Cortical Evolution Research Articles

Development's Inaugural Outstanding Paper Prize.

Development's Inaugural Outstanding Paper Prize.

Threat Memory in the Sensory Cortex: Insights from Olfaction

The amygdala has long held the center seat in the neural basis of threat conditioning. However, a rapidly growing literature has elucidated extra-amygdala circuits in this process, highlighting the sensory cortex for its critical role in the mnemonic aspect of the process. While this literature is largely focused on the auditory system, substantial human and rodent findings on the olfactory system have emerged. The unique nature of the olfactory neuroanatomy and its intimate association with emotion compels a review of this recent literature to illuminate its special contribution to threat memory. Here, integrating recent evidence in humans and animal models, we posit that the olfactory (piriform) cortex is a primary and necessary component of the distributed threat memory network, supporting mnemonic ensemble coding of acquired threat. We further highlight the basic circuit architecture of the piriform cortex characterized by distributed, auto-associative connections, which is prime for highly efficient content-addressable memory computing to support threat memory. Given the primordial role of the piriform cortex in cortical evolution and its simple, well-defined circuits, we propose that olfaction can be a model system for understanding (transmodal) sensory cortical mechanisms underlying threat memory.

Cortical Organoids to Model Microcephaly.

How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man’s place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, many human specificities call for appropriate models. In particular, microcephaly, a neurodevelopmental disorder that is characterized by a smaller head circumference has been challenging to model in mice, which often do not fully recapitulate the human phenotype. The relatively recent development of brain organoid technology from induced pluripotent stem cells (iPSCs) now makes it possible to model human microcephaly, both due to genetic and environmental origins, and to generate developing cortical tissue from the patients themselves. These 3D tissues rely on iPSCs differentiation into cortical progenitors that self-organize into neuroepithelial rosettes mimicking the earliest stages of human neurogenesis in vitro. Over the last ten years, numerous protocols have been developed to control the identity of the induced brain areas, the reproducibility of the experiments and the longevity of the cultures, allowing analysis of the later stages. In this review, we describe the different approaches that instruct human iPSCs to form cortical organoids, summarize the different microcephalic conditions that have so far been modeled by organoids, and discuss the relevance of this model to decipher the cellular and molecular mechanisms of primary and secondary microcephalies.

Assessment of in vivo bone activity patterns in medial mobile-bearing unicompartmental knee arthroplasty : a prospective SPECT/CT study.

Higher osteoblastic bone activity is expected in aseptic loosening and painful unicompartmental knee arthroplasty (UKA). However, insights into normal bone activity patterns after medial UKAs are lacking. The aim of this study was to identify the evolution in bone activity pattern in well-functioning medial mobile-bearing UKAs. In total, 34 patients (13 female, 21 male; mean age 62 years (41 to 79); BMI 29.7 kg/m2 (23.6 to 42.1)) with 38 medial Oxford partial UKAs (20 left, 18 right; 19 cementless, 14 cemented, and five hybrid) were prospectively followed with sequential 99mTc-hydroxymethane diphosphonate single photon emission CT (SPECT)/CT preoperatively, and at one and two years postoperatively. Changes in mean osteoblastic activity were investigated using a tracer localization scheme with volumes of interest (VOIs), reported by normalized mean tracer values. A SPECT/CT registration platform additionally explored cortical tracer evolution in zones of interest identified by previous experimental research. Significant reduction of tracer activity from the preoperative situation was found in femoral and anteromedial tibial VOIs adjacent to the UKA components. Temporarily increased osteoblastic bone activity was observed in VOIs comprising the UKA keel structure at one year postoperatively compared to the preoperative activity. Persistent higher tracer uptake was found in the posterior tibial cortex at final follow-up. Multivariate analysis showed no statistical difference in osteoblastic bone activity underneath cemented or cementless components. Well-functioning medial mobile-bearing UKAs showed distinct changes in patterns of normalized bone tracer activity in the different VOIs adjacent to the prosthetic components, regardless of their type of fixation. Compared to the preoperative situation, persistent high bone activity was found underneath the keel and the posterior tibial cortex at final follow-up, with significant reduced activity only being identified in femoral and anteromedial tibial VOIs. Cite this article: Bone Joint J2022;104-B(1):34-44.

Human brain evolution: Emerging roles for regulatory DNA and RNA.

