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Commonly prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) take weeks to achieve therapeutic benefits1, 2. The underlying mechanisms of why antidepressants take weeks or months to reverse depressed mood are not understood. Using a single cell sequencing approach, we analyzed gene expression changes in mice subjected to stress-induced depression and determined their temporal response to antidepressant treatment in the cerebral cortex. We discovered that both glial and neuronal cell populations elicit gene expression changes in response to stress, and that these changes are reversed upon treatment with fluoxetine (Prozac), a widely prescribed selective serotonin reuptake inhibitor (SSRI). Upon reproducing the molecular signaling events regulated by fluoxetine3 in a cortical culture system, we found that these transcriptional changes are serotonin-dependent, require reciprocal neuron-glia communication, and involve temporally-specified sequences of autoregulation and cross-regulation between FGF2 and BDNF signaling pathways. Briefly, stimulation of Fgf2 synthesis and signaling directly regulates Bdnf synthesis and secretion cell-non-autonomously requiring neuron-glia interactions, which then activates neuronal BDNF-TrkB signaling to drive longer-term neuronal adaptations4–6 leading to improved mood. Our studies highlight temporal and cell type specific mechanisms promoting the onset of the antidepressant response, that we propose could offer novel avenues for mitigating delayed onset of antidepressant therapies.

Secrets of Meissner corpuscles The Meissner corpuscle, a mechanosensory end organ, was discovered more than 165 years ago and has since been found in the glabrous skin of all mammals, including that on human fingertips. Although prominently featured in textbooks, the function of the Meissner corpuscle is unknown. Neubarth et al. generated adult mice without Meissner corpuscles and used them to show that these corpuscles alone mediate behavioral responses to, and perception of, gentle forces (see the Perspective by Marshall and Patapoutian). Each Meissner corpuscle is innervated by two molecularly distinct, yet physiologically similar, mechanosensory neurons. These two neuronal subtypes are developmentally interdependent and their endings are intertwined within the corpuscle. Both Meissner mechanosensory neuron subtypes are homotypically tiled, ensuring uniform and complete coverage of the skin, yet their receptive fields are overlapping and offset with respect to each other. Science , this issue p. eabb2751 ; see also p. 1311

TRAAK is a membrane tension-activated K+channel that has been associated through behavioral studies to mechanical nociception. We used specific monoclonal antibodies in mice to show that TRAAK is localized exclusively to nodes of Ranvier, the action potential propagating elements of myelinated nerve fibers. Approximately 80 percent of myelinated nerve fibers throughout the central and peripheral nervous system contain TRAAK in an all-nodes or no-nodes per axon fashion. TRAAK is not observed at the axon initial segment where action potentials are first generated. We used polyclonal antibodies, the TRAAK inhibitor RU2 and node clamp amplifiers to demonstrate the presence and functional properties of TRAAK in rat nerve fibers. TRAAK contributes to the ‘leak’ K+current in mammalian nerve fiber conduction by hyperpolarizing the resting membrane potential, thereby increasing Na+channel availability for action potential propagation. Mechanical gating in TRAAK might serve a neuroprotective role by counteracting mechanically-induced ectopic action potentials. Alternatively, TRAAK may open in response to mechanical forces in the nodal membrane associated with depolarization during saltatory conduction and thereby contribute to repolarization of the node for subsequent spikes.