European Molecular Biology Laboratory, Heidelberg

Talk Title: Building bilaterian brains: innovations in molecular machinery, neuron types and circuits

Abstract:We study the evolution of animals from a cell type perspective, with a particular focus on the origin and rise of their most fascinating trait, which is the centralized nervous system. For this, we track the evolution of neurons and other constituent cell types across animal phylogeny, focusing on slow-evolving animals. We have chosen the nereid Platynereis dumerilii as a powerful model for comparative studies, with morphologically similar organisms already existing as early as the Cambrian. Taking advantage of its highly stereotypic development, we have built the PlatyBrowser, which combines expression atlases and volume electron microscopy to establish a link between gene expression and cellular and subcellular morphologies for all cell types of the three-days-old young worm. This stage is composed of 12,000 cells only but already possesses a fully differentiated rope-ladder-like nervous system with brain and segmental ganglia, which can be regarded a blueprint of the adult nervous system.

These efforts lead us to outline a basic set of neuron type families and circuits conserved across the bilaterian divide. We trace the assembly of the constituting neuron types into a basic set of neural circuits that make up the bilaterian brain, and postulate that modified versions of these families are found in today’s brains in all major bilaterian lineages.

Max Planck Institute

Talk Title: Inheritance and convergence in the brain: sleep, CPGs, claustrum and texture perception

Abstract: This talk will describe our use of modern approaches to study brain function and designs on two “non-classical” model systems. The first are Australian dragons (reptilian amniotes that diverged from our lineage some 320MY ago), that proved to be remarkable systems to study sleep mechanisms and its evolution. The second are cuttlefish (cephalopods, hence mollusks, that diverged some 700MY ago from our own lineage) which we use to study visual texture perception in the context of camouflage. Using quantitative behavior, scRNAseq, EM connectomics, electrophysiology with these animals, chosen for their behavioral traits and positions in the tree of life, we strive to identify features of brain function that may be of general relevance, and provide a functional and evolutionary understanding for those features.

Allen Institute for Brain Science

Talk Title: Comparative brain cell atlasing to understand human and mammalian brain structure and function

Allen Institute for Brain Science

Talk Title: Viral genetic targeting of brain cell types across mammalian species

Abstract: Advances in single cell genomics have made it possible to rapidly generate comprehensive cell type taxonomies of the brain and to map homologous cell types across diverse species. We are building on this foundational work by leveraging single cell chromatin accessibility data to discover brain region and cell type specific enhancers for use in adeno-associated virus (AAV) vectors. I will briefly introduce our Allen Institute mouse brain enhancer screening pipeline and demonstrate that enhancers can now be discovered to target virtually any cell type in the brain or body. I will highlight our collaborative efforts to test enhancer AAVs in vivo in multiple mammalian species and showcase examples of conservation and species divergence in enhancer activity in the brain. Lastly, I will touch on progress for rational design of synthetic enhances and show that such designs can also mark homologous cell types across species. Such tools hold great promise for enabling genetic dissection of cell type and circuit function in diverse mammalian species including and beyond the mouse model.

Allen Institute for Brain Science

Talk Title: Building High-resolution Transcriptomic and Spatial Cell Type Atlas Across Adult, Aging and Development Mouse Brains

Abstract: The mammalian brain consists of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain, constructed based on a scRNA-seq dataset of ~7 million cells profiled (~4.0 million cells passing quality control) and a spatial transcriptomic dataset of ~4.3 million cells using MERFISH. The atlas is hierarchically organized into four nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. A high degree of correspondence between transcriptomic identity and spatial specificity for each cell type was observed. The study reveals unique characteristics of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain. The study shows that transcription factors are major determinants of cell type classification in the adult mouse brain and identifies a combinatorial transcription factor code that defines cell types across all brain regions. We are currently broadening the scope of the adult whole brain atlas to encompass a wider temporal range, from developmental stages beginning at E11.5 to aging stages extending to 24 months. Our ultimate aim is to create a unified cell type atlas with a consistent nomenclature, enabling users to track the evolution of each adult cell type throughout all stages of development and aging.

