Summary Medial nucleus tractus solitarius (mNTS) neurons express leptin receptors (LepR) and intramNTS delivery of leptin reduces food intake and body weight. Here, the contribution of endogenous LepR signaling in mNTS neurons to energy balance control was examined. Knockdown of LepR in mNTS and area postrema (AP) neurons of rats (LepRKD) via adeno-associated virus short hairpin RNA-interference (AAV-shRNAi) resulted in significant hyperphagia for chow, high-fat and sucrose diets, yielding increased body weight and adiposity. The chronic hyperphagia of mNTS/AP LepRKD rats is likely mediated by a reduction in leptin potentiation of gastrointestinal satiation signaling, as LepRKD rats showed decreased sensitivity to the intake reducing effects of cholecystokinin. LepRKD rats showed increased basal AMP-kinase activity in mNTS/AP micropunches and pharmacological data suggest that this increase provides a likely mechanism for their chronic hyperphagia. Overall these findings demonstrate that LepRs in mNTS and AP neurons are required for normal energy balance control.

Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake.

Elucidation of the molecular basis of disease depends upon continued progress in defining the mechanisms by which genomic information is encoded and expressed. Transcription factor-mediated regulation of mRNA is clearly a major source of regulatory control and has been well studied. The more recent discovery of small RNAs as key regulators of gene function has introduced a new level and mechanism of regulation. Mammalian genomes contain hundreds of microRNAs (miRNAs) that each can potentially downregulate many target genes. This suggests a new source for broad control over gene regulation and has inspired extensive interest in defining miRNAs and their functions. Here, the identification of miRNAs, their biogenesis, and some examples of miRNA effects on biology and disease are reviewed and discussed. Emphasis is placed on the possible role for miRNA in nervous system development, function, and disease.