Research Briefing

Gene expression in the human cortex is shown to exhibit a generalizable three-component architecture that reflects neuronal, metabolic, and immune programmes of healthy brain development. The three components have distinct associations with autism spectrum disorder and schizophrenia, revealing connections between previously unrelated results from studies of case–control neuroimaging, differential gene expression, and genetic risk.

In the first comprehensive mRNA isoform atlas of the developing and adult mouse brain, we discover that region and age influence the isoform repertoire of cell subtypes. We link peak cell type regulation to the critical development period and report attenuated levels in adulthood.

Cold sensor identities in peripheral somatosensory neurons remain obscure. We show that GluK2, a kainate-type glutamate-sensing chemoreceptor that mediates synaptic transmission in the brain, mediates the sensing of cold but not cool temperatures in mouse dorsal root ganglia neurons in the periphery. Thus, we identify GluK2 as a cold-sensing thermoreceptor.

Brain connections modulated by 534 deep-brain-stimulation electrodes revealed a gradient of circuits involved in dystonia, Parkinson’s disease, Tourette’s syndrome and obsessive-compulsive disorder. Together, these circuits begin to describe the human ‘dysfunctome’, a library of dysfunctional circuits that lead to various brain disorders.

Long COVID has remained an on-going public health issue in the years following the global pandemic. Here, we report blood–brain barrier disruption in patients with acute SARS-CoV-2 infection and brain fog, and patients presenting with long COVID, brain fog and cognitive decline, compared to those with long COVID without any neurological symptoms.

A widespread group of cerebellar projections form monosynaptic excitatory synapses with neurons throughout the substantia nigra pars compacta (SNc). These projections contain information associated with movement and reward and can rapidly increase SNc neuron activity, and thereby basal ganglia dopamine levels, which contribute to movement initiation, vigor and reward processing.

This research elucidates that oligodendrocytes detect and respond to fast axonal spiking through K⁺ signaling, and that Kir4.1 channel activation has a pivotal role. This activity-driven interaction regulates axonal metabolic support by oligodendrocytes and influences lactate delivery and glucose metabolism in axons, which is essential for sustaining axonal health.

Using in vivo imaging in zebrafish, we unveiled critical components (PSD-95, gephyrin and neuroligin-3) and dynamic properties of synapses between neurons and oligodendrocyte precursor cells (OPC). Furthermore, we showed that neuron–OPC synapses have a pivotal role in regulating OPC development and CNS myelination.

We show that genetic disruption of TFEB- and vacuolar ATPase-mediated lysosomal signaling leads to increased tau pathology and defective microglia activation. Our findings demonstrate an essential role of the lysosome in regulating microglia activity in tauopathy and Alzheimer’s disease.

We discovered expression of SYNGAP1, which encodes the ‘synaptic’ protein SYNGAP1, within human cortical progenitors. In an organoid model of SYNGAP1 haploinsufficiency, cortical neurogenesis and neuronal network activity were disrupted. This finding reveals an unknown function for SYNGAP1 at early stages of development, providing a new framework for understanding the pathophysiology of autism spectrum disorder.

Sleep is typically considered as a state of behavioral disconnection from the outside world. Recordings of brain activity and facial muscle tone during sleep reveal that humans can respond to external stimuli across most sleep stages. These windows of behavioral responsiveness reveal transient episodes of high-cognitive states with electrophysiological signatures suggestive of a conscious state.

We used single-nucleus sequencing to generate an atlas of gene expression and chromatin accessibility in the amygdala of outbred rats with divergent cocaine addiction-like behaviors. The results implicated dysregulation of metabolic pathways and GABAergic transmission as molecular bases of susceptibility or resistance to addiction.

We developed a 3D human neuroimmune axis model to study the interplay of brain innate immune cells and peripheral adaptive immune cells in Alzheimer’s disease. Alzheimer’s disease pathology induced a marked increase in CD8⁺ T cell infiltration, exacerbating neurodegeneration. The CXCL10–CXCR3 pathway has a key role in mediating this process.

Communication between diverse cell types is crucial to the development of the nervous system. However, the secreted signals that help to switch the cell fates of progenitor cells from neurogenesis to astrogenesis are not fully understood. Experiments in human tissues show that five ligands work together to push astrocyte generation and maturation.

The Dominantly Inherited Alzheimer Network (DIAN) unites researchers aiming to understand autosomal dominant Alzheimer’s disease (ADAD). By longitudinally monitoring families worldwide, the DIAN Observational Study maintains an unprecedented resource of deeply phenotyped, freely available neuroimaging data on individuals with ADAD and their healthy relatives.

By studying axonal pathology in human multiple sclerosis and its models, we observed that myelin ensheathment itself can be detrimental for axonal survival. We hypothesize that oligodendroglial support is disrupted under inflammatory conditions, with the most severe consequences for the axons that remain physically isolated from the extracellular milieu by myelin.

We found reduced N⁶-methyladenosine (m⁶A) RNA modification in neurons differentiated from induced pluripotent stem cells from patients with amyotrophic lateral sclerosis or frontotemporal dementia caused by C9orf72 repeat expansion. This reduction disturbs global gene expression and exacerbates neurodegeneration. Strategies to restore the m⁶A level hold great promise as therapeutic approaches.

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.

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.