Why is ketamine an antidepressant? A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants. Science , this issue p. eaat8078 ; see also p. 129

Significance Skin protects against harmful external cues, one of them UV radiation, which, upon overexposure, causes sunburn as part of the UVB response. Using genetically engineered mice and cultured skin epithelial cells, we have identified the calcium-permeable TRPV4 ion channel in skin epithelial cells as critical for translating the UVB stimulus into intracellular signals and also into signals from epithelial skin cell to sensory nerve cell that innervates the skin, causing pain. These signaling mechanisms underlie sunburn and in particular sunburn-associated pain. Thus, activation of TRPV4 in skin by UVB evokes sunburn pain, highlighting the forefront-signaling role of the skin and TRPV4.

Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, and “therapy-refractoriness” of its pain, and its largely elusive pathogenesis. Against this background we sought to investigate pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation evoked pain behavior in mice, and that trigeminal ganglion pro-nociceptive changes are Trpv4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4−/− mice with TMJ-inflammation, attenuation of bite force was significantly less than in WT mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ-inflammation and mandibular bony changes were apparent after CFA injections, but remarkably independent of Trpv4 genotype. Intriguingly, as a result of TMJ-inflammation, WT mice exhibited significant up-regulation of TRPV4 and phosphorylated ERK in TMJ-innervating trigeminal sensory neurons, absent in Trpv4−/− mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed a similar resistance to reduction of bite-force as Trpv4−/− mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ-inflammation, and likely functions up-stream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in-vivo. TRPV4 therefore represents a novel pro-nociceptive target in TMJ inflammation, and should be considered a target-of-interest in human TMJD.

Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels, and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviours in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behaviour. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.