A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Reassessing the Dialogic Possibilities of Weak-Form Bills of Rights

In recent years, weak-form bills of rights have generated much excitement in contemporary constitutional scholarship because they are believed to create a new balance between parliamentary and judicial supremacy based on inter-branch dialogue between courts and legislatures. Few scholars, however, have examined the foundational question of whether judges and legislators can actually be expected to behave in a way that realizes the dialogic potential of weak-form instruments. This Article takes a new approach to this question, applying the insights of positive theory to engage in a comprehensive assessment of the behavior we can realistically expect of courts and legislatures in both strong- and weak-form systems of judicial review. To the extent that there are discernable differences between systems regarding how the judiciary and the legislature interact, the Article claims that this behavior is more likely to be driven by the existence of structural and/or strategic impediments to effective political action in a particular constitutional system, rather than by any normative desire that judges and legislators may have to engage in inter-branch dialogue. This analysis does not lead to the conclusion, however, that the concept of dialogue should be completely discarded. Instead, the Article takes its positive analysis one step further to claim that weak-form theorists have simply been looking for dialogue in the wrong place. In fact, all systems of judicial review, both strong- and weak-form, should be understood as generating a broader form of society-wide dialogue between the judiciary, the political branches and the people about the meaning and interpretation of fundamental rights

Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology.

A major challenge for neuroscience, public health, and evolutionary biology is to understand the effects of scarcity and uncertainty on the developing brain. Currently, a significant fraction of children and adolescents worldwide experience insecure access to food. The goal of our work was to test in mice whether the transient experience of insecure versus secure access to food during the juvenile-adolescent period produced lasting differences in learning, decision-making, and the dopamine system in adulthood. We manipulated feeding schedules in mice from postnatal day (P)21 to P40 as food insecure or ad libitum and found that when tested in adulthood (after P60), males with different developmental feeding history showed significant differences in multiple metrics of cognitive flexibility in learning and decision-making. Adult females with different developmental feeding history showed no differences in cognitive flexibility but did show significant differences in adult weight. We next applied reinforcement learning models to these behavioral data. The best fit models suggested that in males, developmental feeding history altered how mice updated their behavior after negative outcomes. This effect was sensitive to task context and reward contingencies. Consistent with these results, in males, we found that the two feeding history groups showed significant differences in the AMPAR/NMDAR ratio of excitatory synapses on nucleus-accumbens-projecting midbrain dopamine neurons and evoked dopamine release in dorsal striatal targets. Together, these data show in a rodent model that transient differences in feeding history in the juvenile-adolescent period can have significant impacts on adult weight, learning, decision-making, and dopamine neurobiology

The Polyglot Search Translator (PST): Evaluation of a tool for improving searching in systematic reviews: A randomised cross-over trial

Background: To improve the speed and quality of literature searching for systematic reviews (SRs) we developed an online tool, the Polyglot Search Translator (PST). This tool helps to automatically translate searches across multiple databases by modifying the database-specific syntax, removing the need to do this manually.Objectives: To determine whether the PST improves the speed and quality of database searching for SRs.Methods: From a pool of 20 randomly selected database search strategies from reviews of drug and non-drug interventions, diagnostic tests, prevalence, prognosis and health technology assessments, each of 20 participants were randomly assigned 10 searches and randomly allocated to translate the search manually or with the PST. The participants were asked to translate each search into three databases from the following: PubMed or Ovid MEDLINE, Embase.com or Ovid Embase, the Cochrane Library, CINAHL, Web of Science or Scopus. We measured: 1) the time taken to translate the search strategies using manual methods or the PST (these were compared against each other); 2) the number of search results found by the participants, compared to the number found by a reference standard developed through consensus by two Cochrane information specialists; 3) errors found in the participants' searches, identified through consensus by the two Cochrane information specialists (manual errors will be compared to PST errors).Results: Preliminary results show that when compared with a manual method, using the PST to translate a search saved an average of 10 minutes per database; this increased to over 100 minutes per database on the most complex search. As more data become available, a more accurate representation of the time saving is expected. The number of search results found and errors in the searches are still being analysed.Conclusions: Initial data show that the PST saves time when searching for studies for inclusion in a SR. Analysis has not yet begun of the quality of search translations; these data will be presented.Patient or healthcare consumer involvement: Although not directly involving patients or health care consumers, the PST could open pathways for less experienced individuals to be involved in a SR and speed up SR production, with the benefit to consumers of having access to more up-to-date SRs

Improving the translation of search strategies using the Polyglot Search Translator: a randomized controlled trial

Background: Searching for studies to include in a systematic review (SR) is a time- and labor-intensive process with searches of multiple databases recommended. To reduce the time spent translating search strings across databases, a tool called the Polyglot Search Translator (PST) was developed. The authors evaluated whether using the PST as a search translation aid reduces the time required to translate search strings without increasing errors.Methods: In a randomized trial, twenty participants were randomly allocated ten database search strings and then randomly assigned to translate five with the assistance of the PST (PST-A method) and five without the assistance of the PST (manual method). We compared the time taken to translate search strings, the number of errors made, and how close the number of references retrieved by a translated search was to the number retrieved by a reference standard translation.Results: Sixteen participants performed 174 translations using the PST-A method and 192 translations using the manual method. The mean time taken to translate a search string with the PST-A method was 31 minutes versus 45 minutes by the manual method (mean difference: 14 minutes). The mean number of errors made per translation by the PST-A method was 8.6 versus 14.6 by the manual method. Large variation in the number of references retrieved makes results for this outcome inconclusive, although the number of references retrieved by the PST-A method was closer to the reference standard translation than the manual method.Conclusion: When used to assist with translating search strings across databases, the PST can increase the speed of translation without increasing errors. Errors in search translations can still be a problem, and search specialists should be aware of this.</p