Auburn University

Talk Title: Cutting cross scales to Translate Time across mammals

Abstract: How the neural structures supporting human cognition developed and arose in evolution is an enduring question of interest. Yet, we still lack appropriate procedures to align ages across mammals, and this lacuna has hindered progress in understanding the development and evolution of biological programs. Translating Time (www.translatingtime.org) is a resource that relies on time points to find corresponding ages across species. I discuss recent efforts to expand the resource and how the integration across scales (from behavior, anatomy, and transcription) is useful to align ages across the lifespan of different species. This work not only informs how developmental processes vary across species, it is also serving as a resource for the biomedical community because it enables researchers to map findings from model systems to humans.

University of California San Francisco

Talk Title: Scalable Genome Engineering Approaches for Studying Human Brain Evolution

Abstract: Over the last six million years, human cognition has changed in remarkable ways to support symbolic language, long-term planning, cooperation on vast scales, and the rapid cultural accumulation of technology. During this period, patterns of brain development and life history changed to triple the number of neurons produced prenatally, extend synaptic plasticity through a prolonged phase of development, and restructure connectivity between brain regions. At the same time tens of millions of variants accumulated as fixed changes in the human genome through the processes of selection and drift. A portion of this new genomic information guides the development of uniquely human traits and contributes to disease vulnerabilities shared by all humans. However, connecting human-specific variants to recently evolved traits remains a major challenge because we lack experimental systems for comparative and functional studies of great ape cortical development. Here, I will present scalable approaches for assigning molecular and cellular functions to human-specific genetic differences and for discovering divergent cellular phenotypes. I conclude by discussing a systems-level view of species differences along a trait hierarchy that may enable a more quantitative and integrative understanding of the genetic, molecular and cellular underpinnings of human nervous system evolution.

Yale University

Talk Title: Development and Evolution of the Prefrontal Cortex

Abstract: The prefrontal cortex is central to cognitive functions that define human uniqueness, such as goal-directed behavior, complex social interactions, introspection, and language. Exploring its development and comparing it across species can provide deeper insights into the foundations of what makes us distinctly human.

Duke University

Talk Title: Enhancing development: Genetic basis of cortical evolution

Abstract: The cerebral cortex controls our higher cognitive capacities and helps define us as humans. Aberrant cortical development can result in devastating neurodevelopmental diseases. Our lab aims to elucidate genetic and cellular mechanisms controlling cortical development and contributing to neurodevelopmental pathologies and brain evolution. This talk will highlight some of our recent discoveries regarding the genetic underpinnings of cortical evolution, including new roles for transcriptional enhancers.

Allen Institute for Brain Science

Talk Title: Transcriptomic Innovation in the Evolution of Mammalian Cortex

Abstract: Mammals exhibit diverse behaviors that arise from a common blueprint for brain organization with species specializations in size and cellular architecture. To examine evolutionary changes in motor circuits that may contribute to motor-related traits such as dexterity, we profiled gene expression of over 2 million cells from the primary motor cortex of 25 species, from human to opossum, using single nucleus RNA-seq. We found deep conservation of neuronal and non-neuronal cell subclasses across mammals with a small set of conserved markers and thousands of genes with divergent expression. There were species-specific evolutionary shifts in cell type abundance, such as a nearly complete loss of a layer 6 excitatory neuron population in rodents and rabbits. Moreover, the balance between excitatory and inhibitory neurons varied by 4-fold within and across clades and was closely linked to cortical size. Finally, genes with human-specific expression are enriched near likely adaptive genomic changes and are poised to contribute to human-specialized cortical function.

Duke University

Talk Title: Evo-devo diversification of cortical output channels

University of California, Davis

Talk Title: Cortical Motor Areas and the Emergence of Motor Skills.

Abstract: What changes in neural architecture account for the emergence and expansion of dexterity in primates? Dexterity, or skill in performing motor tasks,

Department of Brain and Cognitive Sciences and McGovern Institute of Technology, Massachusetts Institute of Technology

