Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal

Tabansky, Inna; Liang, Yupu; Frankfurt, Maya; Daniels, Martin A.; Harrigan, Matthew P.; Stern, Sarah A.; Milner, Teresa A.; Leshan, Rebecca L.; Rama, Rrezarta; Moll, Tabea; Friedman, Jeffrey M.; Stern, Joel N. H.; Pfaff, Donald W.

doi:10.1073/pnas.1806123115

Cited by 25 publications

(6 citation statements)

References 57 publications

(70 reference statements)

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“…LC is reported to receive inputs from up to 111 distinct brain regions, including most brain-stem and forebrain regions ( Schwarz et al, 2015 ; Breton-Provencher and Sur, 2019 ; Figure 1B ). Brainstem inputs, most notably from the gigantocellular reticular nucleus ( Jones and Yang, 1985 ) – which responds to tactile, visual, vestibular, and olfactory stimuli ( Tabansky et al, 2018 ) – result in LC activation following salient sensory stimuli. Meanwhile, top-down inputs from the prefrontal cortex (PFC) and central amygdala can modulate the intensity of LC activation ( Sara and Hervé-Minvielle, 1995 ; Jodo et al, 1998 ; McCall et al, 2015 ).…”

Section: Anatomy Of the Ne Systemmentioning

confidence: 99%

Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets

Breton-Provencher

Drummond

Sur

2021

Front. Neural Circuits

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The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. The LC receives input from widespread brain regions, and projects throughout the forebrain, brainstem, cerebellum, and spinal cord. LC neurons release NE to control arousal, but also in the context of a variety of sensory-motor and behavioral functions. Despite its brain-wide effects, much about the role of LC-NE in behavior and the circuits controlling LC activity is unknown. New evidence suggests that the modular input-output organization of the LC could enable transient, task-specific modulation of distinct brain regions. Future work must further assess whether this spatial modularity coincides with functional differences in LC-NE subpopulations acting at specific times, and how such spatiotemporal specificity might influence learned behaviors. Here, we summarize the state of the field and present new ideas on the role of LC-NE in learned behaviors.

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Section: Anatomy Of the Ne Systemmentioning

confidence: 99%

Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets

Breton-Provencher

Drummond

Sur

2021

Front. Neural Circuits

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“…Consistent with our results, the restitution of BDNF/TrkB signaling after a stroke enhanced neuroprotection in the cerebral cortex 58 . Moreover, further recent studies have confirmed the functional implications of eNOS expression in neurons 59 . We focused on NF-κB, a known target of NO and also implicated in both neuroprotective and neurotoxic effects.…”

Section: Discussionmentioning

confidence: 73%

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Caviedes¹,

Maturana²,

Corvalán³

et al. 2021

Cell Death Dis

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Cell death by glutamate excitotoxicity, mediated by N-methyl-d-aspartate (NMDA) receptors, negatively impacts brain function, including but not limited to hippocampal neurons. The NF-κB transcription factor (composed mainly of p65/p50 subunits) contributes to neuronal death in excitotoxicity, while its inhibition should improve cell survival. Using the biotin switch method, subcellular fractionation, immunofluorescence, and luciferase reporter assays, we found that NMDA-stimulated NF-κB activity selectively in hippocampal neurons, while endothelial nitric oxide synthase (eNOS), an enzyme expressed in neurons, is involved in the S-nitrosylation of p65 and consequent NF-κB inhibition in cerebrocortical, i.e., resistant neurons. The S-nitro proteomes of cortical and hippocampal neurons revealed that different biological processes are regulated by S-nitrosylation in susceptible and resistant neurons, bringing to light that protein S-nitrosylation is a ubiquitous post-translational modification, able to influence a variety of biological processes including the homeostatic inhibition of the NF-κB transcriptional activity in cortical neurons exposed to NMDA receptor overstimulation.

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“…Consistent with our results, the restitution of BDNF/TrkB signaling after a stroke enhanced neuroprotection in the cerebral cortex 53 . Moreover, further recent studies have confirmed functional implications of eNOS expression in neurons 54 . We focused on NF-κB, a known target of NO and also implicated in both neuroprotective and neurotoxic effects.…”

Section: Discussionmentioning

confidence: 73%

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Caviedes

Maturana

Corvalán

et al. 2020

Preprint

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Cell death by glutamate excitotoxicity, mediated by N-methyl-D-aspartate (NMDA) receptors, negatively impacts brain function affecting hippocampal, i.e. sensitive neurons. The NF-κB transcription factor (composed mainly of p65/p50 subunits) contributes to neuronal death in excitotoxicity, while its inhibition should improve cell survival. Using the biotin switch method, subcellular fractionation, immunofluorescence and luciferase reporter assays, we found that NMDA stimulated NF-κB activity selectively in hippocampal neurons, while endothelial nitric oxide (eNOS), an enzyme expressed in neurons, is involved in the S-nitrosylation of p65 and consequent NF-κB inhibition in cerebrocortical, i.e. resistant neurons. The S-nitro proteomes of cortical and hippocampal neurons revealed that different biological processes are regulated by S-nitrosylation in susceptible and resistant neurons, bringing to light that protein S-nitrosylation is a ubiquitous posttranslational modification, able to influence a variety of biological processes including the homeostatic inhibition of the NF-κB transcriptional activity in cortical neurons exposed to excitotoxicity. Introduction.Neuronal death by glutamate excitotoxicity is implicated in the pathogenesis of several neurological disorders, ranging from neurodegeneration to epilepsy, stroke and traumatic brain injury (37, 52). The overstimulation of glutamate receptors leads to massive calcium influx, mainly through N-methyl-D-aspartate receptors (NMDA-Rs), triggering several intracellular pro-death signaling pathways (54). Endogenous/homeostatic protective mechanisms in response to glutamate, are incompletely known. In that line, the nuclear factor kappa B (NF-κB) family of transcription factors has been implicated in excitotoxicity in the retina, the striatum, cerebral cortex and hippocampus (29,44,53). This is associated with induction of pro-apoptotic and pro-inflammatory genes, including IL-1β. The canonic activation of the ubiquitous transcription factor NF-κB depends on phosphorylation and degradation of IκB proteins, leading to release and nuclear translocation of NF-κB, a dimer composed most frequently by a p65 and a p50 subunit (10,22). Its transcriptional activity in the nucleus is regulated by several post-translational modifications, such as phosphorylation and S-nitrosylation (i.e. the reversible coupling of nitric oxide (NO) to cysteine residues). In particular, S-nitrosylation of the p65 cysteine 38 inhibits its transcriptional activity in diverse cell types (24,41,46). However, the contribution of this mechanism to excitotoxicity is unknown and might imply a homeostatic regulation of the NF-κB activity. The main source of NO in the brain are nitric oxide synthases, i.e. the neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) enzymes (5,9,15). Considering the novel finding that eNOS is present in neuronal cultures and in glutamatergic synapses (6), we examined whether eNOS is involved in p65 S-nitrosylation and thus, in the regulation of its transcriptional activit...

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Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal

Cited by 25 publications

References 57 publications

Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets

Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

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