIVES:
Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored.
SUBJECTS:
Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice.
INTERVENTIONS:
The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used.

MEASUREMENTS AND MAIN RESULTS:
Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation.

CONCLUSIONS:
These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis."



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Selective damage to dopaminergic transporters following exposure to the brominated flame retardant, HBCDD

Over the last several decades, the use of halogenated organic compounds
has become the cause of environmental and human health concerns. Of
particular notoriety has been the establishment of the neurotoxicity of
polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers
(PBDEs). The subsequent banning of PBDEs has led to greatly increased
use of 1,2,5,6,9,10-hexabromocyclododecane (HBCDD, also known as HBCD)
as a flame retardant in consumer products. The physiochemical
similarities between HBCDD and PBDEs suggest that HBCDD may also be
neurotoxic to the dopamine system, which is specifically damaged in
Parkinson disease (PD). The purpose of this study was to assess the
neurotoxicity of HBCDD on the nigrostriatal dopamine system using an in
vitro and in vivo approach. We demonstrate that exposure to HBCDD
(0-25μM) for 24hrs causes significant cell death in the SK-N-SH
catecholaminergic cell line, as well as reductions in the growth and
viability of TH+ primary cultured neurons at lower concentrations
(0-10μM) after 72hrs of treatment. Assessment of the in vivo
neurotoxicity of HBCDD (25mg/kg for 30days) resulted in significant
reductions in the expression of the striatal dopamine transporter and
vesicular monoamine transporter 2, both of which are integral in
mediating dopamine homeostasis and neurotransmission in the dopamine
circuit. However, no changes were seen in the expression of tyrosine
hydroxylase in the dopamine terminal, or striatal levels of dopamine. To
date, these are the first data to demonstrate that exposure to HBCDD
disrupts the nigrostriatal dopamine system. Given these results and the
ubiquitous nature of HBCDD in the environment, its possible role as an
environmental risk factor for PD should be further investigated.

MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway

Congenital toxoplasmosis and toxoplasmic encephalitis can be associated
with severe neuropsychiatric symptoms. However, which host cell
processes are regulated and how Toxoplasma gondii affects these
changes remain unclear. MicroRNAs (miRNAs) are small noncoding RNA
sequences critical to neurodevelopment and adult neuronal processes by
coordinating the activity of multiple genes within biological networks.
We examined the expression of over 1000 miRNAs in human neuroepithelioma
cells in response to infection with Toxoplasma. MiR-132, a
cyclic AMP-responsive element binding (CREB)-regulated miRNA, was the
only miRNA that was substantially upregulated by all three prototype Toxoplasma strains. The increased expression of miR-132 was also documented in mice following infection with Toxoplasma.
To identify cellular pathways regulated by miR-132, we performed target
prediction followed by pathway enrichment analysis in the transcriptome
of Toxoplasma-infected mice. This led us to identify 20 genes
and dopamine receptor signaling was their strongest associated pathway.
We then examined myriad aspects of the dopamine pathway in the striatum
of Toxoplasma-infected mice 5 days after infection.
Here we report decreased expression of D1-like dopamine receptors (DRD1,
DRD5), metabolizing enzyme (MAOA) and intracellular proteins associated
with the transduction of dopamine-mediated signaling (DARPP-32
phosphorylation at Thr34 and Ser97). Increased concentrations of
dopamine and its metabolites, serotonin (5-HT) and 5-hydroxyindoleacetic
acid were documented by HPLC analysis; however, the metabolism of
dopamine was decreased and 5-HT metabolism was unchanged. Our data show
that miR-132 is upregulated following infection with Toxoplasma
and is associated with changes in dopamine receptor signaling. Our
findings provide a possible mechanism for how the parasite contributes
to the neuropathology of infection.

