Dorsal Raphe Dopamine Neurons Signal Motivational Salience Dependent on Internal State, Expectation, and Behavioral Context

Abstract

The ability to recognize motivationally salient events and adaptively respond to them is critical for survival. Here we tested whether dopamine (DA) neurons in the dorsal raphe nucleus (DRN) contribute to this process in both male and female mice. Population recordings of DRN DA neurons during associative learning tasks showed that their activity dynamically tracks the motivational salience, developing excitation to both reward-and shock-paired cues. The DRN DA response to reward-predicting cues was diminished after satiety, suggesting modulation by internal states. DRN DA activity was also greater for unexpected outcomes than for expected outcomes. Two-photon imaging of DRN DA neurons demonstrated that the majority of individual neurons developed activation to reward-predicting cues and reward but not to shock-predicting cues, which was surprising and qualitatively distinct from the population results. Performing the same fear learning procedures in freely-moving and head-fixed groups revealed that headfixation itself abolished the neural response to aversive cues, indicating its modulation by behavioral context. Overall, these results suggest that DRN DA neurons encode motivational salience, dependent on internal and external factors. Significance statement Dopamine (DA) contributes to motivational control, composed of at least two functional cell typesone signaling for motivational value and another for motivational salience. Here we demonstrate that DA neurons in the dorsal raphe nucleus (DRN) encode the motivational salience in associative learning tasks. Neural responses were dynamic and modulated by the animal's internal state. The majority of single-cells developed responses to reward or paired cues, but not to shock-predicting cues. Further experiments with freely-moving and head-fixed mice showed that head-fixation abolished the development of cue responses during fear learning. This work provides further characterization on the functional roles of overlooked DRN DA populations and an example that neural responses can be altered by head-fixation, which is commonly used in neuroscience.

Aversive motivation and cognitive control

“…Recent evidence from the animal literature suggests that the dorsal raphé nucleus (DRN) may play a central role in modulating mutual inhibition between rewarding and aversive processes (Hayashi et al, 2015;Li et al, 2016;Nakamura, 2013;Nakamura et al, 2008). The DRN contains high concentrations of serotonin neurons (Huang et al, 2019;Kirby et al, 2003;Marinelli et al, 2004;Michelsen et al, 2008) as well as dopamine neurons (Cho et al, 2021;Lin et al, 2021;Matthews et al, 2016;Stratford & Wirtshafter, 1990;Yoshimoto & McBride, 1992). Some have shown that serotonergic DRN neurons play a key modulatory role in reward processing (Browne et al, 2019;Liu et al, 2020;Luo et al, 2015;Nagai et al, 2020;Ren et al, 2018), while dopaminergic DRN neurons appear to encode the motivational salience of incentives (Cho et al, 2021).…”

“…The DRN contains high concentrations of serotonin neurons (Huang et al, 2019;Kirby et al, 2003;Marinelli et al, 2004;Michelsen et al, 2008) as well as dopamine neurons (Cho et al, 2021;Lin et al, 2021;Matthews et al, 2016;Stratford & Wirtshafter, 1990;Yoshimoto & McBride, 1992). Some have shown that serotonergic DRN neurons play a key modulatory role in reward processing (Browne et al, 2019;Liu et al, 2020;Luo et al, 2015;Nagai et al, 2020;Ren et al, 2018), while dopaminergic DRN neurons appear to encode the motivational salience of incentives (Cho et al, 2021). Additionally, serotonergic DRN neurons project to the dopamine-rich ventral tegmental area (VTA) (Chang et al, 2021;Gervais & Rouillard, 2000), revealing its potentially crucial role in providing a more comprehensive understanding of mutual inhibition between DA and 5-HT.…”

Spatiotemporal Control of Noradrenaline-Dependent Synaptic Transmission in Mouse Dorsal Raphe Serotonin Neurons

“…The dorsal raphe nucleus contains a remarkably diverse array of serotonin and non-serotonin neurons, including GABA, glutamate, dopamine, and peptide neurons (Huang et al, 2019). Each class of neurons influences distinct behaviors, largely through nonredundant or reciprocal changes in firing rates in response to rewarding, aversive, or salient stimuli (Liu et al, 2014;Cohen et al, 2015;Li et al, 2016;Matthews et al, 2016;Cho et al, 2017Cho et al, , 2021Nectow et al, 2017;Seo et al, 2019;Gazea et al, 2021;Yu et al, 2021). Differences in noradrenaline a1-A R -dependent signaling across the types of dorsal raphe neurons have received little attention, whether at the level of individual synapses or neural circuits and behavior.…”

Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala

“…Recently, many studies have investigated the functional importance of DA DR-PAG neurons in various behaviors and emotional states; pain sensation ( Li et al, 2016 ; Yu et al, 2021 ), social interactions ( Matthews et al, 2016 ), fear learning ( Groessl et al, 2018 ), responding to salient stimuli ( Cho et al, 2017 , 2021 ), and reward incentives ( Lin et al, 2020 , 2021 ). To study these functions, TH-Cre mice ( Savitt et al, 2005 ) or DAT-Cre mice ( Bäckman et al, 2006 ) were used to selectively manipulate DA neurons.…”

“…Recently, the functional importance of dopaminergic (DA) neurons on affective behaviors in the DR and ventral periaqueductal gray (PAG) regions has been reported in multiple studies in mice. DA neurons in the DR-PAG region (DA DR-PAG ) influence pain sensation ( Li et al, 2016 ; Yu et al, 2021 ), modulate social interactions ( Matthews et al, 2016 ), accelerate fear learning ( Groessl et al, 2018 ), respond to salient stimuli ( Cho et al, 2017 , 2021 ), and control memory related to reward incentives ( Lin et al, 2020 , 2021 ). These studies pointed to the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA), which are known to play significant roles in affective behaviors, as downstream targets of DA DR-PAG neurons.…”