Review
The Raphe Dopamine System: Roles in Salience Encoding, Memory Expression, and Addiction

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Highlights

  • Dopamine (DA) neurons of the dorsal raphe nucleus (DRN) have been classically viewed as a dorsal-caudal extension of the ventral tegmental area (VTA) DA population. Increasingly, however, the DRN DA population is seen as a distinct midbrain DA subpopulation that functions in parallel to the VTA DA subpopulations.

  • Emerging reports using mouse models have demonstrated that DRN DA neurons encode incentive salience and function in both incentive memory expression and sleep regulation.

  • DRN DA neurons and their upstream inputs also contribute to the neural substrate of opioid addiction.

  • Recent studies revealed considerable morphological and transcriptional heterogeneity among DRN DA neurons.

Dopamine (DA) neurons of the dorsal raphe nucleus (DRN) were traditionally viewed as an extension of the ventral tegmental area (VTA) DA population. While the VTA DA population is known to play important roles in reward processing, emerging evidence now supports the view that DRN DA neurons are a specialized midbrain DA subsystem that performs distinct functions in parallel to the VTA DA population. Recent studies have shed new light on the roles of DRN DA neurons in encoding incentive salience and in regulating memory expression and arousal. Here, we review recent findings using mouse models about the physiology and behavioral functions of DRN DA neurons, highlight the engagement of DRN DA neurons and their upstream circuits in opioid addiction, and discuss emerging lines of investigation that reveal multifaceted heterogeneity among DRN DA neurons.

Section snippets

A Specialized Dopamine (DA) Subsystem in the Dorsal Raphe Nucleus (DRN)

Numerous studies have emphasized the importance of midbrain DA neurons in reward processing, motor learning, and drug addiction [1., 2., 3., 4.]. Historically, midbrain DA neurons have been categorized into three major groups, namely the A8–10 cell groups, largely based on their anatomical distributions [5,6]. This concept has long been recognized as an oversimplification. Emerging evidence has revealed enormous heterogeneity in midbrain DA neurons at both the cellular and neural circuit

Physiological Responses of DRN DA Neurons

Superficially, DRN DA neurons share basic electrophysiological properties with VTA DA neurons [16]. In slice preparations, they tend to show low spontaneous firing rates and exhibit spike-frequency adaptation. Their action potentials are broad and are often accompanied by afterhyperpolarizations. Most of DRN DA neurons also have a hyperpolarization-activated inward current that is also a feature of VTA DA neurons. However, until recently the in vivo dynamics of DRN DA neurons have remained

Memory Expression

In light of their physiological responses underlying incentive salience, recent studies have unveiled the essential role of DRN DA neurons in incentive memory expression (Figure 2) [20]. The key evidence emerged from loss-of-function studies using two classic Pavlovian conditioning tests: the conditioned place preference (CPP) test and the fear conditioning test. In a high-fat food-induced CPP test, genetic ablation of DRN DA neurons decreases animal preference for the food-associated chamber.

Heterogeneity among DRN DA Neurons

Although there are only ~1200 DA neurons in the mouse DRN, they are not homogeneous. Early anatomical studies suggested two possible subpopulations within these neurons: a group of neurons with small and round cell body located close to the aqueduct, and a group of larger neurons located ventrally in the DRN [13,61]. Using immunohistochemistry, the neuropeptide vasoactive intestinal peptide (VIP) was found to be selectively expressed in small, periaqueductal DRN DA neurons but not in larger

Interactions between DRN DA Neurons and Other DRN Neuronal Types

Serotonin neurons are the major neuron type in the DRN; these neurons provide the main serotonin tone in the central nervous system. Previous studies have suggested complex crosstalk via local circuits between DRN serotonin neurons and other DRN neuron types, including DRN DA neurons. Similar to VTA DA neurons, DRN serotonin neurons respond primarily to rewards at the population level (recently reviewed elsewhere [64]). DRN serotonin neurons are phasically activated by natural rewards and

DRN DA Neuron Modulation of Downstream Brain Areas

Detailed circuit mechanisms underlying the behavioral functions of DRN DA neurons remain rather elusive. Ex vivo optogenetic stimulation of DRN DA neuron terminals in the CeA or the BNST triggers DA release [17,36]. In vivo fiber photometry recording with a genetically encoded DA sensor [71] revealed event-related DA release from DRN DA neuron terminals in the CeA and the BNST [20]. The DA levels in these two areas are transiently elevated in response to both the conditioned and unconditioned

Concluding Remarks and Future Perspectives

In summary, recent progress has established DRN DA neurons as a specialized midbrain DA system that encodes incentive salience and controls the expression of incentive memory. While these studies have greatly advanced our understanding of the physiology and behavioral functions of DRN DA neurons, many questions still remain (see Outstanding Questions). At the single-neuron level, it is unclear how individual DRN DA neurons process various stimuli. Spatial transcriptomics studies that integrate

Acknowledgments

We thank J.H. Snyder for manuscript editing. Work from the authors’ group is supported by China MOST (2015BAI08B02, 2015CB755602), NNSFC (91432114, 91632302), and the Beijing Municipal Government.

