The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role of the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological conditions. Furthermore, we demonstrate that down-regulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neurons in chronic mild unpredictable stress (CMUS) depressive mice. In consistent with these, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice.

Memory consolidation in Drosophila can be sleep-dependent or sleep-independent, depending on the availability of food. The anterior posterior (ap) alpha′/beta′ (α′/β′) neurons of the mushroom body (MB) are required for sleep-dependent memory consolidation in flies fed after training. These neurons are also involved in the increase of sleep after training, suggesting a coupling of sleep and memory. To better understand the mechanisms underlying sleep and memory consolidation initiation, we analyzed the transcriptome of ap α′/β′ neurons 1 hr after appetitive memory conditioning. A small number of genes, enriched in RNA processing functions, were differentially expressed in flies fed after training relative to trained and starved flies or untrained flies. Knockdown of each of these differentially expressed genes in the ap α′/β′ neurons revealed notable sleep phenotypes for Polr1F and Regnase-1, both of which decrease in expression after conditioning. Knockdown of Polr1F, a regulator of ribosome RNA transcription, in adult flies promotes sleep and increases pre-ribosome RNA expression as well as overall translation, supporting a function for Polr1F downregulation in sleep-dependent memory. Conversely, while constitutive knockdown of Regnase-1, an mRNA decay protein localized to the ribosome, reduces sleep, adult specific knockdown suggests that effects of Regnase-1 on sleep are developmental in nature. We further tested the role of each gene in memory consolidation. Knockdown of Polr1F does not affect memory, which may be expected from its downregulation during memory consolidation. Regnase-1 knockdown in ap α′/β′ neurons impairs all memory, including short-term, implicating Regnase-1 in memory, but leaving open the question of why it is downregulated during sleep-dependent memory. Overall, our findings demonstrate that the expression of RNA processing genes is modulated during sleep-dependent memory and, in the case of Polr1F, this modulation likely contributes to increased sleep.