Challenges for brain repair: insights from adult neurogenesis in birds and mammals

Adult neurogenesis is a widespread phenomenon occurring in many species, including humans. The functional and therapeutic implications of this form of brain plasticity are now beginning to be realized. Comparative approaches to adult neurogenesis will yield important clues about brain repair. Here, we compare adult neurogenesis in birds and mammals. We review recent studies on the glial identity of stem cells that generate new neurons, the different modes of migration used by the newly generated neurons to reach their destinations, and how these systems respond to experimentally induced cell death. We integrate these findings to address how comparative analysis at the molecular level might be used for brain repair

Powers of the Vandermonde determinant, Schur Functions, and recursive formulas

Since every even power of the Vandermonde determinant is a symmetric polynomial, we want to understand its decomposition in terms of the basis of Schur functions. We investigate several combinatorial properties of the coefficients in the decomposition. In particular, we give recursive formulas for the coefficient of the Schur function s_{\m} in the decomposition of an even power of the Vandermonde determinant in $n + 1$ variables in terms of the coefficient of the Schur function s_{\l} in the decomposition of the same even power of the Vandermonde determinant in $n$ variables if the Young diagram of \m is obtained from the Young diagram of \l by adding a tetris type shape to the top or to the left. An extended abstract containing the statement of the results presented here appeared in the Proceedings of FPSAC11Comment: 23 pages; extended abstract appeared in the Proceedings of FPSAC1

FOXP2 as a molecular window into speech and language [Review article]

Rare mutations of the FOXP2 transcription factor gene cause a monogenic syndrome characterized by impaired speech development and linguistic deficits. Recent genomic investigations indicate that its downstream neural targets make broader impacts on common language impairments, bridging clinically distinct disorders. Moreover, the striking conservation of both FoxP2 sequence and neural expression in different vertebrates facilitates the use of animal models to study ancestral pathways that have been recruited towards human speech and language. Intriguingly, reduced FoxP2 dosage yields abnormal synaptic plasticity and impaired motor-skill learning in mice, and disrupts vocal learning in songbirds. Converging data indicate that Foxp2 is important for modulating the plasticity of relevant neural circuits. This body of research represents the first functional genetic forays into neural mechanisms contributing to human spoken language

AID Overlapping and Polη Hotspots Are Key Features of Evolutionary Variation Within the Human Antibody Heavy Chain (IGHV) Genes

© Copyright © 2020 Tang, Bagnara, Chiorazzi, Scharff and MacCarthy. Somatic hypermutation (SHM) of the immunoglobulin variable (IgV) loci is a key process in antibody affinity maturation. The enzyme activation-induced deaminase (AID), initiates SHM by creating C → U mismatches on single-stranded DNA (ssDNA). AID has preferential hotspot motif targets in the context of WRC/GYW (W = A/T, R = A/G, Y = C/T) and particularly at WGCW overlapping hotspots where hotspots appear opposite each other on both strands. Subsequent recruitment of the low-fidelity DNA repair enzyme, Polymerase eta (Polη), during mismatch repair, creates additional mutations at WA/TW sites. Although there are more than 50 functional immunoglobulin heavy chain variable (IGHV) segments in humans, the fundamental differences between these genes and their ability to respond to all possible foreign antigens is still poorly understood. To better understand this, we generated profiles of WGCW hotspots in each of the human IGHV genes and found the expected high frequency in complementarity determining regions (CDRs) that encode the antigen binding sites but also an unexpectedly high frequency of WGCW in certain framework (FW) sub-regions. Principal Components Analysis (PCA) of these overlapping AID hotspot profiles revealed that one major difference between IGHV families is the presence or absence of WGCW in a sub-region of FW3 sometimes referred to as “CDR4.” Further differences between members of each family (e.g., IGHV1) are primarily determined by their WGCW densities in CDR1. We previously suggested that the co-localization of AID overlapping and Polη hotspots was associated with high mutability of certain IGHV sub-regions, such as the CDRs. To evaluate the importance of this feature, we extended the WGCW profiles, combining them with local densities of Polη (WA) hotspots, thus describing the co-localization of both types of hotspots across all IGHV genes. We also verified that co-localization is associated with higher mutability. PCA of the co-localization profiles showed CDR1 and CDR2 as being the main contributors to variance among IGHV genes, consistent with the importance of these sub-regions in antigen binding. Our results suggest that AID overlapping (WGCW) hotspots alone or in conjunction with Polη (WA/TW) hotspots are key features of evolutionary variation between IGHV genes

