scholarly journals Midbrain Dopamine Neurons Defined by TrpV1 Modulate Psychomotor Behavior

2021 ◽  
Vol 15 ◽  
Author(s):  
Gian Pietro Serra ◽  
Adriane Guillaumin ◽  
Sylvie Dumas ◽  
Bianca Vlcek ◽  
Åsa Wallén-Mackenzie
Keyword(s):  
Transient Receptor Potential ◽  
Brain Area ◽  
Glutamate Transporter ◽  
Receptor Potential ◽  
Acute Effect ◽  
Progressive Increase ◽  
Mouse Genetics ◽  
Dopamine Neurons ◽  
Pharmacological Intervention ◽  
Distinct Subpopulation

Dopamine (DA) neurons of the ventral tegmental area (VTA) continue to gain attention as far more heterogeneous than previously realized. Within the medial aspect of the VTA, the unexpected presence of TrpV1 mRNA has been identified. TrpV1 encodes the Transient Receptor Potential cation channel subfamily V member 1, TRPV1, also known as the capsaicin receptor, well recognized for its role in heat and pain processing by peripheral neurons. In contrast, the brain distribution of TrpV1 has been debated. Here, we hypothesized that the TrpV1+ identity defines a distinct subpopulation of VTA DA neurons. To explore these brain TrpV1+ neurons, histological analyses and Cre-driven mouse genetics were employed. TrpV1 mRNA was most strongly detected at the perinatal stage forming a band of scattered neurons throughout the medial VTA, reaching into the posterior hypothalamus. Within the VTA, the majority of TrpV1 co-localized with both Tyrosine hydroxylase (Th) and Vesicular monoamine transporter 2 (Vmat2), confirming a DA phenotype. However, TrpV1 also co-localized substantially with Vesicular glutamate transporter 2 (Vglut2), representing the capacity for glutamate (GLU) release. These TrpV1+/Th+/Vglut2+/Vmat2+ neurons thus constitute a molecularly and anatomically distinct subpopulation of DA-GLU co-releasing neurons. To assess behavioral impact, a TrpV1Cre-driven strategy targeting the Vmat2 gene in mice was implemented. This manipulation was sufficient to alter psychomotor behavior induced by amphetamine. The acute effect of the drug was accentuated above control levels, suggesting super-sensitivity in the drug-na ve state resembling a “pre-sensitized” phenotype. However, no progressive increase with repeated injections was observed. This study identifies a distinct TrpV1+ VTA subpopulation as a critical modulatory component in responsiveness to amphetamine. Moreover, expression of the gene encoding TRPV1 in selected VTA neurons opens up for new possibilities in pharmacological intervention of this heterogeneous, but clinically important, brain area.

scholarly journals Inhibition of Microglia-Derived Oxidative Stress by Ciliary Neurotrophic Factor Protects Dopamine Neurons In Vivo from MPP+ Neurotoxicity

2018 ◽  
Vol 19 (11) ◽  
pp. 3543 ◽  
Author(s):  
Jeong Baek ◽  
Jae Jeong ◽  
Kyoung Kim ◽  
So-Yoon Won ◽  
Young Chung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Ciliary Neurotrophic Factor ◽  
Dopamine Neurons ◽  
Transient Receptor Potential Vanilloid

We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by CAP remain to be determined. Here we report that ciliary neurotrophic factor (CNTF) endogenously produced by CAP-activated astrocytes through TRPV1, but not microglia, inhibits microglial activation and microglia-derived oxidative stress, as assessed by OX-6 and OX-42 immunostaining and hydroethidine staining, respectively, resulting in neuroprotection. The significant increase in levels of CNTF receptor alpha (CNTFRα) expression was evident on microglia in the MPP+-lesioned rat SN and the observed beneficial effects of CNTF was abolished by treatment with CNTF receptor neutralizing antibody. It is therefore likely that CNTF can exert its effect via CNTFRα on microglia, which rescues dopamine neurons in the SN of MPP+-lesioned rats and ameliorates amphetamine-induced rotations. Immunohistochemical analysis revealed also a significantly increased expression of CNTFRα on microglia in the SN from human Parkinson’s disease patients compared with age-matched controls, indicating that these findings may have relevance to the disease. These data suggest that CNTF originated from TRPV1 activated astrocytes may be beneficial to treat neurodegenerative disease associated with neuro-inflammation such as Parkinson’s disease.

scholarly journals Control of Neonatal Spinal Networks by Nociceptors: A Potential Role for TRP Channel Based Therapies

