Central serotonin (5-HT) dysregulation contributes to the susceptibility for mental disorders, including depression, anxiety, and posttraumatic stress disorder, and learning and memory deficits. We report that the formation of hippocampus-dependent spatial memory is compromised, but the acquisition and retrieval of contextual fear memory are enhanced, in central 5-HT-deficient mice. Genetic deletion of serotonin in the brain was achieved by inactivating Lmx1b selectively in the raphe nuclei of the brainstem, resulting in a near-complete loss of 5-HT throughout the brain. These 5-HT-deficient mice exhibited no gross abnormality in brain structures and had normal locomotor activity. Spatial learning in the Morris water maze was unaffected, but the retrieval of spatial memory was impaired. In contrast, contextual fear learning and memory induced by foot-shock conditioning was markedly enhanced, but this enhancement could be prevented by intracerebroventricular administration of 5-HT. Foot shock impaired longterm potentiation and facilitated long-term depression in hippocampal slices in WT mice but had no effect in 5-HT-deficient mice. Furthermore, bath application of 5-HT in 5-HT-deficient mice restored foot shock-induced alterations of hippocampal synaptic plasticity. Thus, central 5-HT regulates hippocampus-dependent contextual fear memory, and 5-HT modulation of hippocampal synaptic plasticity may be the underlying mechanism. The enhanced fear memory in 5-HT-deficient mice supports the notion that 5-HT deficiency confers susceptibility to posttraumatic stress disorder in humans.hippocampus ͉ long-term depression ͉ long-term potentiation ͉ anxiety T he neurotransmitter serotonin (5-HT) exerts a wide spectrum of actions in the nervous system by modulating neural development, synaptic plasticity, pain sensation, rhythm, food intake, and a variety of behaviors (1-4). It has been proposed that perturbation of the 5-HT level in the brain contributes to depression and anxiety, and posttraumatic stress disorder (PTSD) (5-8), which are often accompanied by learning and memory deficits (9-11). The hippocampus is known to be critical for the formation of spatial and contextual fear memories (12-15), and the retrieval of hippocampus-dependent memories was found to be impaired in patients with depression and PTSD (16)(17)(18). Recent studies have also implicated the hippocampus as one of the primary sites for antidepressants (6,(19)(20)(21)(22)(23). Aversive stimuli such as foot shock that led to anxiety, depression, and fear memory in rodents also altered activity-dependent hippocampal synaptic plasticity (24)(25)(26)(27)(28)(29). Because the modulation of 5-HT activity altered hippocampal long-term potentiation (LTP) and long-term depression (LTD) (30-32), it is possible that perturbation of 5-HT level in the brain may affect hippocampusdependent learning and memory, and changes in hippocampal synaptic plasticity may also contribute to mental disorders, including anxiety and fear memory.Inhibitors of 5-HT biosynthesis that...

A fundamental problem in neuroscience is how emotional valences are represented in the brain. We know little about how appetitive and aversive systems interact and the extent to which information regarding these two opposite values segregate and converge. Here we used a new method, tyramide-amplified immunohistochemistry-fluorescence in situ hybridization, to simultaneously visualize the neural correlates of two stimuli of contrasting emotional valence across the limbic forebrain at single-cell resolution. We discovered characteristic patterns of interaction, segregated, convergent and intermingled, between the appetitive and aversive neural ensembles in mice. In nucleus accumbens, we identified a mosaic activation pattern by positive and negative emotional cues, and unraveled previously unappreciated functional heterogeneity in the D1- and D2-type medium-spiny neurons, which correspond to the Go and NoGo pathways. These results provide insights into the coding of emotional valence in the brain and act as a proof of principle of a powerful methodology for simultaneous functional mapping of two distinct behaviors.

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Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing Fto expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampus of Fto knockdown (KD), Fto knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 (Adrb2) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.