Volume 26 Issue 3, March 2023

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.

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.

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.

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.

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.

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.

The authors established a method to map RNA localization sequences (zipcodes) and identified the let-7 site and AU repeat as new zipcodes in primary cortical neurons.

Microglia mediate aberrant synapse engulfment in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Here the authors show a perivascular cells-to-microglia crosstalk that induces microglia phagocytic state resulting in synapse engulfment in two mouse models of AD.

van Lengerich et al. developed a human TREM2 antibody with a transport vehicle (ATV) that improves brain exposure and biodistribution in mouse models. ATV:TREM2 promotes microglial energetic capacity and metabolism via mitochondrial pathways.

Understanding the spatiotemporal dynamics underlying pathology can shed light on its mechanisms. Here the authors introduce STARmap PLUS, a method that combines high-resolution spatial transcriptomics with protein detection.

Tovote and colleagues present an analytical framework that integrates threat-evoked inter-related behavioral and cardiac adjustments and allows identification of short- and long-lasting defensive states and their midbrain neuronal mediators.

Zhou et al. show that the generation and maintenance of chronic neuropathic pain after peripheral nerve injury is crucially dependent on the activation of a parabrachial nucleus–nucleus basalis-S1 pathway during non-REM sleep.

The authors map thalamic synapses onto layer 2/3 mouse visual cortex neurons, showing they are sparse, small and heterogeneously distributed. Modeling these data suggests that a few neurons could together reliably decode thalamic visual input.

This study shows that pyramidal tract (PT) and intratelencephalic (IT) projection neurons process information via distinct parallel subnetworks across cortex, each preferentially associated with either motor events or sensorimotor transformation.

Distinct cortical pyramidal neuron types, defined by developmental lineage, make unique contributions to behavioral decisions. We highlight the importance of interactions among diverse cortical and subcortical areas for successful decision outcomes.

Information flowing among connected peers shapes our beliefs and decisions. Jiang et al. show that learning on social networks is biased toward well-connected individuals, with the dorsal anterior cingulate cortex tracking connectedness on the network that routes learning.

The Neuro-stack is a wearable platform for recording from single neurons in freely moving humans. It also allows for personalized stimulation during real-time decoding of neural activity.