Prioritized memory access explains planning and hippocampal replay, bioRxiv, 2017-11-28
AbstractTo make decisions, animals must evaluate outcomes of candidate choices by accessing memories of relevant experiences. Yet little is known about which experiences are considered or ignored during deliberation, which ultimately governs choice. Here, we propose a normative theory to predict which memories should be accessed at each moment to optimize future decisions. Using nonlocal “replay” of spatial locations in hippocampus as a window into memory access, we simulate a spatial navigation task where an agent accesses memories of locations sequentially, ordered by utility how much extra reward would be earned due to the computation enabling better choices. This prioritization balances two desiderata the need to evaluate imminent choices, vs. the gain from propagating newly encountered information to predecessor states. We show that this theory offers a unifying account of a range of hitherto disconnected findings in the place cell literature such as the balance of forward and reverse replay, biases in the replayed content, and effects of experience. Accordingly, various types of nonlocal events during behavior and rest are re-interpreted as instances of a single choice evaluation operation, unifying seemingly disparate proposed functions of replay including planning, learning and consolidation, and whose dysfunction may underlie pathologies like rumination and craving.
biorxiv neuroscience 0-100-users 2017A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality, bioRxiv, 2017-11-26
SUMMARYModern genetic approaches are powerful in providing access to diverse types of neurons within the mammalian brain and greatly facilitating the study of their function. We here report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically-defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.
biorxiv neuroscience 200-500-users 2017Common risk variants identified in autism spectrum disorder, bioRxiv, 2017-11-26
AbstractAutism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.
biorxiv genetics 200-500-users 2017Deciphering eukaryotic cis-regulatory logic with 100 million random promoters, bioRxiv, 2017-11-26
AbstractDeciphering cis-regulation, the code by which transcription factors (TFs) interpret regulatory DNA sequence to control gene expression levels, is a long-standing challenge. Previous studies of native or engineered sequences have remained limited in scale. Here, we use random sequences as an alternative, allowing us to measure the expression output of over 100 million synthetic yeast promoters. Random sequences yield a broad range of reproducible expression levels, indicating that the fortuitous binding sites in random DNA are functional. From these data we learn models of transcriptional regulation that predict over 94% of the expression driven from independent test data and nearly 89% from sequences from yeast promoters. These models allow us to characterize the activity of TFs and their interactions with chromatin, and help refine cis-regulatory motifs. We find that strand, position, and helical face preferences of TFs are widespread and depend on interactions with neighboring chromatin. Such massive-throughput regulatory assays of random DNA provide the diverse examples necessary to learn complex models of cis-regulatory logic.
biorxiv genomics 200-500-users 2017Human VMPFC encodes early signatures of confidence in perceptual decisions, bioRxiv, 2017-11-26
AbstractChoice confidence, an individual’s internal estimate of judgment accuracy, plays a critical role in adaptive behaviour. Despite its importance, the early (decisional) stages of confidence processing remain underexplored. Here, we recorded simultaneous EEGfMRI while participants performed a direction discrimination task and rated their confidence on each trial. Using multivariate single-trial discriminant analysis of the EEG, we identified a stimulus- and accuracy-independent component encoding confidence, appearing prior to subjects’ choice and explicit confidence report. The trial-to-trial variability in this EEG-derived confidence signal was uniquely associated with fMRI responses in the ventromedial prefrontal cortex (VMPFC), a region not typically associated with confidence for perceptual decisions. Furthermore, we showed that the VMPFC was functionally coupled with regions of the prefrontal cortex that support neural representations of confidence during explicit metacognitive report. Our results suggest that the VMPFC encodes an early confidence readout, preceding and potentially informing metacognitive evaluation and learning, by acting as an implicit valuereward signal.
biorxiv neuroscience 0-100-users 2017Nonequilibrium entropic bounds for Darwinian replicators, bioRxiv, 2017-11-26
Life evolved on our planet by means of a combination of Darwinian selection and innovations leading to higher levels of complexity. The emergence and selection of replicating entities is a central problem in prebiotic evolution. Theoretical models have shown how populations of different types of replicating entities exclude or coexist with other classes of replicators. Models are typically kinetic, based on standard replicator equations. On the other hand, the presence of thermodynamical constrains for these systems remain an open question. This is largely due to the lack of a general theory of out of statistical methods for systems far from equilibrium. Nonetheless, a first approach to this problem has been put forward in a series of novel developements in non-equilibrium physics, under the rubric of the extended second law of thermodynamics. The work presented here is twofold firstly, we review this theoretical framework and provide a brief description of the three fundamental replicator types in prebiotic evolution parabolic, malthusian and hyperbolic. Finally, we employ these previously mentioned techinques to explore how replicators are constrained by thermodynamics.
biorxiv biophysics 0-100-users 2017