Anti-Psychotic Meds (dopamine d2 receptor antagonists ) Offer Hope Against Brain Cancer -- ScienceDaily

Researchers at the University of California, San Diego School of Medicine have discovered that FDA-approved anti-psychotic drugs possess tumor-killing activity against the most aggressive form of primary brain cancer, glioblastoma. The finding was published in this week's online edition of Oncotarget.

Dopamine mediates vagal modulation of the immune system by electroacupuncture : Nature Medicine : Nature Publishing Group

Previous anti-inflammatory strategies against sepsis, a leading cause of
death in hospitals, had limited efficacy in clinical trials, in part
because they targeted single cytokines and the experimental models
failed to mimic clinical settings.
Neuronal networks represent physiological mechanisms, selected by
evolution to control inflammation, that can be exploited for the
treatment of inflammatory and infectious disorders.
Here, we report that sciatic nerve activation with electroacupuncture
controls systemic inflammation and rescues mice from polymicrobial
peritonitis. Electroacupuncture at the sciatic nerve controls systemic
inflammation by inducing vagal activation of aromatic L-amino
acid decarboxylase, leading to the production of dopamine in the
adrenal medulla. Experimental models with adrenolectomized mice mimic
clinical adrenal insufficiency,
increase the susceptibility to sepsis and prevent the anti-inflammatory
effects of electroacupuncture. Dopamine inhibits cytokine production
via dopamine type 1 (D1) receptors. D1 receptor agonists suppress
systemic inflammation and rescue mice with adrenal insufficiency from
polymicrobial peritonitis. Our results suggest a new anti-inflammatory
mechanism mediated by the sciatic and vagus nerves that modulates the
production of catecholamines in the adrenal glands. From a
pharmacological perspective, the effects of selective dopamine agonists
mimic the anti-inflammatory effects of electroacupuncture and can
provide therapeutic advantages to control inflammation in infectious and
inflammatory disorders.

Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains.

Since Toxoplasma gondii can establish a persistent infection in the central nervous system in humans, we studied its effects on a host's neurotransmitter and neuropeptide systems (NNS). Using microarray technology, we have screened the expression of genes coding for NNS in human neuroepithelioma cells in response to representative strains of Toxoplasma to identify potential target genes. Transcripts that displayed expression levels distinct from uninfected controls were examined by RT-PCR and Western blot. Our results indicate the presence of disturbed NNS upon Toxoplasma infection and the extent of this disturbance varies considerably among the three strains. In cells infected by type I strain, three neurotransmitter systems (dopamine, glutamate and serotonin) and two neuropeptides (PROK2 and TAC1) displayed abnormalities relative to controls. Type III infection led to the change of a critical enzyme, TDO2, in the kynurenine pathway. No significant effects of type II infection were found in the NNS. These data may have implications for understanding the pathogenesis and heterogeneity of neurologic disturbances in toxoplasmosis.

Fat influences decisions taken by brain cells for production and survival

Swedish scientists from the Karolinska Institute have identified two molecules, cholic acid and 24, 25-epoxycholesteriol,  that play an important role in the survival and production of nerve cells in the brain, including nerve cells that produce dopamine. The discovery, which is published in the journal Nature Chemical Biology, may be significant in the long term for the treatment of several diseases, such as Parkinson's disease.

Effects of two commonly found strains of influenza a virus on developing dopaminergic neurons, in relation to the pathophysiology of schizophrenia.

Influenza virus (InfV) infection during pregnancy is a known risk factor for neurodevelopment abnormalities in the offspring, including the risk of schizophrenia, and has been shown to result in an abnormal behavioral phenotype in mice. However, previous reports have concentrated on neuroadapted influenza strains, whereas increased schizophrenia risk is associated with common respiratory InfV. In addition, no specific mechanism has been proposed for the actions of maternal infection on the developing brain that could account for schizophrenia risk. We identified two common isolates from the community with antigenic configurations H3N2 and H1N1 and compared their effects on developing brain with a mouse modified-strain A/WSN/33 specifically on the developing of dopaminergic neurons. We found that H1N1 InfV have high affinity for dopaminergic neurons in vitro, leading to nuclear factor kappa B activation and apoptosis. Furthermore, prenatal infection of mothers with the same strains results in loss of dopaminergic neurons in the offspring, and in an abnormal behavioral phenotype. We propose that the well-known contribution of InfV to risk of schizophrenia during development may involve a similar specific mechanism and discuss evidence from the literature in relation to this hypothesis.