Website

Talk Title: The language system in the broader landscape of the human brain

Abstract: I seek to understand how our brains understand and produce language. I will discuss three things that my lab has discovered about the “language network”, a set of frontal and temporal brain areas that store thousands of words and constructions and use these representations to extract meaning from word sequences (to understand or decode linguistic messages) and to convert abstract ideas into word sequences (to produce or encode messages). First, the language network is highly selective for language processing. Language areas show little neural activity when individuals solve math problems, listen to music, or reason about others’ minds. Further, some individuals with severe aphasia lose the ability to understand and produce language but can still do math, play chess, and reason about the world. Thus, language does not appear to be necessary for thinking and reasoning. Second, processing the meanings of individual words and putting words together into phrases and sentences are not spatially segregated in the language network: every region within the language network is robustly sensitive to both word meanings and linguistic structure. This finding overturns the popular idea of an abstract syntactic module but aligns with evidence from behavioral psycholinguistic work, language development, and computational modeling. And third, representations from large language models like GPT-2 predict neural responses during language processing in humans, which suggests that these language models capture something about how the human language system represents linguistic information.

University of California San Francisco

Website

Talk Title: Functional organization of human speech cortex

Website

Talk Title: TBA

Abstract: TBA

The Rockefeller University

Talk Title: Evolution of brain circuits for vocal learning and spoken language

Department of Brain & cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology

Website

University of California, Berkeley

University of Oregon

Talk Title: Cell types and functional organization of the octopus visual system

Abstract: Cephalopods are the only branch of the animal kingdom besides vertebrates to evolve large brains and camera-type eyes, resulting in a sophisticated visual system that underlies a wide array of visually guided behaviors. Because their brains evolved mostly independently from vertebrates and other invertebrates, the neural organization of their visual system is dramatically different. Studying visual processing in cephalopods therefore has the potential to reveal common computational principles for vision across vastly different neural architectures, as well as to identify novel neural circuitry and computations that might have arisen. However, we know very little about the organization or function of the cephalopod visual system at the neural level.

Washington University

Talk Title: Evolution of Mammalian Visual Cortex

Abstract: Vision is the dominant sensory modality in primates and many other mammals. Intensive studies in diverse species have revealed major principles of visual cortical organization, including a large number of hierarchically organized visual areas and a complex pattern of functional organization that includes concurrent processing streams that originate in the retina and extend to high-level areas. This talk will focus on structural, functional, and transcriptomic analyses of mammalian visual cortex, with an emphasis on comparing humans and nonhuman primates.

Massachusetts Institute of Technology | McGovern Institute for Brain Research

Website

Talk Title: The Basal Ganglia and Value-Based Decision-Making

Abstract: Canonical basal ganglia Go-NoGo circuits have Go-No Go opponents with opposite sign effects poised to insert limbic control

Harvard University | Alice and Rodman W. Moorhead III Professor of Neurobiology | Investigator, Howard Hughes Medical Institute | Co-director of the Kempner Institute

Website

Bernardo Sabatini is a professor in the Department of Neurobiology at Harvard Medical School and an Investigator of the Howard Hughes Medical Institute. His laboratory focuses on understanding the function and regulation of synapses in the mammalian brain with a particular focus on the basal ganglia, an evolutionarily conserved brain region that controls many aspects of behavior and whose perturbation leads to devastating neuropsychiatric diseases. In order to conduct their studies, Dr. Sabatini’s laboratory creates new optical and chemical tools to observe and manipulate the biochemical signaling associated with synapse function.

Dr. Sabatini obtained a PhD from the Department of Neurobiology at Harvard Medical School and his MD from the Harvard University/MIT Program in Health Sciences and Technology in 1999.  After completing a postdoctoral fellowship with Dr. Karel Svoboda at Cold Spring Harbor Laboratory in New York, Dr. Sabatini joined the faculty at Harvard Medical School in 2001.  In 2008 Dr. Sabatini was named an investigator of the Howard Hughes Medical Institute, in 2010 the Takeda Professor of Neurobiology, and in 2014 the Alice and Rodman W. Moorhead III Professor of Neurobiology at Harvard Medical School.  He is a member of the National Academy of Science and the American Academy of Arts and Sciences.

Dr. Sabatini’s current research focuses on action selection, neural plasticity, and learning. The Sabatini Lab studies how brain plasticity and computation allow animals to adapt to changing contexts.  In particular, the Lab studies the processes of action selection (choosing what to do), evaluation (deciding if the outcome was good or bad), and plan updating (should something different be done in the future). These processes depend on evolutionarily old and phylogenetically old parts of the brain that, when perturbed, have profound effects on human behavior. Motivated by biological studies, Sabatini seeks to understand what features of natural brains and nervous systems endow animals with such facility to learn and understand their environments.  He hopes to identify features of brain cells and circuits that, when incorporated into artificial systems, endow them with new capabilities.  Conversely, the Sabatini Lab will work with computer scientists and mathematicians to develop methods to test if theories used to explain how artificial neural networks learn apply to the brain.

