Organisation of cingulum bundle fibres connecting the anterior thalamic nuclei with the rodent anterior cingulate and retrosplenial cortices

Despite considerable interest in the properties of the cingulum bundle, descriptions of the composition of this major pathway in the rodent brain have not kept pace with advances in tract tracing. Using complementary approaches in rats and mice, this study examined the dense, reciprocal connections the anterior thalamic nuclei have with the cingulate and retrosplenial cortices, connections thought to be major contributors to the rodent cingulum bundle. The rat data came from a mixture of fluorescent and viral tracers, some injected directly into the bundle. The mouse data were collated from the Allen Mouse Brain Atlas. The projections from the three major anterior thalamic nuclei occupied much of the external medullary stratum of the cingulum bundle, where they were concentrated in its more medial portions. These anterior thalamic projections formed a rostral-reaching basket of efferents prior to joining the cingulum bundle, with anteromedial efferents taking the most rostral routes, often reaching the genu of the corpus callosum, while anterodorsal efferents took the least rostral route. In contrast, the return cortico-anterior thalamic projections frequently crossed directly through the bundle or briefly joined the internal stratum of the cingulum bundle, often entering the internal capsule before reaching the anterior thalamus. These analyses confirm that anterior thalamic connections comprise an important component of the rodent cingulum bundle, while also demonstrating the very different routes used by thalamo-cortical and cortico-thalamic projections. This information reveals how the composition of the cingulum bundle alters along its length

Chemogenetics reveal an anterior cingulate-thalamic pathway for attending to task-relevant information

In a changing environment, organisms need to decide when to select items that resemble previously rewarded stimuli and when it is best to switch to other stimulus types. Here, we used chemogenetic techniques to provide causal evidence that activity in the rodent anterior cingulate cortex and its efferents to the anterior thalamic nuclei modulate the ability to attend to reliable predictors of important outcomes. Rats completed an attentional set-shifting paradigm that first measures the ability to master serial discriminations involving a constant stimulus dimension that reliably predicts reinforcement (intradimensional-shift), followed by the ability to shift attention to a previously irrelevant class of stimuli when reinforcement contingencies change (extradimensional-shift). Chemogenetic disruption of the anterior cingulate cortex (Experiment 1) as well as selective disruption of anterior cingulate efferents to the anterior thalamic nuclei (Experiment 2) impaired intradimensional learning but facilitated 2 sets of extradimensional-shifts. This pattern of results signals the loss of a corticothalamic system for cognitive control that preferentially processes stimuli resembling those previously associated with reward. Previous studies highlight a separate medial prefrontal system that promotes the converse pattern, that is, switching to hitherto inconsistent predictors of reward when contingencies change. Competition between these 2 systems regulates cognitive flexibility and choice

The Anatomical Boundary of the Rat Claustrum

The claustrum is a subcortical nucleus that exhibits dense connectivity across the neocortex. Considerable recent progress has been made in establishing its genetic and anatomical characteristics, however, a core, contentious issue that regularly presents in the literature pertains to the rostral extent of its anatomical boundary. The present study addresses this issue in the rat brain. Using a combination of immunohistochemistry and neuroanatomical tract tracing, we have examined the expression profiles of several genes that have previously been identified as exhibiting a differential expression profile in the claustrum relative to the surrounding cortex. The expression profiles of parvalbumin (PV), crystallin mu (Crym), and guanine nucleotide binding protein (G protein), gamma 2 (Gng2) were assessed immunohistochemically alongside, or in combination with cortical anterograde, or retrograde tracer injections. Retrograde tracer injections into various thalamic nuclei were used to further establish the rostral border of the claustrum. Expression of all three markers delineated a nuclear boundary that extended considerably (∼500 μm) beyond the anterior horn of the neostriatum. Cortical retrograde and anterograde tracer injections, respectively, revealed distributions of cortically-projecting claustral neurons and cortical efferent inputs to the claustrum that overlapped with the gene marker-derived claustrum boundary. Finally, retrograde tracer injections into the thalamus revealed insular cortico-thalamic projections encapsulating a claustral area with strongly diminished cell label, that extended rostral to the striatum

