eLife最新文献

Goal-directed movements can fail due to errors in our perceptual and motor systems. While these errors may arise from random noise within these sources, they also reflect systematic motor biases that vary with the location of the target. The origin of these systematic biases remains controversial. Drawing on data from an extensive array of reaching tasks conducted over the past 30 years, we evaluated the merits of various computational models regarding the origin of motor biases. Contrary to previous theories, we show that motor biases produced by human participants do not arise from systematic errors associated with the sensed hand position during motor planning or from the biomechanical constraints imposed during motor execution. Rather, motor biases are primarily caused by a misalignment between eye-centric and body-centric representations of position. This model can account for motor biases across a wide range of contexts, encompassing movements with the right versus left hand, finger versus hand movements, visible and occluded starting positions, as well as before and after sensorimotor adaptation.

We previously identified the roles of the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) in sensory preconditioning in male and female rats (Wong et al., 2025). Here, we used variations of a sensory preconditioning protocol to test a general theory that the BLA and PRh represent focal and peripheral states of attention, respectively. We specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N-methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus, as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required NMDAR-activation in the BLA and not the PRh, regardless of whether the stimulus and shock were presented contiguously or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required NMDAR-activation in the BLA and not the PRh. However, when a pre-exposed stimulus was indirectly paired with shock - because it was associatively activated at the time of shock or separated from the shock by another stimulus - its conditioning required NMDAR-activation in the PRh and not the BLA. These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.

Stochastic variation in protein expression generates phenotypic heterogeneity in a cell population and has an important role in antibiotic persistence, mutation penetrance, tumor growth, and therapy resistance. Studies investigating molecular origins of noise have predominantly focused on the transcription process. However, the noise generated in the transcription process is further modulated by translation. This influences the expression noise at the protein level which eventually determines the extent of phenotypic heterogeneity in a cell population. Studies across different organisms have revealed a positive association between translational efficiency and protein noise. However, the molecular basis of this association has remained unknown. In this work, through stochastic modeling of translation in single mRNA molecules and empirical measurements of protein noise, we show that ribosome demand associated with high translational efficiency in a gene drives the correlation between translational efficiency and protein noise. We also show that this correlation is present only in genes with bursty transcription. Thus, our work reveals the molecular basis of how coding sequence of genes, along with their promoters, can regulate noise. These findings have important implications for investigating protein noise and phenotypic heterogeneity across biological systems.

The recurrent pathogenic variant KCNC1-p.Ala421Val (A421V) is a cause of developmental and epileptic encephalopathy characterized by moderate-to-severe developmental delay/intellectual disability, and infantile-onset treatment-resistant epilepsy with multiple seizure types, including myoclonic seizures. Yet, the mechanistic basis of this disease, and of the KCNC1 disease spectrum, remains unclear. KCNC1 encodes Kv3.1, a voltage-gated potassium channel subunit that is strongly and selectively expressed in neurons capable of generating action potentials at high frequency, including parvalbumin-positive fast-spiking GABAergic inhibitory interneurons in cerebral cortex (PV-INs) that are known to be important for cognitive function and plasticity as well as control of network excitation to prevent seizures. In this study, we generate a novel transgenic mouse model with conditional expression of the A421V pathogenic missense variant (Kcnc1-A421V/+ mice) to explore the specific physiological mechanisms of KCNC1 developmental and epileptic encephalopathy. Our results indicate that global heterozygous expression of the A421V variant leads to cognitive impairment, epilepsy, and premature lethality. We observe decreased PV-IN cell surface expression of Kv3.1 via immunohistochemistry, decreased voltage-gated potassium current density in PV-INs using outside-out nucleated macropatch recordings in brain slice, and profound impairments in the intrinsic excitability of cerebral cortex PV-INs (but not excitatory neurons) via current-clamp electrophysiology. In vivo two-photon calcium imaging revealed altered activity in Kcnc1-A421V/+ PV-INs and excitatory cells, as well as hypersynchronous discharges correlated with brief paroxysmal movements that were subsequently shown to be myoclonic seizures on electroencephalography. We found alterations in PV-IN-mediated inhibitory neurotransmission in young adult but not juvenile Kcnc1-A421V/+ mice relative to wild-type controls. Together, these results establish the specific impact of the recurrent Kv3.1-A421V variant on neuronal excitability and synaptic physiology across development to drive network dysfunction underlying KCNC1 epileptic encephalopathy.

