Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors

Paquelet, Grace E.; Carrion, Kassandra; Lacefield, Clay; Zhou, Pengcheng; Hen, René; Miller, Bradley R.

doi:10.1016/j.neuron.2022.05.015

Cited by 70 publications

(51 citation statements)

References 62 publications

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“…Crucially, for both sexes the degree of BNST5HT2c neuronal activation in response to the first interaction with a novel juvenile social target was greater than that of any other stimulus tested, suggesting that this may be reflective of a salience-driven signal, as opposed to a valence-driven signal. This is consistent with a recent report illustrating that a large proportion of individual DRN-BNST neurons respond to a variety of valenced stimuli, including social stimuli, electric shock, and contextual threat (Paquelet et al, 2022). Only in our voluntary alcohol consumption fiber photometry experiments did we observe a notable divergence between patterns of 5-HT release onto LHb5HT2c and BNST5HT2c neurons and patterns of calcium activity in these neurons.…”

Section: Discussionsupporting

confidence: 93%

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT_2creceptor-containing neurons

Flanigan

Hon

D’Ambrosio

et al. 2022

Preprint

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Serotonin 5HT2c receptors have been implicated in the pathophysiology of both mood disorders and substance use disorders, but the precise cells and circuits mediating the effects on behavior have yet to be identified. In this study, we employed anatomical tracing, in-vivo fiber photometry with both calcium and serotonin sensors, electrophysiology, chemogenetics, and genetic manipulations of the 5HT2c receptor to identify two populations of neurons expressing serotonin 5HT2c receptors, one in the lateral habenula and one in the bed nucleus of the stria terminalis, that sex-specifically co-regulate affective behaviors and are modulated by binge alcohol consumption. These findings may have implications for the development of sex-specific treatments for mood disorders and substance use disorders targeting the brain serotonin systems.

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Section: Discussionsupporting

confidence: 93%

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT_2creceptor-containing neurons

Flanigan

Hon

D’Ambrosio

et al. 2022

Preprint

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“…Recent work has indicated that there are multiple, largely non-overlapping submodules or cellular subgroups within DRN with distinct connectivity and functional rules (Ren et al, 2018; Huang et al, 2019; Paquelet et al, 2022), leading us to ask whether recurrent connections and their particular dynamics could gate interaction between functionally separate submodules or cellular assemblies. We modelled the canonical scenario of reward anticipation, where 5-HT neurons have been shown to display a ramping up of their activity from the time of cue to reward delivery (Zhong et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Nonlinear computation by a habenula-driven recurrent inhibitory network in the raphe

Lynn

Geddes

Chahrour

et al. 2022

Preprint

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Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) receive a diverse constellation of long-range synaptic inputs, yet unifying principles of local circuitry and its dynamics are largely unknown - a crucial component of understanding how 5-HT output controls behavior. Here, we developed a formalism bridging optogenetic, electrophysiological, computational and behavioral strategies to reveal how the dynamics of local circuitry in DRN control the expression of reward associations. Using long-range input from lateral habenula (LHb) to interrogate functional DRN circuitry, we uncover 5-HT1A receptor-mediated local recurrent connections between 5-HT neurons, refuting classical theories of autoinhibition by 5-HT1A receptors. These inhibitory 5-HT connections were slow, stochastic, strongly facilitating, and gated spike output of 5-HT neurons. Targeted physiology and modeling approaches revealed that these functional connectivity features collectively support the emergence of a paradoxical excitation-driven inhibition in response to high frequency LHb activation, and of a winner-take-all computation over protracted timescales. In vivo, we found that optogenetic activation of LHb inputs to DRN transiently disrupted expression of a reward-conditioned response in an auditory conditioning task. In accordance with quantitative model predictions, this disruption occurred exclusively at the conjunction of high frequency LHb activation and high predicted reward value, and was not due to a modulation of the underlying reward association. Thus, we propose that recurrent dynamics in the DRN support a contextual value computation, where stable learned associations are integrated with dynamic environmental inputs to support sharp behavioral state transitions in changing environments.

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“…Fiber photometry recordings of serotonergic neurons in the DR, when studied as one population, display also biphasic responses to footshock, however, these response properties were thought to originate from anatomically distinct subpopulations 29 . Recent miniscope imaging with single cell resolution, has now impressively shown, that different response types (activation or inhibition) to emotional stimuli, such as reward or footshock, are even present in anatomically defined projections 30 . This heterogeneity could be one explanation to our observed biphasic response in the PFC.…”

Section: Discussionmentioning

confidence: 99%

Next generation genetically encoded fluorescent sensors for serotonin

et al. 2022

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We developed a family of genetically encoded serotonin (5-HT) sensors (sDarken) on the basis of the native 5-HT1A receptor and circularly permuted GFP. sDarken 5-HT sensors are bright in the unbound state and diminish their fluorescence upon binding of 5-HT. Sensor variants with different affinities for serotonin were engineered to increase the versatility in imaging of serotonin dynamics. Experiments in vitro and in vivo showed the feasibility of imaging serotonin dynamics with high temporal and spatial resolution. As demonstrated here, the designed sensors show excellent membrane expression, have high specificity and a superior signal-to-noise ratio, detect the endogenous release of serotonin and are suitable for two-photon in vivo imaging.

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Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors

Cited by 70 publications

References 62 publications

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT_2creceptor-containing neurons

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT_2creceptor-containing neurons

Nonlinear computation by a habenula-driven recurrent inhibitory network in the raphe

Next generation genetically encoded fluorescent sensors for serotonin

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Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors

Cited by 70 publications

References 62 publications

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT2creceptor-containing neurons

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT2creceptor-containing neurons

Nonlinear computation by a habenula-driven recurrent inhibitory network in the raphe

Next generation genetically encoded fluorescent sensors for serotonin

Contact Info

Product

Resources

About

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT_2creceptor-containing neurons

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT_2creceptor-containing neurons