nNOS-expressing neurons in the ventral tegmental area and substantia nigra pars compacta

Paul, Eleanor J.; Kalk, Eliza; Tossell, Kyoko; Irvine, Elaine E.; Withers, Dominic J.; Leiper, James; Ungless, Mark A.

doi:10.1101/251843

Cited by 6 publications

(7 citation statements)

References 65 publications

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“…For this paper, we focus on the midline VTA, which contains GABA (VTA Vgat ) and glutamate/nitric oxide synthase (VTA Vglut2 ) neurons 23,32,33 . These VTA Vgat and VTA Vglut2/NOS1 neurons inhibit and excite, respectively, the dopamine cells, but also, by projecting out of the VTA, exert effects independent of dopamine 23 .…”

Section: Introductionmentioning

confidence: 99%

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Zhao

et al. 2019

Preprint

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The ventral tegmental area (VTA), an important source of dopamine, regulates goal-and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTA Vgat ) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTA Vgat neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleepdeprived baseline, suggesting that the sleep homeostasis process was bypassed. The manialike behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect.The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTA Vgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTA Vgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTA Vgat neurons are centrally positioned to help set an animal's (and human's) level of mental and physical activity. Inputs that inhibit VTA Vgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival.Taken to the extreme, however, decreased or failed inhibition from VTA Vgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).

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Section: Introductionmentioning

confidence: 99%

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Zhao

et al. 2019

Preprint

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“…For this purpose, we performed DARPP‐32 and nNOS (neuronal nitric oxide synthase) immunohistochemistry in VTA (Figure B,C). nNOS is expressed in a subset of interneurons in the VTA . Interestingly, we found some colocalization of DARPP‐32 and nNOS in VTA as indicated by the white arrowheads (Figure C).…”

Section: Resultsmentioning

confidence: 65%

“…Remarkably, a study showed that neuronal nitric oxide synthase (nNOS) is also another marker of interneurons in VTA. nNOS was identified as a marker of VTA GABA interneurons that is not expressed in VTA DA neurons, and putatively expressed in glutamatergic projecting neurons, mostly in the rostral linear nucleus of the raphe (RLi) . Although, glutamatergic neurons represent only 2%‐3% of total VTA neurons .…”

Section: Discussionmentioning

confidence: 99%

Regulatory system of mGluR group II in the nucleus accumbens for methamphetamine‐induced dopamine increase by the medial prefrontal cortex

Haddar

Uno

Hamatani

et al. 2019

Neuropsychopharm Rep

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Aim We previously reported that methamphetamine (METH)‐induced conditioned place preference was attenuated by Shati/Nat8l overexpression in the medial prefrontal cortex (mPFC). Shati/Nat8l overexpression in the mPFC expressed lower levels of both glutamate and dopamine (DA) in the nucleus accumbens (NAc) and attenuated METH‐induced DA elevation. We suggested a mechanism in which a decline of glutamate levels in the NAc decreases extracellular DA levels. However, the hypothesis has not confirmed. Methods We conducted a recovery experiments by pre‐microinjection of an mGluR group II antagonist, LY341495, into the NAc shell of mPFC‐Shati/Nat8l‐overexpressed mice followed by METH injection and DA levels measurement by in vivo microdialysis. Results Pretreatment with LY341495 was able to restore METH‐induced DA increase. Furthermore, mice injected with an adeno‐associated virus vector containing GFP (AAV‐GFP vector) in the mPFC expressed a colocalization of GFP with DARPP‐32 a medium spiny neuron (MSN) marker. Next, co‐immunostaining of DARPP‐32 and neuronal nitric oxide synthase (nNOS: expressed in a subtype of gamma‐Aminobutyric acid (GABA interneurons) in ventral tegmental area (VTA) showed a colocalization of nNOS and DARPP‐32. Conclusion These results provided a proof that Shati/Nat8l attenuation of METH‐induced DA increase is mediated by mGluR group II in the NAc. Moreover, immunohistochemical study showed a direct connection of mPFC projection neurons with NAc MSN and a connection of MSN projection neurons with a subtype of GABA interneurons in VTA.

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“…Interestingly, cell‐type specific virus‐based anterograde tracing in mice has shown that PBP and SNc GABAergic neurons expressing nNOS do not make any detectable projection outside their residing area and thus appear to be interneurons (Paul et al, 2018). In contrast, the glutamatergic nNOS‐expressing neurons of the RLi have been shown to project to a number of regions, including the LHA, the ventral pallidum, and the median raphe nucleus (Paul et al, 2018). Interestingly, a study from 2019 showed that the chemogenic activation of the subset of glutamatergic neurons of the VTA expressing nNOS projecting to the LHA has wake‐promoting effects, while the activation of the GABAergic neurons of the VTA‐PBN expressing nNOS did not induce either sleep or wakefulness (X. Yu et al, 2019).…”

Section: Anatomical Distribution and Phenotypic Diversity Of Nos Neurmentioning

confidence: 99%

“…In the midbrain, while nNOS-expressing neurons in the PBP part of the VTA and the SNc appear to be GABAergic, nNOS neuron in the RLi of the VTA have been shown to be mostly glutamatergic (Paul et al, 2018;X. Yu et al, 2019).…”

Section: Phenotypic Heterogeneity Of Nnos Neuronsmentioning

confidence: 99%

Nitric oxide signalling in the brain and its control of bodily functions

Chachlaki

Prévot

2019

British J Pharmacology

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Funding information Agence Nationale de la Recherche, Grant/ Award Number: ANR-17-CE16-0015-01; Fédération Hospital-Universitaire "1000 days for health"; European Genomic Institute for Diabetes; LabEx DISTALZ Nitric oxide (NO) is a versatile molecule that plays key roles in the development and survival of mammalian species by endowing brain neuronal networks with the ability to make continual adjustments to function in response to moment-to-moment changes in physiological input. Here, we summarize the progress in the field and argue that NO-synthetizing neurons and NO signalling in the brain provide a core hub for integrating sensory-and homeostatic-related cues, control key bodily functions, and provide a potential target for new therapeutic opportunities against several neuroendocrine and behavioural abnormalities. 1 | INTRODUCTION Nitric oxide (NO), originally referred to as endothelium relaxing fac

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nNOS-expressing neurons in the ventral tegmental area and substantia nigra pars compacta

Abstract: 20GABA neurons in the ventral tegmental area (VTA) and substantia nigra pars compact (SNc) 21 play key roles in reward and aversion through their local inhibitory control of dopamine 22

Cited by 6 publications

References 65 publications

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

Regulatory system of mGluR group II in the nucleus accumbens for methamphetamine‐induced dopamine increase by the medial prefrontal cortex

Nitric oxide signalling in the brain and its control of bodily functions

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