Reviews & Analysis

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.

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.

Two monkeys solved combinatorial optimization problems for rewards. They deliberated for extended durations, approximated efficient computational algorithms for managing complexity, and even selected algorithms according to the computational complexity of the trial. These findings reveal evidence for algorithm-based reasoning and establish a paradigm for studying the neurophysiological basis of deliberative thought.

In the brains of patients with epilepsy, apolipoprotein E-mediated lipid transfer from hyperactive neurons to astrocytes results in lipid metabolism reprogramming and formation of lipid-accumulated reactive astrocytes. These astrocytes exacerbate abnormal discharges of neighboring neurons and, in mice, aggravate seizure symptoms, leading to disease progression.

We developed a wearable platform (the Neuro-stack) for recording single-neuron and local field potentials in freely moving humans. The Neuro-stack enabled the recording of single-neuron activity during walking behavior in humans. The platform also enables personalized stimulation during real-time decoding of neural activity, which can potentially improve neurostimulation treatments.

Despite extensive studies on how social networks affect behavior at the population level, little is known about how the human brain makes decisions in networked environments. This study shows that the brain flexibly weighs information received from a social contact according to how well-connected that contact is on the network responsible for information transmission.

STARmap PLUS is a new spatial gene mapping method combined with histological staining. With STARmap PLUS, we created high-resolution, comprehensive maps of altered molecular pathways and reactive cells in a mouse model of Alzheimer’s disease. These maps enabled us to infer the trajectories of biological processes and cell states during disease progression.

The defense response to threat involves complex behavioral and autonomic adjustments. We identified integrated, short-lasting microstates and long-lasting macrostates evoked by threat, consisting of patterned behavioral and cardiac responses, which are dynamically interrelated, dependent on environmental threat levels, and controlled by neurons in the midbrain periaqueductal gray region.