Sleep and Serotonin Modulate Paracapsular Nitric Oxide Synthase Expressing Neurons of the Amygdala

Bocchio, Marco; Fisher, Simon P.; Ünal, Güneş; Ellender, Tommas J.; Vyazovskiy, Vladyslav V.; Capogna, Marco

doi:10.1523/eneuro.0177-16.2016

Cited by 13 publications

(11 citation statements)

References 85 publications

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“…Here, the 5-HT 1A -mediated responses showed desensitization within tens of seconds. Therefore, bath application could fail to detect these slow IPSCs, although bath-applied 5-HT 1A -mediated effects have been reported in other amygdala regions ( Bocchio et al, 2016a ).…”

Section: Discussionmentioning

confidence: 99%

Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission

et al. 2017

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The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Therefore, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1 Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed that this effect was mediated by glutamate and not 5-HT because it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10–20 Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT because they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often coexisted in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons, but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell-type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output.SIGNIFICANCE STATEMENT The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders. Therefore, it is essential to determine the physiological mechanisms through which 5-HT neurons in the dorsal raphe nuclei modulate amygdala circuits. Here, we combined optogenetic, electrophysiological, and pharmacological approaches to study the effects of activation of 5-HT axons in the basal nucleus of the amygdala (BA). We found that 5-HT neurons co-release 5-HT and glutamate onto BA neurons in a cell-type-specific and frequency-dependent manner. Therefore, we suggest that theories on the contribution of 5-HT neurons to amygdala function should be revised to incorporate the concept of 5-HT/glutamate cotransmission.

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Section: Discussionmentioning

confidence: 99%

Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission

et al. 2017

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“…nNOS cells receive serotonergic innervation (Cauli et al, 2004), and serotonin concentration is elevated in the cerebral cortex during wake relative to SWS (Portas et al, 1998; Bjorvatn et al, 2002). Bath application of serotonin hyperpolarizes via 5-HT1A receptors nNOS neurons located along the external capsule of the amygdala (Bocchio et al, 2016). Because the neurochemical profile of these neurons is similar to cortical nNOS neurons (Wang et al, 2017), it is possible that type I nNOS neurons in the cerebral cortex are also inhibited by serotonin.…”

Section: Discussionmentioning

confidence: 99%

Sleep State Dependence of Optogenetically evoked Responses in Neuronal Nitric Oxide Synthase-positive Cells of the Cerebral Cortex

et al. 2018

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Slow-wave activity (SWA) in the electroencephalogram during slow-wave sleep (SWS) varies as a function of sleep-wake history. A putative sleep-active population of neuronal nitric oxide synthase (nNOS)-containing interneurons in the cerebral cortex, defined as such by the expression of Fos in animals euthanized after protracted deep sleep, may be a local regulator of SWA. We investigated whether electrophysiological responses to activation of these cells are consistent with their role of a local regulator of SWA. Using a Cre/loxP strategy, we targeted the population of nNOS interneurons to express the light-activated cation channel Channelrhodopsin2 and the histological marker tdTomato in mice. We then performed histochemical and optogenetic studies in these transgenic mice. Our studies provided histochemical evidence of transgene expression and electrophysiological evidence that the cerebral cortex was responsive to optogenetic manipulation of these cells in both anesthetized and behaving mice. Optogenetic stimulation of the cerebral cortex of animals expressing Channelrhodopsin2 in nNOS interneurons triggered an acute positive deflection of the local field potential that was followed by protracted oscillatory events only during quiet wake and slow wave sleep. The response during wake was maximal when the electroencephalogram (EEG) was in a negative polarization state and abolished when the EEG was in a positive polarization state. Since the polarization state of the EEG is a manifestation of slow-wave oscillations in the activity of underlying pyramidal neurons between the depolarized (LFP negative) and hyperpolarized (LFP positive) states, these data indicate that sleep-active cortical neurons expressing nNOS function in sleep slow-wave physiology.

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“…The NO/nNOS production in the basal hypothalamus further leads to the rapid eye movement sleep rebound that happens after a sleep deprivation . Sleep regulates paracapsular NOS expressing neurons of the amygdala . Then, high concentrations of ADMA and elevated DDAH‐1 expression are investigated in the brain and spinal cord .…”

Section: Discussionmentioning

confidence: 99%

Procyanidin B2 from lotus seedpod regulate NO/ADMA/DDAH pathway to treat insomnia in rats

Wang

Liang

et al. 2019

Fundamemntal Clinical Pharma

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Recent studies show that nitric oxide/asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase (NO/ADMA/DDAH) pathway may contribute to the development of sleep disorder. The objective of this study was to explore the inhibitory effect of procyanidin B2 from lotus seedpod (LSPC), a naturally occurring catechin compound, on insomnia and the mechanisms involved. The experiments were performed in brain from Sprague‐Dawley rat control and insomniac rats treated or not with LSPC (15, 30, and 45 mg/kg, intragastrically) for 7 days. LSPC treatment reduced walking time and forelimb lifting‐up frequency, cerebral levels of noradrenaline, glutamic acid, ADMA, sleep latency, and 8‐isoprostane; increased sleep duration, cerebral concentrations of 5‐hydroxytryptamine, γ‐aminobutyric acid, and NO concomitantly with upregulated cerebral expression of DDAH 1, DDAH2, and neuronal NO synthases in insomniac rats. The present results suggest that LSPC may regulate NO/ADMA/DDAH pathway by inhibiting oxidative stress to treat insomnia in rats when sleep evaluation was achieved on the basis of behavioral criteria.

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Sleep and Serotonin Modulate Paracapsular Nitric Oxide Synthase Expressing Neurons of the Amygdala

Cited by 13 publications

References 85 publications

Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission

Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission

Sleep State Dependence of Optogenetically evoked Responses in Neuronal Nitric Oxide Synthase-positive Cells of the Cerebral Cortex

Procyanidin B2 from lotus seedpod regulate NO/ADMA/DDAH pathway to treat insomnia in rats

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