Split-second control of specific dopamine neurones can switch depression-related behavior on and off (NIH)

A specific pattern of neuronal firing in a brain reward circuit instantly rendered mice vulnerable to depression-like behavior induced by acute severe stress, a study supported by the National Institutes of Health has found. When researchers used a high-tech method to mimic the pattern, previously resilient mice instantly succumbed to a depression-like syndrome of social withdrawal and reduced pleasure-seeking &mdash: they avoided other animals and lost their sweet tooth. When the firing pattern was inhibited in vulnerable mice, they instantly became resilient.

Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity.

Schizophrenia is characterized by a slow deteriorating mental illness. Although the pathophysiology mechanisms are not fully understood, different studies have suggested a role for the immune system in the pathogenesis of schizophrenia. To date, an altered expression or signaling of neurotransmitters receptors is observed in immune cells during psychiatric disorders. In the present study, we investigated the expression of different serotonin and dopamine receptors in T-cells of schizophrenic and control patients. We used flow cytometry to determine the pattern of expression of dopamine (D2 and D4) and serotonine receptors (SR1A, SR1C, SR2A, SR2B), as well as serotonin transporter (ST), in T-cell subsets (CD4 and CD8). Expression of serotonin receptors and ST in T-cells of schizophrenic patients were not different from controls. However, the percentages of CD4+D4+ and CD8+D4+ were increased in schizophrenic patients as compared to controls. In addition, increased percentages of CD8+D2+ cells were also observed in schizophrenic patients, albeit this population revealed lower CD4+D2+ cells in comparison to controls. Interestingly, a relationship between clinical symptoms and immunological parameters was also observed. We showed that the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were positively related to CD8+D2+ cells, though AIMS was inversely related to CD4+D4+ cells. In conclusion, the alteration in the pattern of cell population and molecules expressed by them might serve as a promising biomarker for diagnosis of schizophrenia.

New model explains role of dopamine in immune regulation

Dopamine is a neurotransmitter that is associated with emotions, movement, and the brain's pleasure and reward system. In the current issue of Advances in Neuroimmune Biology, investigators provide a broad overview of the direct and indirect role of dopamine in modulating the immune system and discuss how recent research has opened up new possibilities for treating diseases such as Parkinson's and Alzheimer's disease, schizophrenia, multiple sclerosis or even the autoimmune disorders.

Brain parasite directly alters brain chemistry

Research shows infection by the brain parasite Toxoplasma gondii, found in 10-20 per cent of the UK's population, directly affects the production of dopamine, a key chemical messenger in the brain.

The neurotropic parasite toxoplasma gondii increases dopamine metabolism.

These effects may be mediated by a tyrosine hydroxylase belonging to the parasite.

Related articles

• Researchers discover how 'promiscuous parasites' hijack host immune cells (sciencedaily.com)

Is There a Liberal Gene? : Discovery News

This liberal gene is the dopamine receptor DRD4 gene: This has also been implicated in schizophrenia, although not in the USA . The flood of GWAS studies is likely to uncover many more strange but true  associations.

New regulator of circadian clock identified: Dopamine study may have impact on activity and sleep rhythms in Parkinson's disease

New regulator of circadian clock identified: Dopamine study may have impact on activity and sleep rhythms in Parkinson's disease

Interesting, as circadian genes have been implicated in both Bipolar disorder and schizophrenia  Database

STEP : Abstract : UCSD-Nature Molecule Pages

STEP is a key mediator regulating glutamate, dopamine and adrenaline signalling .