Hyperactivity of a midbrain dopamine to 5-HT circuit causes anorexia.

Anorexia nervosa (AN) is a severe eating disorder that can eventually lead to death, but effective therapies are missing due to a lack of knowledge about its pathophysiology. Dopamine (DA) neurons in the ventral tegmental area (VTA) and serotonin (5-HT) neurons in the dorsal Raphe nucleus (DRN) play essential roles in the control of eating and have been reported to be associated with human AN (Zhou and Palmiter, 1995; Xu et al., 2017; Watson et al., 2019; He et al., 2021). However, this association has not been validated in animal models. In addition, how DA and 5-HT neurons interact with each other to contribute to the pathology of AN remains to be elucidated.

In our recent publication (Cai et al., 2022), we demonstrated that DAVTA neurons regulate the activity of 5-HTDRN neurons in a strength-dependent manner. DA receptors D1 (DRD1) and D2 (DRD2) are co-expressed in a sub-population of 5-HTDRN neurons. DRD1 is a Gαs-coupled excitatory receptor that can be activated by high levels of DA (Kern et al., 2015). On the other hand, DRD2 is a Gαi-coupled inhibitory receptor that has high affinity to DA when its concentration is low (Richfield et al., 1989). These opposite features of the two DA receptors permit bi-directional regulation of 5-HT neurons by DA. Indeed, while low-frequency (2 Hz) tonic firing of DAVTA neurons inhibits 5-HTDRN neurons via DRD2 and promotes feeding, high-frequency (20 Hz) phasic bursting of DAVTA neurons activates 5-HTDRN neurons via DRD1 and suppresses feeding.

We further revealed that hyperactivity of the DAVTA to 5-HTDRN circuit underlies the AN-like behaviors through a widely used rodent model for AN, activity-based anorexia (ABA), a paradigm comprised of unlimited access to a running wheel and restricted feeding (Figure 1). In this ABA model that resembles human AN, the DA and 5-HT neuronal activities were constantly elevated. Deletion of Drd2 in the DRN resulted in no significant changes in feeding and physical activity when mice were suffering from ABA. By contrast, inhibition of the DAVTA to 5-HTDRN circuit or blocking the function of DRD1 in the DRN could partially rescue the AN phenotypes. Therefore, our findings shed light on developing therapeutic strategies against AN by targeting DRD1.

Figure 1

Low-frequency tonic firing of DAVTA neurons inhibits 5-HTDRN neurons via DRD2-mediated neurotransmission in normal control mice to promote feeding, whereas high-frequency phasic bursting of DAVTA neurons activates 5-HTDRN neurons via DRD1-dependent mechanisms to suppress feeding behavior in the ABA mouse model.

Despite the breakthrough discovery on the DAVTA to 5-HTDRN neural circuit in mediating the AN-like behaviors, there remain some challenges. For example, 5-HTDRN neurons also receive local gamma-aminobutyric acid (GABA) inputs from the DRN. Whether and how these GABADRN neurons participate in the development of AN requires exploration. Additionally, women are more prone to AN, but whether there is a sex-dependent effect of the DAVTA to 5-HTDRN circuit on feeding regulation remains unclear. Moreover, 5-HT system has emerged as a promising target for a number of metabolic and psychiatric diseases, including obesity, anxiety, and depression (Daut and Fonken, 2019; van Galen et al., 2021). Given that a subset of DAVTA neurons can project to and bi-directionally modulate the activity of 5-HTDRN neurons, it would be of interest to test whether such behaviors can also be bi-directionally controlled by the DAVTA to 5-HTDRN circuit in a strength-dependent manner.

[The investigators were supported by grants from the Unite States Department of Agriculture (51000-064-01S to Y.X.).]