Temporal regularity increases with repertoire complexity in the Australian pied butcherbird's song

Music maintains a characteristic balance between repetition and novelty. Here, we report a similar balance in singing performances of free-living Australian pied butcherbirds. Their songs include many phrase types. The more phrase types in a bird's repertoire, the more diverse the singing performance can be. However, without sufficient temporal organization, avian listeners may find diverse singing performances difficult to perceive and memorize. We tested for a correlation between the complexity of song repertoire and the temporal regularity of singing performance. We found that different phrase types often share motifs (notes or stereotyped groups of notes). These shared motifs reappeared in strikingly regular temporal intervals across different phrase types, over hundreds of phrases produced without interruption by each bird. We developed a statistical estimate to quantify the degree to which phrase transition structure is optimized for maximizing the regularity of shared motifs. We found that transition probabilities between phrase types tend to maximize regularity in the repetition of shared motifs, but only in birds of high repertoire complexity. Conversely, in birds of low repertoire complexity, shared motifs were produced with less regularity. The strong correlation between repertoire complexity and motif regularity suggests that birds possess a mechanism that regulates the temporal placement of shared motifs in a manner that takes repertoire complexity into account. We discuss alternative musical, mechanistic and ecological explanations to this effect

Long-Distance Retinoid Signaling in the Zebra Finch Brain

All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, is a powerful signaling molecule that regulates large-scale morphogenetic processes during vertebrate embryonic development, but is also involved post-natally in regulating neural plasticity and cognition. In songbirds, it plays an important role in the maturation of learned song. The distribution of the ATRA-synthesizing enzyme, zRalDH, and of ATRA receptors (RARs) have been described, but information on the distribution of other components of the retinoid signaling pathway is still lacking. To address this gap, we have determined the expression patterns of two obligatory RAR co-receptors, the retinoid X receptors (RXR) α and γ, and of the three ATRA-degrading cytochromes CYP26A1, CYP26B1, and CYP26C1. We have also studied the distribution of zRalDH protein using immunohistochemistry, and generated a refined map of ATRA localization, using a modified reporter cell assay to examine entire brain sections. Our results show that (1) ATRA is more broadly distributed in the brain than previously predicted by the spatially restricted distribution of zRalDH transcripts. This could be due to long-range transport of zRalDH enzyme between different nuclei of the song system: Experimental lesions of putative zRalDH peptide source regions diminish ATRA-induced transcription in target regions. (2) Four telencephalic song nuclei express different and specific subsets of retinoid-related receptors and could be targets of retinoid regulation; in the case of the lateral magnocellular nucleus of the anterior nidopallium (lMAN), receptor expression is dynamically regulated in a circadian and age-dependent manner. (3) High-order auditory areas exhibit a complex distribution of transcripts representing ATRA synthesizing and degrading enzymes and could also be a target of retinoid signaling. Together, our survey across multiple connected song nuclei and auditory brain regions underscores the prominent role of retinoid signaling in modulating the circuitry that underlies the acquisition and production of learned vocalizations

A tool for rating chronic disease prevention and public health interventions

Bridging the gap between research and practice requires more than evaluating the effectiveness of interventions in controlled studies. To bridge this gap, evidence needs to be defined in different ways, and opportunities need to be provided for practice-based evidence to be replicated and disseminated. Community-based interventions are often not conducted or evaluated in controlled settings, yet they provide more real-world context and have the potential to have a greater effect on population health than findings from controlled studies that are limited in generalizability. The purpose of this article is to describe an approach to identify community-based programs and interventions that have the potential for replication and dissemination. In our study, such interventions met criteria in 3 primary domains: innovativeness, effectiveness, and sustainability. The criteria and tool developed were applied to 2 obesity-prevention programs to demonstrate the usefulness of the tool for identifying potential programs for replication and dissemination, contributing to practice-based evidence. Funders, practitioners, and researchers can apply these criteria to identify programs, environmental changes, or policies that may be replicated and disseminated