Coupling between motor cortex and striatum increases during sleep over long-term skill learning
The strength of cortical connectivity to the striatum influences the balance between behavioral variability and stability. Learning to consistently produce a skilled action requires plasticity in corticostriatal connectivity associated with repeated training of the action. However, it remains unknown whether such corticostriatal plasticity occurs during training itself or 'offline' during time away from training, such as sleep. Here, we monitor the corticostriatal network throughout long-term skill learning in rats and find that non-REM (NREM) sleep is a relevant period for corticostriatal plasticity. We first show that th...
Source: eLife - September 10, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Coherent theta activity in the medial and orbital frontal cortices encodes reward value
This study examined how the medial frontal (MFC) and orbital frontal (OFC) cortices process reward information. We simultaneously recorded local field potentials in the two areas as rats consumed liquid sucrose rewards. Both areas exhibited a 4-8 Hz 'theta' rhythm that was phase locked to the lick cycle. The rhythm tracked shifts in sucrose concentrations and fluid volumes, demonstrating that it is sensitive to differences in reward magnitude. The coupling between the rhythm and licking was stronger in MFC than OFC and varied with response vigor and absolute reward value in the MFC. Spectral analysis revealed zero-lag cohe...
Source: eLife - September 10, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Structural basis for membrane recruitment of ATG16L1 by WIPI2 in Autophagy
Autophagy is a cellular process that degrades cytoplasmic cargo by engulfing it in a double membrane vesicle, known as the autophagosome, and delivering it to the lysosome. The ATG12-5-16L1 complex is responsible for conjugating members of the ubiquitin-like ATG8 protein family to phosphatidylethanolamine in the growing autophagosomal membrane, known as the phagophore. ATG12-5-16L1 is recruited to the phagophore by a subset of the phosphatidylinositol 3-phosphate-binding seven bladed รข-propeller WIPI proteins. We determined the crystal structure of WIPI2d in complex with the WIPI2 interacting region (W2IR) of ATG16L1 comp...
Source: eLife - September 10, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

End-of-life targeted auxin-mediated degradation of DAF-2 Insulin/IGF-1 receptor promotes longevity free from growth-related pathologies
Preferably, lifespan-extending therapies should work when applied late in life without causing undesired pathologies. Reducing Insulin/IGF-1 signaling (IIS) increases lifespan across species, but the effects of reduced IIS interventions in extreme geriatric ages remains unknown. Using the nematodeC. elegans, we engineered the conditional depletion of the DAF-2/insulin/IGF-1 transmembrane receptor using an auxin-inducible degradation (AID) system. This allowed for the temporal and spatial reduction in DAF-2 protein levels at time points after which interventions such as RNAi become ineffective. Using this system, we found t...
Source: eLife - September 10, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Little evidence that Eurasian jays protect their caches by responding to cues about a conspecific's desire and visual perspective
Eurasian jays have been reported to protect their caches by responding to cues about either the visual perspective or current desire of an observing conspecific, similarly to other corvids. Here, we used established paradigms to test whether these birds can - like humans - integrate multiple cues about different mental states and perform an optimal response accordingly. Across five experiments, which also include replications of previous work, we found little evidence that our jays adjusted their caching behaviour in line with the visual perspective and current desire of another agent, neither by integrating these social c...
Source: eLife - September 10, 2021 Category: Biomedical Science Tags: Ecology Source Type: research

Heterogeneous side-effects of cortical inactivation in behaving animals
Cortical inactivation represents a key causal manipulation that allows the study of cortical circuits and their impact on behavior. A key assumption in these studies is that the neurons in the target area become silent while the surrounding cortical tissue is only negligibly impacted. However, individual neurons are embedded in complex local circuits comprised of excitatory and inhibitory cells with connections extending hundreds of microns. This raises the possibility that silencing one part of the network could induce complex, unpredictable activity changes in neurons outside the targeted inactivation zone. These off-tar...
Source: eLife - September 10, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

