Dopamine and serotonin production are regulated by the system of the brain.

“We would like provisionally to name it serotonin, which indicates that its source is serum and its activity is one of causing constriction” (Rapport et al., 1948). Serotonin (5-hydroxytryptamine, 5-HT), first named after the study of Rapport et al. in 1948, is now a classic and perhaps one of the most described neuromodulators. The functions of this crystalline substance go well beyond the vasoconstriction effect described in 1948. Indeed, although secreted to a minor extent in the brain compared to the massive amount found in the gastrointestinal tract (Bertrand and Bertrand, 2010), 5-HT has a major role in neuronal function.

Primarily found in the raphe nuclei (RN), subdivided into the Dorsal Raphe Nucleus (DRN) and Median Raphe Nucleus (MRN), 5-HT neurons compose 30–50 % of these nuclei (Belin et al., 1983; Descarries et al., 1982; Huang et al., 2019). The function of this monoaminergic system starts early in development and 5-HT has been shown to have a key role in neural development (Khozhai and Otellin, 2012; Lavdas et al., 1997; Shah et al., 2018; Vichier-Guerre et al., 2017). In addition, the massive distribution of 5-HT fibers to practically all parts of the brain combined with the diversity of receptors (over 14 subtypes) explain the involvement of 5-HT in a long list of physiological and behavioral functions (Berger et al., 2009; Linley et al., 2013, 2017; Rodriguez et al., 2011; Vasudeva et al., 2011; Vertes, 1991; Vertes et al., 2010; Zhou and Azmitia, 1986) including respiration, reproduction, cardiovascular regulation, sleep-wake cycle, locomotion, emotion, learning, and memory (Charnay and Leger, 2010; Gervasoni et al., 2000; Jacobs and Fornal, 1993; King et al., 2008; Lucki, 1998; Teixeira et al., 2018; Teran et al., 2014; Urbain et al., 2006).

Among all the roles of the 5-HT system, one that is still being dissected is its role in reward (For review: (Hayes and Greenshaw, 2011; Hu, 2016; Kranz et al., 2010; Luo et al., 2015)). In animals, it was notably shown that electrical stimulation of the RN can be reinforcing (Miliaressis, 1977; Miliaressis et al., 1975; Van Der Kooy et al., 1978). In humans, using fMRI, the DRN is activated during a reward-related task (Tanaka et al., 2004).

The RN has strong connections to brain areas involved in reward processing including the nucleus accumbens (NAc), the amygdala, the medial prefrontal cortex and the olfactory tubercle (Beart and McDonald, 1982; Berridge and Kringelbach, 2008; Brown and Molliver, 2000; Macoveanu, 2014; Moore et al., 1978; Paton et al., 2006; Steinbusch et al., 1981; Vertes, 1991). But the most important interconnection linking the serotonergic system with reward function is the one with the dopaminergic system, dopamine (DA) being the well-recognized neurotransmitter involved in reward processing (Schultz, 1997; Schultz et al., 1997; Wise, 1996). The RN project massively to the ventral tegmental area (VTA) and to the substantia nigra (Herve et al., 1987; Miller et al., 1975; Vertes, 1991; Watabe-Uchida et al., 2012). The RN also receive, although to a lesser extent, projections back from the dopaminergic system (Kalen et al., 1988) (Ogawa et al., 2014; Vertes and Linley, 2008). Different views have emerged on the respective role of DA and 5-HT in reward functions either opposing them or making them allies (Boureau and Dayan, 2011; Cools et al., 2011; Daw et al., 2002). The complexity of this relationship notably lies in the fact that there is a heterogeneous expression of 5 H T receptors in the VTA on both DA and non-DA neurons (De Deurwaerdere and Di Giovanni, 2017). The heterogeneous expression of receptors also holds true in other structures involved in reward processing (Hayes and Greenshaw, 2011). That may explain why manipulation of 5-HT levels has complex effects on reward processing. For example, in humans, there is a disparity in the effects of acute tryptophan depletion on reward-related processes and on the activation of reward-related brain areas (Cools et al., 2005, 2008; Faulkner and Deakin, 2014; Finger et al., 2007; Macoveanu, 2014; Rogers et al., 2003; Tanaka et al., 2007).