Declaration of Interests

The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

References (79)

  • C. Li

    Alcohol effects on synaptic transmission in periaqueductal gray dopamine neurons

    Alcohol

    (2013)
  • M. Ungless et al.

    S.16.02 Dopamine neuron subgroups in the dorsal raphe and ventral tegmental area exhibit distinct synaptic adaptations in response to social isolation and drugs of abuse

    Eur. Neuropsychopharmacol.

    (2014)
  • M. DenBleyker

    Activating μ-opioid receptors in the lateral parabrachial nucleus increases c-Fos expression in forebrain areas associated with caloric regulation, reward and cognition

    Neuroscience

    (2009)
  • J.A. Flores

    Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: critical role for D1 (not D2) dopamine receptors

    Pain

    (2004)
  • L. Léger

    Dopaminergic neurons expressing Fos during waking and paradoxical sleep in the rat

    J. Chem. Neuroanat.

    (2010)
  • S.K. Jha

    Sleep-related neurons in the central nucleus of the amygdala of rats and their modulation by the dorsal raphe nucleus

    Physiol. Behav.

    (2005)
  • E. Arrigoni

    To eat or to sleep: that is a lateral hypothalamic question

    Neuropharmacology

    (2019)
  • K.A. Porter-Stransky

    Noradrenergic transmission at alpha1-adrenergic receptors in the ventral periaqueductal gray modulates arousal

    Biol. Psychiatry

    (2019)
  • Z. Liu

    Dorsal raphe neurons signal reward through 5-HT and glutamate

    Neuron

    (2014)
  • V. Niederkofler

    Identification of serotonergic neuronal modules that affect aggressive behavior

    Cell Rep.

    (2016)
  • A.M. Stamatakis

    Amygdala and bed nucleus of the stria terminalis circuitry: implications for addiction-related behaviors

    Neuropharmacology

    (2014)
  • A.M. Graybiel

    The basal ganglia and adaptive motor control

    Science (New York, N.Y.)

    (1994)
  • W. Schultz

    A neural substrate of prediction and reward

    Science

    (1997)
  • C. Lüscher

    The emergence of a circuit model for addiction

    Annu. Rev. Neurosci.

    (2016)
  • W. Schultz

    Behavioral theories and the neurophysiology of reward

    Annu. Rev. Psychol.

    (2005)
  • A. Dahlstroem et al.

    Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons

    Acta Physiol. Scand. Suppl.

    (1964)
  • L. Descarries

    Dopaminergic projection from nucleus raphe dorsalis to neostriatum in the rat

    J. Comp. Neurol.

    (1986)
  • R.H. Hasue et al.

    Origin of the dopaminergic innervation of the central extended amygdala and accumbens shell: a combined retrograde tracing and immunohistochemical study in the rat

    J. Comp. Neurol.

    (2002)
  • K. Tiklová

    Single-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development

    Nat. Commun.

    (2019)
  • A.G. Dougalis

    Functional properties of dopamine neurons and co-expression of vasoactive intestinal polypeptide in the dorsal raphe nucleus and ventro-lateral periaqueductal grey: DRN/vlPAG dopamine neurons

    Eur. J. Neurosci.

    (2012)
  • J.R. Cho

    Dorsal raphe dopamine neurons modulate arousal and promote wakefulness by salient stimuli

    Neuron

    (2017)
  • F. Groessl

    Dorsal tegmental dopamine neurons gate associative learning of fear

    Nat. Neurosci.

    (2018)
  • R. Lin

    The raphe dopamine system controls the expression of incentive memory

    Neuron

    (2020)
  • J.R. Cho

    Dorsal raphe dopamine neurons signal motivational salience dependent on internal and external states

    bioRxiv

    (2020)
  • A. Eban-Rothschild

    VTA dopaminergic neurons regulate ethologically relevant sleep–wake behaviors

    Nat. Neurosci.

    (2016)
  • W. Zhong

    Learning and stress shape the reward response patterns of serotonin neurons

    J. Neurosci.

    (2017)
  • C.M. Teixeira

    Hippocampal 5-HT input regulates memory formation and Schaffer collateral excitation

    Neuron

    (2018)
  • A. Sengupta et al.

    A discrete dorsal raphe to basal amygdala 5-HT circuit calibrates aversive memory

    Neuron

    (2019)
  • S.E. Hyman

    Addiction: a disease of learning and memory

    Am. J. Psychiatry

    (2005)

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