2013 ◽  
Vol 16 (2) ◽  
pp. 313 ◽  
Author(s):  
Sravan Mandadi ◽  
Peter Hong ◽  
Arjun Sunny Dhoopar ◽  
Patrick Whelan
Keyword(s):  
Spinal Cord ◽  
Transient Receptor Potential ◽  
Pediatric Population ◽  
Receptor Potential ◽  
Basic Research ◽  
Spinal Pain ◽  
Mouse Genetics ◽  
Motor Dysfunction ◽  
Cord Injury ◽  
Nociceptive Afferents

Pediatric spinal cord injury (SCI) often leads to increased nociceptive input resulting in aberrant motor output like tremor and spasticity. Acute plasticity within spinal pain and motor networks following pediatric SCI may result in long-term sensorimotor disabilities. Despite this, pediatric SCI remains poorly understood. Part of the problem lies in the paucity of detailed studies aimed at defining sensorimotor control by nociceptors during development. This review provides an overview of work that highlights afferent control of sensorimotor networks by defined nociceptors in the developing spinal cord. Here, we focus on the well established and widely used neonatal sensorimotor model called sacrocaudal afferent (SCA) pathway. Until recently, the identity of specific subclasses of nociceptive afferents in the SCA pathway controlling developing sensorimotor networks was unknown. We highlight here the use of members of the Transient Receptor Potential (TRP) ion channels and mouse genetics to identify specific subsets of nociceptive afferents in the SCA pathway. In addition, we highlight the use of mouse genetics to map sensorimotor networks during development and potential future applications. A neonatal spinal cord model of central neuropathic pain via a defined set of nociceptors is presented as a probe into potential therapeutic avenues in neonatal SCI. Finally, knowledge translation from neonatal basic research to the pediatric population in the clinic is described. In conclusion, studies in neonatal models may lead to therapeutic strategies and pharmaceuticals for chronic pain and motor dysfunction after SCI during development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Involvement of transient receptor potential-like channels in responses to mGluR-I activation in midbrain dopamine neurons

2003 ◽  
Vol 18 (8) ◽  
pp. 2133-2145 ◽  
Author(s):  
Alessandro Tozzi ◽  
C. Peter Bengtson ◽  
Patrizia Longone ◽  
Corrado Carignani ◽  
Francesca R. Fusco ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Dopamine Neurons ◽  
Midbrain Dopamine ◽  
Transient Receptor ◽  
Midbrain Dopamine Neurons

scholarly journals Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349

2017 ◽  
Vol 474 (13) ◽  
pp. 2159-2175 ◽  
Author(s):  
Ralf Fliegert ◽  
Joanna M. Watt ◽  
Anja Schöbel ◽  
Monika D. Rozewitz ◽  
Christelle Moreau ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Rational Design ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Site Directed Mutagenesis ◽  
Structural Basis ◽  
Pharmacological Intervention ◽  
Hydroxyl Groups

TRPM2 (transient receptor potential channel, subfamily melastatin, member 2) is a Ca2+-permeable non-selective cation channel activated by the binding of adenosine 5′-diphosphoribose (ADPR) to its cytoplasmic NUDT9H domain (NUDT9 homology domain). Activation of TRPM2 by ADPR downstream of oxidative stress has been implicated in the pathogenesis of many human diseases, rendering TRPM2 an attractive novel target for pharmacological intervention. However, the structural basis underlying this activation is largely unknown. Since ADP (adenosine 5′-diphosphate) alone did not activate or antagonize the channel, we used a chemical biology approach employing synthetic analogues to focus on the role of the ADPR terminal ribose. All novel ADPR derivatives modified in the terminal ribose, including that with the seemingly minor change of methylating the anomeric-OH, abolished agonist activity at TRPM2. Antagonist activity improved as the terminal substituent increasingly resembled the natural ribose, indicating that gating by ADPR might require specific interactions between hydroxyl groups of the terminal ribose and the NUDT9H domain. By mutating amino acid residues of the NUDT9H domain, predicted by modelling and docking to interact with the terminal ribose, we demonstrate that abrogating hydrogen bonding of the amino acids Arg1433 and Tyr1349 interferes with activation of the channel by ADPR. Taken together, using the complementary experimental approaches of chemical modification of the ligand and site-directed mutagenesis of TRPM2, we demonstrate that channel activation critically depends on hydrogen bonding of Arg1433 and Tyr1349 with the terminal ribose. Our findings allow for a more rational design of novel TRPM2 antagonists that may ultimately lead to compounds of therapeutic potential.

scholarly journals Trpc5 deficiency causes hypoprolactinemia and altered function of oscillatory dopamine neurons in the arcuate nucleus