Humans diverge from other primates in numerous ways, including their neuroanatomy and cognitive capacities. Human-specific features are particularly prominent in the cerebral cortex, which has undergone an expansion in size and acquired unique cellular composition and circuitry. Human-specific gene expression is postulated to explain neocortical anatomical differences across evolution. In particular, noncoding regulatory loci are strongly linked to human traits, including progenitor proliferation and cortical size. In this review, we highlight emerging noncoding elements implicated in human cortical evolution, including roles for regulatory DNA and RNA. Further, we discuss the association of human-specific genetic changes with neurodevelopmental diseases.

Structural Connectivity Gradients of the Temporal Lobe Serve as Multiscale Axes of Brain Organization and Cortical Evolution.

The temporal lobe is implicated in higher cognitive processes and is one of the regions that underwent substantial reorganization during primate evolution. Its functions are instantiated, in part, by the complex layout of its structural connections. Here, we identified low-dimensional representations of structural connectivity variations in human temporal cortex and explored their microstructural underpinnings and associations to macroscale function. We identified three eigenmodes which described gradients in structural connectivity. These gradients reflected inter-regional variations in cortical microstructure derived from quantitative magnetic resonance imaging and postmortem histology. Gradient-informed models accurately predicted macroscale measures of temporal lobe function. Furthermore, the identified gradients aligned closely with established measures of functional reconfiguration and areal expansion between macaques and humans, highlighting their potential role in shaping temporal lobe function throughout primate evolution. Findings were replicated in several datasets. Our results provide robust evidence for three axes of structural connectivity in human temporal cortex with consistent microstructural underpinnings and contributions to large-scale brain network function.

Role of NDE1 in the Development and Evolution of the Gyrified Cortex.

An expanded cortex is a hallmark of human neurodevelopment and endows increased cognitive capabilities. Recent work has shown that the cell cycle-related gene NDE1 is essential for proper cortical development. Patients who have mutations in NDE1 exhibit congenital microcephaly as a primary phenotype. At the cellular level, NDE1 is essential for interkinetic nuclear migration and mitosis of radial glial cells, which translates to an indispensable role in neurodevelopment. The nuclear migration function of NDE1 is well conserved across Opisthokonta. In mammals, multiple isoforms containing alternate terminal exons, which influence the functionality of NDE1, have been reported. It has been noted that the pattern of terminal exon usage mirrors patterns of cortical complexity in mammals. To provide context to these findings, here, we provide a comprehensive review of the literature regarding NDE1, its molecular biology and physiological relevance at the cellular and organismal levels. In particular, we outline the potential roles of NDE1 in progenitor cell behavior and explore the spectrum of NDE1 pathogenic variants. Moreover, we assessed the evolutionary conservation of NDE1 and interrogated whether the usage of alternative terminal exons is characteristic of species with gyrencephalic cortices. We found that gyrencephalic species are more likely to express transcripts that use the human-associated terminal exon, whereas lissencephalic species tend to express transcripts that use the mouse-associated terminal exon. Among gyrencephalic species, the human-associated terminal exon was preferentially expressed by those with a high order of gyrification. These findings underscore phylogenetic relationships between the preferential usage of NDE1 terminal exon and high-order gyrification, which provide insight into cortical evolution underlying high-order brain functions.

Learning about cell lineage, cellular diversity and evolution of the human brain through stem cell models.

Here, we summarize the current knowledge on cell diversity in the cortex and other brain regions from in vivo mouse models and in vitro models based on pluripotent stem cells. We discuss the mechanisms underlying cell proliferation and temporal progression that leads to the sequential generation of neurons dedicated to different layers of the cortex. We highlight models of corticogenesis from stem cells that recapitulate specific transcriptional and connectivity patterns from different cortical areas. We overview state-of-the art of human brain organoids modeling different brain regions, and we discuss insights into human cortical evolution from stem cells. Finally, we interrogate human brain organoid models for their competence to recapitulate the essence of human brain development.

Behavior and lineage progression of neural progenitors in the mammalian cortex.

The cerebral cortex is a central structure in the mammalian brain that enables higher cognitive functions and intellectual skills. It is the hallmark of the mammalian nervous system with enormous complexity, consisting of a large number of neurons and glia that are diverse in morphology, molecular expression, biophysical properties, circuit connectivity and physiological function. Cortical neurons and glia are generated by neural progenitor cells during development. Ensuring the correct cell cycle kinetics, fate behavior and lineage progression of neural progenitor cells is essential to determine the number and types of neurons and glia in the cerebral cortex, which together constitute neural circuits for brain function. In this review, we discuss recent findings on mammalian cortical progenitor cell types and their lineage behaviors in generating neurons and glia, cortical evolution and expansion, and advances in brain organoid technology that allow the modeling of human cortical development under normal and disease conditions.

Evolution: Does More Time Buy More Neurons?

