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Phasic Activation of Dorsal Raphe Serotonergic Neurons Increases Pupil Size.

ABSTRACT: Transient variations in pupil size (PS) under constant luminance are coupled to rapid changes in arousal state,^1-3 which have been interpreted as vigilance,⁴ salience,⁵ or a surprise signal.^6-8 Neural control of such fluctuations presumably involves multiple brain regions⁵^,^9-11 and neuromodulatory systems,³^,¹²^,¹³ but it is often associated with phasic activity of the noradrenergic system.⁹^,¹²^,¹⁴^,¹⁵ Serotonin (5-HT), a neuromodulator also implicated in aspects of arousal¹⁶ such as sleep-wake transitions,¹⁷ motivational state regulation,¹⁸ and signaling of unexpected events,¹⁹ seems to affect PS,^20-24 but these effects have not been investigated in detail. Here we show that phasic 5-HT neuron stimulation causes transient PS changes. We used optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) of head-fixed mice performing a foraging task. 5-HT-driven modulations of PS were maintained throughout the photostimulation period and sustained for a few seconds after the end of stimulation. We found no evidence that the increase in PS with activation of 5-HT neurons resulted from interactions of photostimulation with behavioral variables, such as locomotion or licking. Furthermore, we observed that the effect of 5-HT on PS depended on the level of environmental uncertainty, consistent with the idea that 5-HT could report a surprise signal.¹⁹ These results advance our understanding of the neuromodulatory control of PS, revealing a tight relationship between phasic activation of 5-HT neurons and changes in PS.

SUBMITTER: Cazettes F

PROVIDER: S-EPMC7808753 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Phasic Activation of Dorsal Raphe Serotonergic Neurons Increases Pupil Size.

Cazettes Fanny F Reato Davide D Morais João P JP Renart Alfonso A Mainen Zachary F ZF

Current biology : CB 20201112 1

Transient variations in pupil size (PS) under constant luminance are coupled to rapid changes in arousal state,1-3 which have been interpreted as vigilance,4 salience,5 or a surprise signal.6-8 Neural control of such fluctuations presumably involves multiple brain regions5,9-11 and neuromodulatory systems,3,12,13 but it is often associated with phasic activity of th ...[more]

PMID: 33186549

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Project description:Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.

Dataset Information

Phasic Activation of Dorsal Raphe Serotonergic Neurons Increases Pupil Size.

Publications

Phasic Activation of Dorsal Raphe Serotonergic Neurons Increases Pupil Size.

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