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Astrocytes have important roles in disease and are difficult to modulate, owing to a paucity of known targets. Clayton et al. develop a screening platform to unbiasedly identify modulators of astrocyte reactivity. They discover that HDAC3 inhibitors regulate astrocyte transitions into their reactive phenotype in vitro and in vivo.

C9orf72 ALS/FTD polyGR and polyPR knock-in mice show cortical hyperexcitability and motor neuron loss accompanied by an increase in extracellular matrix proteins in the spinal cord that is conserved in patient iPS cell-derived neurons and is neuroprotective.

Sias et al. show that dopamine projections to the basolateral amygdala drive the reward learning that supports the predictions and inferences needed for adaptive decision-making.

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.

Hollunder et al. identify networks where deep brain stimulation reduces symptoms for Parkinson’s disease, Tourette’s syndrome, dystonia and obsessive-compulsive disorder. This revealed a fronto-rostral topography that segregates the frontal cortex.

Long COVID is a major public health issue since 2020 and exhibits frequent neurological symptoms. Greene et al. propose that brain fog results from leaky brain blood vessels and a hyperactive immune system, shedding light on this phenomenon.

Astrocytes have important roles in disease. However, modulation of their reactive state is challenging. Here the authors present a phenotypic in vitro screening platform they can leverage to identify chemical compounds able to modulate astrocyte reactivity in vitro and in vivo.

Using single-neuron recordings in patients with epilepsy, Kunz et al. show that stimulus-specific neurons activate together during hippocampal ripples when humans encode and retrieve associative memories.

Radke et al. found an interferon response in the brainstem nuclei of acute COVID-19 that, in addition to the inflammatory reaction, spreads throughout the vascular unit altering glial cells and resolves in late disease states in the absence of brain infection.

The Sehgal lab presents data showing that the non-cell autonomous pathway of glial lipid droplet formation occurs during sleep and helps to resolve neuronal reactive oxygen species (ROS). This promotes neuronal function after an active day. Hence, this pathway has an important physiological function beyond its previously described role in ROS-associated diseases, including Alzheimer’s disease.

Both caloric restriction and obesity affect autoimmune diseases. The activation of brainstem neurons in the ventrolateral medulla (VLM) with fasting suppresses experimental autoimmune diseases. Stimulation of VLM neurons alters T cell traffic by redistributing immune cells to bone marrow and reduces inflammatory cytokine production, thus providing therapy of experimental autoimmunity.

Haynes et al. report a daily, sleep-dependent neuron–glia lipid metabolic cycle. ApoE-dependent lipid transfer from neurons to glia protects neurons from oxidative damage during waking, and lipids are cleared from glia during sleep.

Despite a long history of studying perceptual biases in neuroscience, many of the biases remain difficult to explain and even appear to be contradictory. The authors propose a unifying theory that sheds new light on such puzzling perceptual biases.

Muller et al. demonstrate that reward signals recorded from the frontal cortex of nonhuman primates exhibit a population-based scheme for learning probability distributions over reward values. This study provides evidence that neural signals outside of the midbrain reflect the principles of distributional reinforcement-learning theory.

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 Nancy Ip, Morningside Professor of Life Science and president of the Hong Kong University of Science and Technology. We discussed her path from academia to industry and back, her experiences as a working mother and how she has helped scientific research in Hong Kong to flourish.

Wang et al. identify a molecularly defined tetra-synaptic pathway for olfaction-evoked innate fear and anxiety in mice. These findings reveal a forebrain-to-hindbrain neural substrate for sensory-triggered fear and anxiety that bypasses the amygdala.

Minakuchi et al. find that separable inhibitory inputs to a critical hypothalamic aggression-control node can influence the evolution of an aggressive state by independently modulating either the motivational phase or the action phase.

The basal ganglia control the execution of motor actions. However, how they engage spinal motor networks is unclear. Here the authors show that the basal ganglia–spinal cord pathway controls locomotor asymmetries in adult mice.