Neuron最新文献

Mammalian transmembrane channel-like proteins 1 and 2 (TMC1 and TMC2) have emerged as very promising candidate mechanotransduction channels in hair cells. However, controversy persists because the heterogeneously expressed TMC1/2 in cultured cells lack evidence of mechanical gating, primarily due to their absence from the plasma membrane. By employing domain swapping with OSCA1.1 and subsequent point mutations, we successfully identified membrane-localized mouse TMC1/2 mutants, demonstrating that they are mechanically gated in heterologous cells. Further, whole-genome CRISPRi screening enabled wild-type human TMC1/2 localization in the plasma membrane, where they responded robustly to poking stimuli. In addition, wild-type human TMC1/2 showed stretch-activated currents and clear single-channel current activities. Deafness-related TMC1 mutations altered the reversal potential of TMC1, indicating that TMC1/2 are pore-forming mechanotransduction channels. In summary, our study provides evidence that human TMC1/2 are pore-forming, mechanically activated ion channels, supporting their roles as mechanotransduction channels in hair cells.

It has long been a decades-old dogma that image perception is mediated solely by rods and cones, while intrinsically photosensitive retinal ganglion cells (ipRGCs) are responsible only for non-image-forming vision, such as circadian photoentrainment and pupillary light reflexes. Surprisingly, we discovered that ipRGC activation enhances the orientation selectivity of layer 2/3 neurons in the primary visual cortex (V1) of mice by both increasing preferred-orientation responses and narrowing tuning bandwidth. Mechanistically, we found that the tuning properties of V1 excitatory and inhibitory neurons are differentially influenced by ipRGC activation, leading to a reshaping of the excitatory/inhibitory balance that enhances visual cortical orientation selectivity. Furthermore, light activation of ipRGCs improves behavioral orientation discrimination in mice. Importantly, we found that specific activation of ipRGCs in human participants through visual spectrum manipulation significantly enhances visual orientation discriminability. Our study reveals a visual channel originating from "non-image-forming photoreceptors" that facilitates visual orientation feature perception.

In this issue of Neuron, Xin et al.¹ reveal how the dorsomedial prefrontal cortex (dmPFC) orchestrates social dominance through subcortical pathways to the amygdala and brainstem. Using optogenetics and functional mapping, they identify opposing win- and lose-related circuits, uncovering a laminar organization driving competitive behavior in mice.

Recalling systems-consolidated neocortex-dependent remote memories re-engages the hippocampus in a process called systems reconsolidation. However, underlying mechanisms, particularly for the origin of the reinstated hippocampal memory engram, remain elusive. By developing a triple-event labeling tool and employing two-photon imaging, we trace hippocampal engram ensembles from memory acquisition to systems reconsolidation and find that remote recall recruits a new engram ensemble in the hippocampus for subsequent memory retrieval. Consistently, recruiting new engrams is supported by adult hippocampal neurogenesis-mediated silencing of original engrams. This new engram ensemble receives currently experienced contextual information, incorporates new information into the remote memory, and supports remote memory updating. Such a reconstructed hippocampal memory is then integrated with the valence of remote memory via medial prefrontal cortex projection-mediated activity coordination between the hippocampus and amygdala. Thus, the reconstruction of new memory engrams underlies systems reconsolidation, which explains how remote memories are updated with new information.

Memories for events that we experience in our lives are not immutable but change organizationally and qualitatively over time. In this issue of Neuron, Lei and colleagues¹ highlight how memory recall triggers these changes, leading to the formation of a new, updated memory trace (or engram) in the hippocampus.

Inhibitory interneurons are highly heterogeneous circuit elements often characterized by cell biological properties, but how these factors relate to specific roles underlying complex behavior remains poorly understood. Using chronic silicon probe recordings, we demonstrate that distinct interneuron groups perform different inhibitory roles within HVC, a song production circuit in the zebra finch forebrain. To link these functional subtypes to molecular identity, we performed two-photon targeted electrophysiological recordings of HVC interneurons followed by post hoc immunohistochemistry of subtype-specific markers. We find that parvalbumin-expressing interneurons are highly modulated by sensory input and likely mediate auditory gating, whereas a more heterogeneous set of somatostatin-expressing interneurons can strongly regulate activity based on arousal. Using this strategy, we uncover important cell-type-specific network functions in the context of an ethologically relevant motor skill.

High-throughput methods are revolutionizing our ability to classify neurons based on their transcriptome. In this issue of Neuron, Hozhabri and colleagues¹ first categorize songbird GABAergic neurons by functional role and then link these functional subtypes to molecular identity.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function. These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.

Transient exposure to ketamine can trigger lasting changes in behavior and mood. We found that brief ketamine exposure causes long-term suppression of futility-induced passivity in larval zebrafish, reversing the "giving-up" response that normally occurs when swimming fails to cause forward movement. Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit responsible for passivity. After ketamine washout, this circuit exhibits hyposensitivity to futility, leading to long-term increased perseverance. Pharmacological, chemogenetic, and optogenetic manipulations show that norepinephrine and astrocytes are necessary and sufficient for ketamine's long-term perseverance-enhancing aftereffects. In vivo calcium imaging revealed that astrocytes in adult mouse cortex are similarly activated during futility in the tail suspension test and that acute ketamine exposure also induces astrocyte hyperactivation. The cross-species conservation of ketamine's modulation of noradrenergic-astroglial circuits and evidence that plasticity in this pathway can alter the behavioral response to futility hold promise for identifying new strategies to treat affective disorders.

Social competition determines hierarchical social status, which profoundly influences animals' behavior and health. The dorsomedial prefrontal cortex (dmPFC) plays a fundamental role in regulating social competitions, but it was unclear how the dmPFC orchestrates win- and lose-related behaviors through its downstream neural circuits. Here, through whole-brain c-Fos mapping, fiber photometry, and optogenetics- or chemogenetics-based manipulations, we identified anatomically segregated win- and lose-related neural pathways downstream of the dmPFC in mice. Specifically, layer 5 neurons projecting to the dorsal raphe nucleus (DRN) and periaqueductal gray (PAG) promote social competition, whereas layer 2/3 neurons projecting to the anterior basolateral amygdala (aBLA) suppress competition. These two neuronal populations show opposite changes in activity during effortful pushes in competition. In vivo and in vitro electrophysiology recordings revealed inhibition from the lose-related pathway to the win-related pathway. Such antagonistic interplay may represent a central principle in how the mPFC orchestrates complex behaviors through top-down control.