To clearly decipher the role of the serotonergic system in reward and on the dopaminergic system, there is a need to target specific circuits. This can notably be achieved through the use of recent tools including opto- and chemo-genetics allowing to specifically tag different neuronal subsets. In this review, we will first describe the evidence linking 5-HT to reward, discuss the conflicting evidence emerging on the effects of the serotonergic system over the dopaminergic system and then focus on recent studies specifically tagging the RN to VTA pathway in the context of reward.

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  Rostral zona incerta (ZIR) evokes feeding by sending GABA transmission to paraventricular thalamus (PVT). Although central serotonin (5-HT) signaling is known to play critical roles in the regulation of food intake and eating disorders, it remains unknown whether raphe 5-HT neurons functionally innervate ZIR-PVT neural pathway for feeding control. Here, we sought to reveal how raphe 5-HT signaling regulates both ZIR and PVT for feeding control.

  We used retrograde neural tracers to map 5-HT projections in Sert-Cre mice and slice electrophysiology to examine the mechanism by which 5-HT modulates ZIR GABA neurons. We also used optogenetics to test the effects of raphe-ZIR and raphe-PVT 5-HT projections on feeding motivation and food intake in mice regularly fed, 24 h fasted, and with intermittent high-fat high-sugar (HFHS) diet. In addition, we applied RNAscope in situ hybridization to identify 5-HT receptor subtype mRNA in ZIR.

  We show raphe 5-HT neurons sent projections to both ZIR and PVT with partial collateral axons. Photostimulation of 5-HT projections inhibited ZIR but excited PVT neurons to decrease motivated food consumption. However, both acute food deprivation and intermittent HFHS diet downregulated 5-HT inhibition on ZIR GABA neurons, abolishing the inhibitory regulation of raphe-ZIR 5-HT projections on feeding motivation and food intake. Furthermore, we found high-level 5-HT1a and 5-HT2c as well as low-level 5-HT7 mRNA expression in ZIR. Intermittent HFHS diet increased 5-HT7 but not 5-HT1a or 5-HT2c mRNA levels in the ZIR.

  Our results reveal that raphe-ZIR 5-HT projections dynamically regulate ZIR GABA neurons for feeding control, supporting that a dynamic fluctuation of ZIR 5-HT inhibition authorizes daily food intake but a sustained change of ZIR 5-HT signaling leads to overeating induced by HFHS diet.

• Treatment-resistant depression with anhedonia: Integrating clinical and preclinical approaches to investigate distinct phenotypes

  2022, Neuroscience and Biobehavioral Reviews

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  In our clinical work with treatment-resistant depressed (TRD) patients, certain patterns have emerged in terms of patients’ presentations of anhedonia. Multiple studies have investigated anhedonia either as a state or a trait variable in depression, but anhedonia is a multifaceted construct and, as we better understand anhedonia, we increase our ability to measure and treat it. With the aim of personalizing medicine for more efficacious treatments, this paper focuses on clinical patterns we have seen in anhedonic TRD and argues for studies to be done in support of translational, face, and construct validity. Three representative clinical presentations of TRD with anhedonia are described: a congenital type, a stress-induced type, and a type exacerbated by medication. Each case is followed with discussion relating the clinical features to clinical and preclinical research relevant to putative mechanisms for the case. Animal models that are best suited to investigate and validate the existence of etiologies and mechanisms underlying anhedonia constructs unique to each case are proposed, as are potential directions for research in humans.

• Environmentally-relevant concentrations of the antipsychotic drugs sulpiride and clozapine induce abnormal dopamine and serotonin signaling in zebrafish brain

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• Classic psychedelics and alcohol use disorders: A systematic review of human and animal studies

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• Effects of Environmentally Relevant Concentrations of Antipsychotic Drugs (Sulpiride and Clozapine) on Serotonergic and Dopaminergic Neurotransmitter Systems in Octopus Brain Tissue

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