2019 ◽  
Vol 116 (30) ◽  
pp. 15236-15243 ◽  
Author(s):  
Thomas Blum ◽  
Ana Moreno-Pérez ◽  
Martina Pyrski ◽  
Bernd Bufe ◽  
Anela Arifovic ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Normal Function ◽  
The Body ◽  
Dopamine Neurons ◽  
Potential Oscillations ◽  
Female Mice ◽  
Transient Receptor

Dopamine neurons of the hypothalamic arcuate nucleus (ARC) tonically inhibit the release of the protein hormone prolactin from lactotropic cells in the anterior pituitary gland and thus play a central role in prolactin homeostasis of the body. Prolactin, in turn, orchestrates numerous important biological functions such as maternal behavior, reproduction, and sexual arousal. Here, we identify the canonical transient receptor potential channel Trpc5 as an essential requirement for normal function of dopamine ARC neurons and prolactin homeostasis. By analyzing female mice carrying targeted mutations in the Trpc5 gene including a conditional Trpc5 deletion, we show that Trpc5 is required for maintaining highly stereotyped infraslow membrane potential oscillations of dopamine ARC neurons. Trpc5 is also required for eliciting prolactin-evoked tonic plateau potentials in these neurons that are part of a regulatory feedback circuit. Trpc5 mutant females show severe prolactin deficiency or hypoprolactinemia that is associated with irregular reproductive cyclicity, gonadotropin imbalance, and impaired reproductive capabilities. These results reveal a previously unknown role for the cation channel Trpc5 in prolactin homeostasis of female mice and provide strategies to explore the genetic basis of reproductive disorders and other malfunctions associated with defective prolactin regulation in humans.

scholarly journals Is TRPA1 Burning Down TRPV1 as Druggable Target for the Treatment of Chronic Pain?

2019 ◽  
Vol 20 (12) ◽  
pp. 2906 ◽  
Author(s):  
Simona Giorgi ◽  
Magdalena Nikolaeva-Koleva ◽  
David Alarcón-Alarcón ◽  
Laura Butrón ◽  
Sara González-Rodríguez
Keyword(s):  
Chronic Pain ◽  
Clinical Trials ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trp Channel ◽  
Pharmacological Intervention ◽  
Future Directions ◽  
Cationic Channel ◽  
Transient Receptor ◽  
Noxious Cold

Over the last decades, a great array of molecular mediators have been identified as potential targets for the treatment of chronic pain. Among these mediators, transient receptor potential (TRP) channel superfamily members have been thoroughly studied. Namely, the nonselective cationic channel, transient receptor potential ankyrin subtype 1 (TRPA1), has been described as a chemical nocisensor involved in noxious cold and mechanical sensation and as rivalling TRPV1, which traditionally has been considered as the most important TRP channel involved in nociceptive transduction. However, few TRPA1-related drugs have succeeded in clinical trials. In the present review, we attempt to discuss the latest data on the topic and future directions for pharmacological intervention.

scholarly journals Dopamine neuron glutamate cotransmission evokes a delayed excitation in lateral dorsal striatal cholinergic interneurons

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Nao Chuhma ◽  
Susana Mingote ◽  
Leora Yetnikoff ◽  
Abigail Kalmbach ◽  
Thong Ma ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Metabotropic Glutamate Receptor ◽  
Brain Slices ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Editorial Note ◽  
Projection Neurons ◽  
Cholinergic Interneurons

Dopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA neurons do not signal to spiny projection neurons in the medial dStr, while they elicit ionotropic glutamate responses in the lateral dStr. The DA neurons mediating these excitatory signals are in the substantia nigra (SN). Thus, SN dopamine neurons engage different receptors in different postsynaptic neurons in different dStr subregions to convey strikingly different signals.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

scholarly journals Substantia nigra dopamine neurons evoke a delayed excitation in lateral dorsal striatal cholinergic interneurons via glutamate cotransmission

2018 ◽  
Author(s):  
Nao Chuhma ◽  
Susana Mingote ◽  
Leora Yetnikoff ◽  
Abigail Kalmbach ◽  
Thong Ma ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Transient Receptor Potential ◽  
Metabotropic Glutamate Receptor ◽  
Brain Slices ◽  
Dorsal Striatum ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Dopamine Neurons ◽  
Projection Neurons ◽  
Cholinergic Interneurons

SummaryDopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA neurons do not signal to spiny projection neurons in the medial dStr, while they elicit ionotropic glutamate responses in the lateral dStr. The DA neurons mediating these excitatory signals are in the substantia nigra (SN). Thus, SN dopamine neurons engage different receptors in different postsynaptic neurons in different dStr subregions to convey strikingly different signals.

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