Differences in immunity between males and females in living organisms are generally thought to be due to sex hormones and sex chromosomes, and it is often assumed that males have a weaker immune response. Here, we report that in fish, males exhibit stronger antiviral immune responses, the male-biased gene cyp17a2 as a critical mediator of this enhanced response. First, we observed that male zebrafish exhibit enhanced antiviral resistance compared to females, and notably, zebrafish lack sex chromosomes. Through transcriptomic screening, we found that cyp17a2 was specifically highly expressed in male fish. Cyp17a2 knockout males were equivalent to wild-type males in terms of sex organs and androgen secretion, but the ability to upregulate IFN as well as antiviral resistance was greatly reduced. Then, Cyp17a2 is identified as a positive IFN regulator which is located at the endoplasmic reticulum and specifically interacts with and enhances STING-mediated antiviral responses. Mechanistically, Cyp17a2 stabilizes STING expression by recruiting the E3 ubiquitin ligase bloodthirsty-related gene family member 32 (btr32), which facilitates K33-linked polyubiquitination. The capacity of IFN induction of Cyp17a2 was abolished when STING was knocked down. Meanwhile, Cyp17a2 also attenuates viral infection directly to strengthen the antiviral capacity. As an antiviral protein, Cyp17a2 degrades the spring viremia of carp virus (SVCV) P protein by utilizing USP8 to reduce its K33-linked polyubiquitination. These findings reveal a sex-based regulatory mechanism in teleost antiviral immunity, broadening our understanding of sexual dimorphism in immune responses beyond the conventional roles of sex chromosomes and hormones.

The presence of an organelle called the fusome in species as diverse as Drosophila and mammals indicates an ancient, conserved programme of germ cell development.

During nervous system development, diverse types of neurons and glia are sequentially generated by self-renewing neural stem cells (NSCs). Temporal changes in gene expression within NSCs are thought to regulate neural diversity; however, the mechanisms regulating the timing of these temporal gene transitions remain poorly understood. Drosophila type 2 NSCs, like human outer radial glia, divide to self-renew and generate intermediate neural progenitors, amplifying and diversifying the population of neurons innervating the central complex, a brain region crucial for sensorimotor coordination. Type 2 NSCs express over a dozen genes temporally, broadly classified as early- and late-expressed genes. A conserved gene, seven-up, mediates early-to-late gene expression by activating ecdysone receptor (EcR) expression. However, the timing of EcR expression and, consequently, the transition from early-to-late gene expression remain unknown. This study investigates whether intrinsic mechanisms of cell cycle progression and cytokinesis are required to induce the NSC early-late transition. By generating mutant clones that arrest the NSC cell cycle or block cytokinesis, we show that both processes are necessary for the early-to-late transition. When NSCs are cell cycle or cytokinesis arrested, the early gene Imp fails to be downregulated and persists in the old NSCs, while the late factors EcR and Syncrip fail to be expressed. Furthermore, we demonstrate that the early factor Seven-up is insufficient to drive the transition, despite its normal expression in cell cycle- or cytokinesis-inhibited NSCs. These results suggest that both cell-intrinsic (cell cycle/cytokinesis) and -extrinsic (hormone) cues are required for the early-late NSC gene expression transition.

Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS + images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS + and CS- category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+-specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS + exemplars presented during CC, and retroactively also for CS + exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.

Ctenophores possess a unique gravity receptor (statocyst) in their aboral organ formed by four clusters of ciliated balancer cells that collectively support a statolith. During reorientation, differential loads on the balancer cilia lead to altered beating of the ciliated comb rows to elicit turns. To study the neural bases of gravity sensing, we used volume electron microscopy to image the aboral organ of the ctenophore Mnemiopsis leidyi. We reconstructed 1011 cells, including syncytial neurons that form a nerve net. The syncytial neurons synapse on the balancer cells and also form reciprocal connections with the bridge cells that span the statocyst. High-speed imaging revealed that balancer cilia beat and arrest in a coordinated manner but with differences between the sagittal and tentacular planes of the animal, reflecting nerve-net organization. Our results suggest a coordinating rather than sensory-motor function for the nerve net and inform our understanding of the diversity of nervous-system organization across animals.