The amyloid precursor protein is a conserved Wnt receptor
The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP...
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Neuronal calmodulin levels are controlled by CAMTA transcription factors
The ubiquitous Ca2+ sensor calmodulin (CaM) binds and regulates many proteins, including ion channels, CaM kinases, and calcineurin, according to Ca2+-CaM levels. What regulates neuronal CaM levels, is, however, unclear. CaM-binding transcription activators (CAMTAs) are ancient proteins expressed broadly in nervous systems and whose loss confers pleiotropic behavioral defects in flies, mice, and humans. UsingCaenorhabditis elegans andDrosophila, we show that CAMTAs control neuronal CaM levels. The behavioral and neuronal Ca2+ signaling defects in mutants lackingcamt-1, the soleC. elegans CAMTA, can be rescued by supplement...
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Genetics and Genomics Neuroscience Source Type: research

Lipid droplets and ferritin heavy chain: a devilish liaison in human cancer cell radioresistance
Although much progress has been made in cancer treatment, the molecular mechanisms underlying cancer radioresistance (RR) as well as the biological signatures of radioresistant cancer cells still need to be clarified. In this regard, we discovered that breast, bladder, lung, neuroglioma and prostate 6 Gy X-ray resistant cancer cells were characterized by an increase of Lipid Droplet (LD) number and that the cells containing highest LDs showed the highest clonogenic potential after irradiation. Moreover, we observed that LD content was tightly connected with the iron metabolism and in particular with the presence of the fer...
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Finding the right sequence of drugs
Rapidly switching between similar antibiotics may help to slow down the evolution of resistance. (Source: eLife)
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Correction: RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination
(Source: eLife)
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Cell Biology Immunology and Inflammation Source Type: research

The corticospinal tract primarily modulates sensory inputs in the mouse lumbar cord
It is generally assumed that the main function of the corticospinal tract (CST) is to convey motor commands to bulbar or spinal motoneurons. Yet the CST has also been shown to modulate sensory signals at their entry point in the spinal cord through primary afferent depolarization (PAD). By sequentially investigating different routes of corticofugal pathways through electrophysiological recordings and an intersectional viral strategy, we here demonstrate that motor and sensory modulation commands in mice belong to segregated paths within the CST. Sensory modulation is executed exclusively by the CST via a population of lumb...
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Witnessing the structural evolution of an RNA enzyme
An RNA polymerase ribozyme that has been the subject of extensive directed evolution efforts has attained the ability to synthesize complex functional RNAs, including a full-length copy of its own evolutionary ancestor. During the course of evolution, the catalytic core of the ribozyme has undergone a major structural rearrangement, resulting in a novel tertiary structural element that lies in close proximity to the active site. Through a combination of site-directed mutagenesis, structural probing, and deep sequencing analysis, the trajectory of evolution was seen to involve the progressive stabilization of the new struct...
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

How infectious diseases arrived in the colonial Americas
Analysis of viral DNA from human remains suggests that the transatlantic slave trade may have introduced new pathogens that contributed to the devastating disease outbreaks in colonial Mexico. (Source: eLife)
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Genetics and Genomics Microbiology and Infectious Disease Source Type: research

Enhanced Cas12a multi-gene regulation using a CRISPR array separator
The type V-A Cas12a protein can process its CRISPR array, a feature useful for multiplexed gene editing and regulation. However, CRISPR arrays often exhibit unpredictable performance due to interference between multiple guide RNA (gRNAs). Here, we report that Cas12a array performance is hypersensitive to the GC content of gRNA spacers, as high-GC spacers can impair activity of the downstream gRNA. We analyze naturally occurring CRISPR arrays and observe that natural repeats always contain an AT-rich fragment that separates gRNAs, which we term aCRISPR separator. Inspired by this observation, we design short, AT-rich synthe...
Source: eLife - September 9, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Evolutionary Biology Source Type: research