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Compounds targeting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling are being investigated in multiple clinical settings, but drug resistance may reduce their benefit. Compound rechallenge after drug holidays can overcome such resistance, yet little is known about the impact of drug holidays on cell biochemistry. We found that PI3K inhibitor (PI3Ki)-resistant cells cultured in the absence of PI3Ki developed a proliferative defect, increased oxygen consumption and accumulated reactive oxygen species (ROS), leading to lactate production through hypoxia-inducible factor-1α. This metabolic imbalance was reversed by mammalian target of rapamycin complex 1 (mTORC1) inhibitors. Interestingly, neither AKT nor c-MYC was involved in mediating the metabolic phenotype, despite the latter contributing to resistant cells' proliferation. These data suggest that an AKT-independent PI3K/mTORC1 axis operates in these cells. The excessive ROS hampered cell division, and the metabolic phenotype made resistant cells more sensitive to hydrogen peroxide and nutrient starvation. Thus, the proliferative defect of PI3Ki-resistant cells during drug holidays is caused by defective metabolic adaptation to chronic PI3K/mTOR pathway inhibition. This metabolic imbalance may open the therapeutic window for challenge with metabolic drugs during drug holidays.

A common strategy when searching for cognitive‐enhancing drugs has been to target the N‐methyl‐d‐aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D‐amino acid oxidase (DAO) degrades neutral D‐amino acids such as D‐serine, the primary endogenous co‐agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long‐term potentiation and facilitated water maze acquisition of ddY/Dao − mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao −/−) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao −/− mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao −/− mice exhibited normal performance in two alternative assays of long‐term spatial memory: the appetitive and aversive Y‐maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long‐term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.

Background and Purpose Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq‐protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here, we investigated both ebselen and lithium in models of the 5‐HT2A receptor, a Gq‐protein coupled receptor involved in lithium's actions. Experimental Approach 5‐HT2A receptor function was assessed in mice by measuring the behavioural (head‐twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c‐fos, Egr2) responses to 5‐HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5‐HT2A receptor function. Because lithium and 5‐HT2A receptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co‐administration with the SSRI citalopram in microdialysis (extracellular 5‐HT) experiments. Key Results Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5‐HT2A receptor agonist DOI. Repeated lithium also inhibited DOI‐evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L‐690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR‐A014418) did not. Finally, ebselen enhanced the increase in extracellular 5‐HT induced by citalopram, and also increased regional brain 5‐HT synthesis. Conclusions and Implications Our data demonstrated lithium‐mimetic effects of ebselen in different experimental models of 5‐HT2A receptor function, probably mediated by IMPase inhibition. This evidence of lithium‐like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent.

International audience; Characteristics and initial description of the 18 holes and 515m of cores recovered (cumulative length) at Rochechouart.

Impacts are a fundamental geologic process that has influenced the formation and modification of asteroids and planets throughout time. An important part of the impact history of the solar system is recorded in shocked meteorites. The asteroid Vesta has experienced large impacts, evidenced by two ~400-500 km impact structures that overprint the south pole region. While a range of shock-induced effects such as brecciation, melting and the formation of maskelynite has been reported in howardite-eucrite-diogenite (HED) meteorites originating from Vesta, high-pressure minerals have previously only been described in two eucrites [1-2]. Here, we present results on an inventory of shock effects and high-pressure minerals preserved in the polymict eucrite NWA 10658.

The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Thus, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin (ChR2) genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed this effect was mediated by glutamate and not 5-HT since it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10-20Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT since they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often co-existed in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons (PNs), but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output. SIGNIFICANCE STATEMENT: The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders. Hence, it is essential to dissect the physiological mechanisms through which 5-HT neurons in the dorsal raphe nuclei modulate amygdala circuits. Here, we combined optogenetic, electrophysiological and pharmacological approaches to study the effects of activation of 5-HT axons in the basal nucleus (BA) of the amygdala. We found that 5-HT neurons co-release 5-HT and glutamate onto BA neurons in a cell type-specific and frequency-dependent manner. Thus, we suggest that theories on the contribution of 5-HT neurons to amygdala function should be revised to incorporate the concept of 5-HT/glutamate co-transmission.