Reviews & Analysis

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.

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.

Genome-wide association studies for brain and behavioral traits have provided insights but also present challenges related to privacy and misuse. We discuss these ethical issues and how to mitigate potential negative consequences.

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 this issue, Shinn et al. demonstrate a close relationship between complex brain network topology and lower-level statistical properties of neuroimaging data. They also highlight the potential of these statistical measures, which capture similarity in space and time, to provide imaging-based markers of aging and pharmacological states.

Zhu et al. show that basal forebrain cholinergic neurons send fast, specific information about a broad range of sensory stimuli to the auditory cortex, modulated by slower fluctuations in cholinergic activity. These findings help us to understand how the cholinergic system multiplexes diverse representations to fulfil its multifaceted roles in attention, learning and memory.

Stegemann et al. have unraveled a long-lasting role for fear engrams in future pain perception. Prefrontal pain and fear representations become entangled following a fearful event. As subsequent painful experiences also reactivate the fear network, silencing the fear engram alone can alleviate both tonic pain and hypersensitivity in chronic pain.

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.

Loss-of-function variants of TREM2 increase risk for Alzheimer’s disease. A new study presents a therapeutic candidate — ATV:TREM2, a TREM2-activating antibody engineered with a transferrin receptor binding site to facilitate blood-to-brain transport. Treatment of a mouse model of Alzheimer’s disease with ATV:TREM2 improved energy metabolism and microglial function.

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.

Microglial synapse engulfment precedes brain amyloid plaque formation and probably contributes to early cognitive decline in Alzheimer’s disease. The mechanisms that regulate microglia-mediated synapse engulfment are unclear. De Schepper et al. show that perivascular SPP1 induces microglia-mediated synapse engulfment, highlighting a neuroimmune interaction that contributes to synapse loss in amyloid pathology.

In this Review, Villeda and colleagues describe blood-to-brain communication from a systems physiology perspective, with an emphasis on blood-derived signals as potent drivers of both age-related brain dysfunction and brain rejuvenation.

Craving is a core characteristic of drug addiction and eating disorders. A new study identifies an fMRI-based neural signature of craving that is common to both food and drugs, predicts self-reported craving, distinguishes drug users from non-users, and tracks the efficacy of a cognitive therapy technique to reduce craving.

Single-cell genomics reveal that Alzheimer’s dementia involves the complex interplay of virtually every major brain cell type. Cell-type-specific molecular perturbations modulate signaling pathways related to lipid handling, immune signaling and metabolic reprogramming.

Sulaman et al. detail the neuronal underpinnings of sleep–wake states and discuss their intersection with hunger, fear and thermoregulatory circuits. They propose a de-arousal model for sleep initiation and highlight lingering questions in the field.