Functional Diversity of Serotonin Neurons in the Dorsal and Median Raphe Nuclei in Emotional Responses

Abstract

Of serotonergic nuclei in the central nervous system, mainly the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) project to the forebrain and midbrain; therefore, these nuclei are involved in emotional/cognitive functions and psychiatric disorders. Researchers have often generalized findings from the DRN to represent the functions of the entire serotonergic system, primarily due to the fact that the DRN is the largest serotonergic nucleus and due to the assumption that the serotonergic system operates as a single, cohesive unit. However, recent evidence is challenging this perspective and necessitating a reevaluation. In this brief review, we summarize recent studies demonstrating the functional diversity of the DRN alongside the functional unity of the MRN. These findings suggest that different subpopulations within the serotonergic system may exert opposing effects on emotional functions. Furthermore, this diversity-aware approach will help settle ongoing debates regarding the serotonin hypothesis of depression, which stems from the difficulty in the application of this approach in humans. We advocate for increased efforts to identify factors associated with these functional subgroups, which could lead to more targeted and effective interventions.

Keywords: 5‐HT; antidepressants; midbrain raphe.

FIGURE 1

Sagittal and coronal views of the central serotonergic system in mice. (A) Schematic drawing of the sagittal view of the central serotonergic system. We described the patterns of serotonergic projections based on Jacobs and Azmitia [3] and Muzerelle et al. [4]. (B–D) Representative examples of coronal sections containing serotonin neurons. Green colors indicate TPH2 (a marker of serotonin neurons) staining. The immunohistochemistry procedure was described in Kawai et al. [5]. Aq, Aqueduct. White bar = 200 μm.

FIGURE 2

Present and future views of functional roles and classifications of central serotonergic systems. (A) Present view indicates that the functions of the DRN subpopulations and MRN are sometimes opposite to each other. However, it remains unknown whether the DRN and MRN directly regulate each other's activities. CeA: Central nucleus of the amygdala, BNST: Bed nucleus of stria terminalis, OFC: Orbitofrontal cortex. (B) In future studies, we need to consider several other viewpoints to classify the subpopulations. We described the patterns of input based on Ogawa et al. [22] and Pollak Dorocic et al. [23]. However, it does not mean these inputs are mutually exclusive. LH: Lateral hypothalamus, IPN: Interpeduncular nucleus. Modified schematic is from the mouse brain atlas [28].