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Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness 1,2 . These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies 3-9 . Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the 'open state' versus the 'closed state' provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease., (© 2023. The Author(s).)

Highly selective, positive allosteric modulators (PAMs) of the M 1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M 1 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M 1 receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M 1 receptor signaling in native systems, and it is not clear whether biased M 1 PAMs display differences in modulating M 1 -mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M 1 -dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M 1 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M 1 -dependent LTD in the PFC. In contrast, biased and nonbiased M 1 PAMs acted similarly in potentiating M 1 -dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M 1 PAMs to modulate certain central nervous system (CNS) functions and that biased M 1 PAMs function differently in brain regions implicated in cognition., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Male bushcrickets transfer large spermatophores of up to 40% of male body mass to the females during mating. These large nuptial gifts are later consumed by the female and have been shown to affect the size and number of eggs laid after mating in some species. The composition of the spermatophores in five species of phytophagous phaneropterid bushcrickets (genera Ancistrura, Barbitistes, Metaplastes, Poecilimon) was examined in respect to water content, elemental composition, protein concentration, and the content of lipids, carbohydrates, urea and uric acid. In addition, the amino acid composition of the spermatophore was compared with that of the egg proteins. In all species, water content was found to be about 85% of wet mass. Eleven to 16% of the dry mass consisted of nitrogen, corresponding to a protein content of about 70 to more than 90% of the dry mass. Urea and uric acid were only present in traces. The proteins contained a high amount of glycine (about 26mol %), together with asparagine/aspartic acid, 12% and glutamic acid, 11%, which differed distinctly from the amino acid composition of the egg proteins. The results are discussed with respect to the advantages the male may receive by producing these large nuptial gifts.