Brain expansion and increased neuronal number are hallmarks of cortical evolution, particularly in humans. A new study establishes a link between the length of gestation, neurogenesis, the maternal environment, and key features associated with more complex brains.

Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex

Changes in transcriptional regulation through cis-regulatory elements are thought to drive brain evolution. However, how this impacts the identity ofprimate cortical neurons is still unresolved. Here,we show that primate-specific cis-regulatory sequences upstream of the Dbx1 gene promote human-like expression in the mouse embryonic cerebral cortex, and this imparts cell identity. Indeed, while Dbx1 is expressed in highly restricted cortical progenitors in the mouse ventral pallium, it is maintained in neurons in primates. Phenocopy of the primate-like Dbx1 expression in mouse cortical progenitors induces ectopic Cajal-Retzius and subplate (SP) neurons, which are transient populations playing crucial roles in cortical development. A conditional expression solely in neurons uncouples mitotic and postmitotic activities of Dbx1 and exclusively promotes a SP-like fate. Our results highlight how transcriptional changes of a single fate determinant in postmitotic cells may contribute to the expansion of neuronal diversity during cortical evolution.

A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

BackgroundNeurogenesis in the murine cerebral cortex involves the coordinated divisions of two main types of progenitor cells, whose numbers, division modes and cell cycle durations set up the final neuronal output. To understand the respective roles of these factors in the neurogenesis process, we combine experimental in vivo studies with mathematical modeling and numerical simulations of the dynamics of neural progenitor cells. A special focus is put on the population of intermediate progenitors (IPs), a transit amplifying progenitor type critically involved in the size of the final neuron pool.ResultsA multiscale formalism describing IP dynamics allows one to track the progression of cells along the subsequent phases of the cell cycle, as well as the temporal evolution of the different cell numbers. Our model takes into account the dividing apical progenitors (AP) engaged into neurogenesis, both neurogenic and proliferative IPs, and the newborn neurons. The transfer rates from one population to another are subject to the mode of division (proliferative, or neurogenic) and may be time-varying. The model outputs are successfully fitted to experimental cell numbers from mouse embryos at different stages of cortical development, taking into account IPs and neurons, in order to adjust the numerical parameters. We provide additional information on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction.ConclusionsApplying the model to a mouse mutant for Ftm/Rpgrip1l, a gene involved in human ciliopathies with severe brain abnormalities, reveals a shortening of the neurogenic period associated with an increased influx of newborn IPs from apical progenitors at mid-neurogenesis. Our model can be used to study other mouse mutants with cortical neurogenesis defects and can be adapted to study the importance of progenitor dynamics in cortical evolution and human diseases.

A Single-Cell Transcriptomic Atlas of Human Neocortical Development during Mid-gestation

We performed RNA sequencing on 40,000 cells to create a high-resolution single-cell gene expression atlas of developing human cortex, providing the first single-cell characterization of previously uncharacterized cell types, including human subplate neurons, comparisons with bulk tissue, and systematic analyses of technical factors. These data permit deconvolution of regulatory networks connecting regulatory elements and transcriptional drivers to single-cell gene expression programs, significantly extending our understanding of human neurogenesis, cortical evolution, and the cellular basis of neuropsychiatric disease. We tie cell-cycle progression with early cell fate decisions during neurogenesis, demonstrating that differentiation occurs on a transcriptomic continuum; rather than only expressing a few transcription factors that drive cell fates, differentiating cells express broad, mixed cell-type transcriptomes before telophase. By mapping neuropsychiatric disease genes to cell types, we implicate dysregulation of specific cell types in ASD, ID, and epilepsy. We developed CoDEx, an online portal to facilitate data access and browsing.

Dedication of Retinal Special Issue to: Harvey J. Karten, M.D.

Dedication of Retinal Special Issue to: Harvey J. Karten, M.D.

Chaotic and Fast Audiovisuals Increase Attentional Scope but Decrease Conscious Processing

Audiovisual cuts involve spatial, temporal, and action narrative leaps. They can even change the meaning of the narrative through film editing. Many cuts are not consciously perceived, others are, just as we perceive or not the changes in real events. In this paper, we analyze the effects of cuts and different editing styles on 36 subjects, using electroencephalographic (EEG) techniques and the projection of stimuli with different audiovisual style of edition but the same narrative. Eyeblinks, event-related potentials (ERPs), EEG spectral power and disturbances, and the functional and effective connectivity before and after the cuts were analyzed. Cuts decreased blink frequency in the first second following them. Cuts also caused an increase of the alpha rhythm, with a cortical evolution from visual toward rostral areas. There were marked differences between a video-clip editing style, with greater activities evoked in visual areas, and the classic continuous style of editing, which presented greater activities in the frontal zones. This was reflected by differences in the theta rhythm between 200 and 400 ms, in visual and frontal zones, and can be connected to the different demands that each style of edition makes on working memory and conscious processing after cutting. Also, at the time of cuts, the causality between visual, somatosensory, and frontal networks is altered in any editing style. Our findings suggest that cuts affect media perception and chaotic and fast audiovisuals increase attentional scope but decrease conscious processing.

