Neuron最新文献

Pain hypersensitivity arises from the induction of plasticity in peripheral and spinal somatosensory neurons, which modifies nociceptive input to the brain, altering pain perception. We applied longitudinal calcium imaging of spinal dorsal projection neurons to determine whether and how the representation of somatosensory stimuli in the anterolateral tract, the principal pathway transmitting nociceptive signals to the brain, changes between distinct pain states. In healthy mice, we identified stable outputs selective for cooling or warming and a neuronal ensemble activated by noxious thermal and mechanical stimuli. Induction of acute peripheral sensitization by topical capsaicin transiently re-tuned nociceptive output neurons to encode low-intensity stimuli. In contrast, peripheral nerve injury resulted in a persistent suppression of innocuous spinal outputs coupled with persistent activation of a normally silent population of high-threshold neurons. These results demonstrate differential modulation of spinal outputs to the brain during nociceptive and neuropathic pain states.

Hippocampal place cells have single, bell-shaped place fields in small environments. Recent experiments, however, reveal that, in large environments, place cells have multiple fields with heterogeneous shapes and sizes. We show that this diversity is explained by a surprisingly simple mathematical model, in which place fields are generated by thresholding a realization of a random Gaussian process. The model captures the statistics of field arrangements and generates new quantitative predictions about the statistics of field shapes and topologies. These predictions are quantitatively verified in bats and rodents, in one, two, and three dimensions, in both small and large environments. These results imply that common mechanisms underlie the diverse statistics observed in different experiments and further suggest that synaptic projections to CA1 are predominantly random.

Visual neuroscience benefits from high-quality datasets with neuronal responses to many images. Several neuroimaging datasets have been published in recent years, but no comparable dataset with spiking activity exists. Here, we introduce the THINGS ventral stream spiking dataset (TVSD). We extensively sampled neuronal activity in response to >25,000 natural images from the THINGS database in macaques, using high-channel-count implants in three key cortical regions: primary visual cortex (V1), V4, and the inferotemporal cortex. We showcase the utility of TVSD by using an artificial neural network to visualize the tuning of neurons. We also characterize the correlated fluctuations in activity within and between areas and demonstrate that these noise correlations are strongest between neurons with similar tuning. The TVSD allows researchers to answer many questions about neuronal tuning, analyze the interactions within and between cortical regions, and compare spiking activity in monkeys to human neuroimaging data.

PIEZO1 is a mechanically activated cation channel that undergoes force-induced activation and inactivation. However, its distinct structural states remain undefined. Here, we employed an open-prone PIEZO1-S2472E mutant to capture an intermediate open structure. Compared with the curved and flattened structures of PIEZO1, the S2472E-Intermediate structure displays partially flattened blades, a downward and rotational motion of the top cap, and a spring-like compression of the linker connecting the cap to the pore-lining inner helix. These conformational changes open the cap gate and the hydrophobic transmembrane gate, whereas the intracellular lateral plug gate remains closed. The flattened structure of PIEZO1 with an up-state cap and closed cap gate might represent an inactivated state. Molecular dynamics (MD) simulations of ion conduction support the closed, intermediate open, and inactivated structural states. Mutagenesis and electrophysiological studies identified key domains and residues critical for the mechanical activation of PIEZO1. These studies collectively define the distinct structural states and gating transitions of PIEZO1.

The lateral parabrachial nucleus (PBN) is critically involved in neuropathic pain modulation. However, the cellular and molecular mechanisms underlying this process remain largely unknown. Here, we report that in mice, the right-sided, but not the left-sided, PBN plays an essential role in the development of hyperalgesia following nerve injury, irrespective of the injury side. Spino-parabrachial pathways targeting the right-sided PBN display short-term facilitation, and right-sided PBN neurons exhibit an increase in the excitability and activity after nerve injury. Inhibiting Tacr1-positive neurons, blocking Tacr1-encoding tachykinin 1 receptor (NK1R), or knocking down the Tacr1 gene in the right-sided, rather than left-sided, PBN alleviates neuropathic pain-induced sensory hypersensitivity. Additionally, the right-sided PBN plays a critical role in the development of hyperalgesia during the early phase of neuropathic pain. These results highlight the essential role of NK1R in the lateralized modulation of neuropathic pain by the PBN, providing new insights into the mechanisms underlying neuropathic pain.

A microglia subpopulation termed "dark microglia" has been associated with aging and neurodegeneration, although its role has remained elusive. New research from Flury et al. in this issue of Neuron shows that dark microglia drive neurodegeneration via secretion of toxic lipids.¹.

The interplay between two major forebrain structures-cortex and subcortical striatum-is critical for flexible, goal-directed action. Traditionally, it has been proposed that striatum is critical for selecting what type of action is initiated, while the primary motor cortex is involved in specifying the continuous parameters of an upcoming/ongoing movement. Recent data indicate that striatum may also be involved in specification. These alternatives have been difficult to reconcile because comparing very distinct actions, as is often done, makes essentially indistinguishable predictions. Here, we develop quantitative models to reveal a somewhat paradoxical insight: only comparing neural activity across similar actions makes strongly distinguishing predictions. We thus developed a novel reach-to-pull task in which mice reliably selected between two similar but distinct reach targets and pull forces. Simultaneous cortical and subcortical recordings were uniquely consistent with a model in which cortex and striatum jointly specify continuous parameters governing movement execution.