Cingulate cortex-anterior thalamic connectivity: Anatomy and function

The cingulum bundle is a highly complex fibre pathway that is implicated in a wide array of functions, yet little is known about its constituent connections and their differential contributions to cognition. This thesis investigated the dense interconnections between the cingulate cortices and the anterior thalamic nuclei, many of which join the cingulum. Initially, contemporary viral-based tract tracing techniques in the rat provided an anatomical reappraisal of this major component of the tract. This investigation revealed that many fibres between the anterior cingulate cortex and the anteromedial thalamic nucleus are present in the anterior cingulum, a subsection typically associated with executive function. Connections between the retrosplenial cortex and the anteroventral thalamic nucleus, meanwhile, primarily occupy the posterior cingulum, a subsection linked to memory. Next, this thesis investigated the role of anterior cingulate-anterior thalamic interconnectivity in attention. Existing evidence implicates both regions in intradimensional set-shifting, where discriminations are most effectively solved by responding to a stimulus dimension that previously predicted reward. A series of DREADDs manipulations confirmed that the anterior cingulate cortex supports this attentional function in rats, and novel evidence indicated that projections to the anterior thalamic nuclei critically contribute to this capacity. This thesis further found that in the absence of normal anterior cingulate function, inappropriate attention appears to be directed to unreliable reward predictors, facilitating performance when contingencies change (extradimensional shift). These findings are best explained by dual-process theories of attention where competing learning parameters, with distinct neural underpinnings, mediate the allocation of attentional resources. One process directs attention to reliable predictors of outcomes (reliant on the anterior cingulate cortex and its actions on the anterior thalamic nuclei), while another biases attention towards unreliable predictors of outcome

CRISPR Deletion of a SVA Retrotransposon Demonstrates Function as a cis-Regulatory Element at the TRPV1/TRPV3 Intergenic Region

SINE-VNTR-Alu (SVA) retrotransposons are a subclass of transposable elements (TEs) that exist only in primate genomes. TE insertions can be co-opted as cis-regulatory elements (CREs); however, the regulatory potential of SVAs has predominantly been demonstrated using bioinformatic approaches and reporter gene assays. The objective of this study was to demonstrate SVA cis-regulatory activity by CRISPR (clustered regularly interspaced short palindromic repeats) deletion and subsequent measurement of direct effects on local gene expression. We identified a region on chromosome 17 that was enriched with human-specific SVAs. Comparative gene expression analysis at this region revealed co-expression of TRPV1 and TRPV3 in multiple human tissues, which was not observed in mouse, highlighting key regulatory differences between the two species. Furthermore, the intergenic region between TRPV1 and TRPV3 coding sequences contained a human specific SVA insertion located upstream of the TRPV3 promoter and downstream of the 3′ end of TRPV1, highlighting this SVA as a candidate to study its potential cis-regulatory activity on both genes. Firstly, we generated SVA reporter gene constructs and demonstrated their transcriptional regulatory activity in HEK293 cells. We then devised a dual-targeting CRISPR strategy to facilitate the deletion of this entire SVA sequence and generated edited HEK293 clonal cell lines containing homozygous and heterozygous SVA deletions. In edited homozygous ∆SVA clones, we observed a significant decrease in both TRPV1 and TRPV3 mRNA expression, compared to unedited HEK293. In addition, we also observed an increase in the variability of mRNA expression levels in heterozygous ∆SVA clones. Overall, in edited HEK293 with SVA deletions, we observed a disruption to the co-expression of TRPV1 and TRPV3. Here we provide an example of a human specific SVA with cis-regulatory activity in situ, supporting the role of SVA retrotransposons as contributors to species-specific gene expression

Discovery of an edge-on circumstellar debris disk around BD+45° 598 : a newly identified member of the β Pictoris moving group

We report the discovery of a circumstellar debris disk viewed nearly edge-on and associated with the young, K1 star BD+45° 598 using high-contrast imaging at 2.2 μm obtained at the W.M. Keck Observatory. We detect the disk in scattered light with a peak significance of ∼5σ over three epochs, and our best-fit model of the disk is an almost edge-on ∼70 au ring, with inclination angle ∼87°. Using the NOEMA interferometer at the Plateau de Bure Observatory operating at 1.3 mm, we find resolved continuum emission aligned with the ring structure seen in the 2.2 μm images. We estimate a fractional infrared luminosity of LIR/Ltot $\simeq \,{6}_{-1}^{+2}$ × 10−4, higher than that of the debris disk around AU Mic. Several characteristics of BD+45° 598, such as its galactic space motion, placement in a color–magnitude diagram, and strong presence of lithium, are all consistent with its membership in the β Pictoris Moving Group with an age of 23 ± 3 Myr. However, the galactic position for BD+45° 598 is slightly discrepant from previously known members of the β Pictoris Moving Group, possibly indicating an extension of members of this moving group to distances of at least 70 pc. BD+45° 598 appears to be an example from a population of young circumstellar debris systems associated with newly identified members of young moving groups that can be imaged in scattered light, key objects for mapping out the early evolution of planetary systems from ∼10–100 Myr. This target will also be ideal for northern-hemisphere, high-contrast imaging platforms to search for self-luminous, planetary mass companions residing in this system

Genome-wide analysis of Structural Variants in Parkinson's Disease.

ObjectiveIdentification of genetic risk factors for Parkinson's disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.MethodsWe leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data.ResultsWe genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2kb intronic deletion within the gene LRRN4.InterpretationWe identify three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. This article is protected by copyright. All rights reserved