High-Expanding Regions in Primate Cortical Brain Evolution Support Supramodal Cognitive Flexibility.

Primate cortical evolution has been characterized by massive and disproportionate expansion of a set of specific regions in the neocortex. The associated increase in neocortical neurons comes with a high metabolic cost, thus the functions served by these regions must have conferred significant evolutionary advantage. In the present series of analyses, we show that evolutionary high-expanding cortex - as estimated from patterns of surface growth from several primate species - shares functional connections with different brain networks in a context-dependent manner. Specifically, we demonstrate that high-expanding cortex is characterized by high internetwork functional connectivity; is recruited flexibly over many different cognitive tasks; and changes its functional coupling pattern between rest and a multimodal task-state. The capacity of high-expanding cortex to connect flexibly with various specialized brain networks depending on particular cognitive requirements suggests that its selective growth and sustainment in evolution may have been linked to an involvement in supramodal cognition. In accordance with an evolutionary-developmental view, we find that this observed ability of high-expanding regions - to flexibly modulate functional connections as a function of cognitive state - emerges gradually through childhood, with a prolonged developmental trajectory plateauing in young adulthood.

The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis

Non-coding regions comprise most of the human genome and harbor a significant fraction of risk alleles for neuropsychiatric diseases, yet their functions remain poorly defined. We created a high-resolution map of non-coding elements involved in human cortical neurogenesis by contrasting chromatin accessibility and gene expression in the germinal zone and cortical plate of the developing cerebral cortex. We link distal regulatory elements (DREs) to their cognate gene(s) together with chromatin interaction data and show that target genes of human-gained enhancers (HGEs) regulate cortical neurogenesis and are enriched in outer radial glia, a cell type linked to human cortical evolution. We experimentally validate the regulatory effects of predicted enhancers for FGFR2 and EOMES. We observe that common genetic variants associated with educational attainment, risk for neuropsychiatric disease, and intracranial volume are enriched within regulatory elements involved in cortical neurogenesis, demonstrating the importance of this early developmental process for adult human cognitive function.

Understanding Motivational Interviewing: an Evolutionary Perspective

Motivational interviewing (MI) is a well-known scientifically tested method of affecting behavior change in humans. In MI, interventionists are instructed not to directly provide clients with advice to change as it is often ineffective. Instead, they are trained to direct the client’s cognition towards modifying the target behavior. The delivery of MI-based interventions in diverse areas of behavior modification is based on the efficacy data that demonstrate that they influence behavior but without an integrative theoretical basis necessary for comprehensive understanding. This article uses an evolutionary framework to identify potential mediators of the effects of MI on behavior. Specifically, it argues that the techniques used in MI are adaptively significant, signaling to the client that he/she is social hierarchically and physically safe. By not directly providing advice to change and by enhancing the client’s perception of social support, the interventionist is not perceived as attempting to impose social-hierarchical discipline. This, in turn, bypasses the unconsciously primed, evolutionary salient human trait of psychological reactance, which is argued, in this paper, to have evolved, in part, to facilitate the maintenance of social dominance hierarchies. This non-socially threatening environment created by MI allows the human cortex to process information and engage in cognitive reasoning and decision making without strong influence from unconscious instinctual subcortical processes that ruled behavior prior to cortical evolution. Understanding the adaptive significance of counseling strategies that facilitate successful outcomes allows for greater insight into the underlying mechanisms by which these strategies impact on behavior, which may assist in the design and refinement of behavior modification programs.ᅟ

Junk DNA Used in Cerebral Cortical Evolution

In this issue of Neuron, Rani etal. (2016) address important questions about the mechanisms of cerebral cortical evolution. They describe how a primate-specific long non-coding RNA titrates the levels of a microRNA that regulates an ancient signaling pathway controlling neuronal numbers.

Stem Cells Expand Insights into Human Brain Evolution

Substantial expansion in the number of cerebral cortex neurons is thought to underlie cognitive differences between humans and other primates, although the mechanisms underlying this expansion are unclear. Otanietal. (2016) utilize PSC-derived brain organoids to study how species-specific differences in cortical progenitor proliferation may underlie cortical evolution.