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Psychedelics induce fast and long-lasting antidepressant effects and neuronal plasticity, but their hallucinogenic effects limit their use. We show that, in mice, psychedelics bind directly to TrkB (the brain-derived neurotrophic factor (BDNF) receptor) with high affinity and promote BDNF-mediated plasticity and antidepressant-like effects, whereas their hallucinogenic-like effects are independent of TrkB binding.

Vasek et al. demonstrate that distal processes of microglia locally translate specific mRNAs including those related to immunity and phagocytosis. They then show that local protein synthesis is necessary for microglial process-initiated phagocytosis.

Moliner et al. show that psychedelics directly bind to the BDNF receptor TrkB with high affinity and promote BDNF-mediated plasticity and antidepressant-like effects, whereas their hallucinogenic-like effects are independent of TrkB binding.

As Nature Neuroscience celebrates its 25th anniversary, we are having conversations with both established leaders in the field and those earlier in their careers to discuss how the field has evolved and where it is heading. This month we are talking to Carla Shatz, who is the Sapp Family Provostial Professor, Catherine Holman Johnson Director of Stanford Bio-X, and Professor of Biology and Neurobiology at Stanford University. Her work has illuminated mechanisms of visual system development and plasticity and has focused more recently on synaptic pruning mechanisms.

A study by Holstein-Rønsbo, Gan et al. published in this issue of Nature Neuroscience adds another dimension to the ‘glymphatic’ story — the role of functional hyperemia facilitating perivascular flow of cerebrospinal fluid along pial arteries.

Sleep helps to stabilize long-term memories, possibly through the temporal synchronization of neuronal activity in different brain regions. Intracranial stimulation during sleep using prefrontal electric pulses, precisely timed with slow-wave activities in the medial temporal lobe, enhanced the coupling of neuronal oscillations across regions of the human brain and improved memory performance.

β2-Microglobulin (β₂M) is an amyloidogenic protein. β₂M coaggregates with β-amyloid (Aβ) in the brains of patients with Alzheimer’s disease and enhances Aβ deposition. β₂M is essential for Aβ neurotoxicity in vivo, and neutralization of pathogenetic β₂M–Aβ aggregates ameliorates the amyloid pathology and cognitive deficits associated with disease in a mouse model.

Geva-Sagiv et al. performed real-time closed-loop intracranial stimulation in human sleep. Brief prefrontal pulses, precisely timed with MTL slow-wave active periods, led to correlated enhancements in sleep oscillation coupling and memory accuracy.

Holstein-Rønsbo et al. show that functional hyperemia increases glymphatic CSF inflow and clearance. Direct stimulation of vascular smooth muscle cells, in the absence of neuronal activation, similarly enhances glymphatic flow.

Sun et al. analyzed 22,514 human brain vascular single-nucleus transcriptomes from 428 individuals and uncovered AD-related gene expression and cell–cell interaction linked to genetics, as well as vascular dysfunction in APOE-associated cognitive decline.

Zhao et al. identified β₂-microglobulin (β₂M) as an essential factor driving β-amyloid (Aβ) neurotoxicity and cognitive impairment in mouse models of Alzheimer’s disease (AD) and implicated targeting β₂M–Aβ coaggregation as a strategy for AD therapeutics.

Hahamy et al. demonstrate that, at the transitions between narrative events, the human brain reactivates past information that is relevant for the understanding of the current narrative stage.

Reconstitution of TDP-43 filaments that exhibit sequence and morphological features similar to those found in the brain helps to uncover a new mechanism for the formation and propagation of pathology in amyotrophic lateral sclerosis and other neurodegenerative diseases.

This study tests a key hypothesis of cerebellar motor correction, showing that inputs to the cerebellum that drive errors during skilled movements are rapidly adjusted over trials to enhance motor accuracy.

Endocannabinoids are important modulators of synaptic transmission, although their mechanism of release is unknown. In this study, the authors found that endocannabinoid postsynaptic release is mediated by synucleins via a synuclein-dependent and SNARE-dependent mechanism.

The immune system plays a critical role in neurodegenerative diseases. Resident and peripheral immune cells contribute to disease progression. Here, the authors review the role of peripheral immune cells both when infiltrating the CNS or when remaining in the periphery.

Using long-term brain recordings in patients with chronic pain, we identified objective biomarkers of real-world subjective pain intensity over many months. Spontaneous chronic pain states were predicted most reliably by sustained changes in the activity of the orbitofrontal cortex, whereas acute pain was most associated with signals from the anterior cingulate cortex.