Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia.

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Short-Term Influence of Recent Trial History on Perceptual Choice Changes with Stimulus Strength.

Perceptual decisions, especially for difficult stimuli, can be influenced by choices and outcomes in previous trials. However, it is not well understood how stimulus strength modulates the temporal characteristics as well as the magnitude of trial history influence. We addressed this question using a contrast detection task in freely moving mice. We found that, at lower as compared to higher stimulus contrast, the current choice of the mice was more influenced by choices and outcomes in the past trials and the influence emerged from a longer history. To examine the neural basis of stimulus strength-dependent history influence, we recorded from the secondary motor cortex (M2), a prefrontal region that plays an important role in cue-guided actions and memory-guided behaviors. We found that more M2 neurons conveyed information about choices on the past two trials at lower than at higher contrast. Furthermore, history-trial activity in M2 was important for decoding upcoming choice at low contrast. Thus, trial history influence of perceptual choice is adaptive to the strength of sensory evidence, which may be important for action selection in a dynamic environment.