Talk Title: Functional, anatomical, and molecular heterogeneity of the globus pallidus externus

Abstract: The globus pallidus externus (GPE), once considered a relatively homogeneous internal relay nucleus of the basal ganglia, contains several classes of neurons with distinct molecular, physiological, and anatomical properties. In addition, the GPE has complex internal interconnectivity and sends long range projections to directly to cortex, bypassing traditional basal ganglia output nuclei. I will discuss recent findings from the lab on the molecular characteristics of these GPE neurons and their contribution to learning and execution of a cued Go/No-Go task.

Talk Title: Linking Neural Cell Types to Disease and Behavior Using Machine Learning

Abstract: New single cell sequencing techniques are rapidly uncovering an increasing number of neural cell types and neuron subtypes, each with their own unique programs of gene expression and epigenetic features. Linking these neuron subtypes to different human disease phenotypes and behaviors across species has remained difficult due to the complexity of the brain. To disentangle the roles that different neuron subtypes play in disease and behavior, the Pfenning laboratory has been leveraging new methods that can measure cell type-specific evolutionary conservation. While the vast majority of methods to measure evolutionary conservation model how individual nucleotides evolve, the newly-developed TACIT (Tissue Aware Conservation Inference Toolkit) applies machine learning to infer epigenetic similarities and differences in specific cell types. We have applied TACIT to trace the evolutionary history of neuron subtypes in the striatum and cortex. In the area of behavioral evolution, TACIT is able to identify how cell type- and tissue-specific enhancers near Autism-associated genes have evolved with vocal learning behavior. In the area of human disease annotation, TACIT has been able to infer how genetic variants impact specific cell types to influence the predisposition to neurological and psychiatric disorders. As the technology advances, TACIT has the potential to develop tools allowing researchers to manipulate specific cell populations and circuits in traditional and non-traditional model organisms.

Walsh Lab Website
Brain Evolution Website

Talk Title: Molecular Genetics of Human Brain Development and Evolution

Abstract:

Gladstone Institutes | University of California San Francisco

Website

Talk Title: Decoding Human Accelerated Regions

Abstract: Human accelerated regions (HARs) are sequences that have been highly conserved through millions of years of vertebrate evolution and then changed dramatically in the human genome since divergence from our common ancestor with chimpanzees. This evolutionary signature suggests that HARs play important roles and that their functions may have been lost or changed in our ancestors, making HARs exciting candidates for understanding the genetic basis for what makes us human. However, it has been challenging to determine what HARs do and why the evolutionary forces constraining HAR sequences in other species suddenly changed in our lineage. In this talk, I will described machine learning approaches that have shed light on the neurodevelopmental functions and evolutionary histories of HARs. These predictive models and the experiments they inspired have shown that both enhancer hijacking and compensatory evolution contributed to the emergence of HARs. Compared to chimpanzee accelerated regions, HARs are particularly enriched for roles in excitatory neurons and may play roles in the evolution of neural plasticity.

University of Washington

Talk Title: Comparative telomere-to-telomere ape genome sequencing and the evolution of the human genome

Abstract: The discovery and resolution of genetic variation is critical to understanding disease and evolution. I will present our most recent work sequencing diverse human and nonhuman primate (NHP) genomes using both ultra-long and high-fidelity long-read sequencing technologies to fully phase and assemble diploid genomes with & without parental data. This allows us to detect and sequence resolve most structural variants irrespective of size, shedding new insights into the mutational processes shaping the human genome. This is leading to new genetic associations, the discovery of pathogenic variants previously missed by short-reads, the identification of newly duplicated genes, and candidates for selection in specific human populations and species-specific changes. Assembly-based variant discovery has the potential to provide a complete understanding of the evolution of every base pair of the human genome and an improved model of the genetic changes, especially neurodevelopmental genes that make us uniquely human.

The University of Texas Southwestern

Talk Title: Cell type-specific transcriptional networks in brain evolution

Abstract: The human brain is comprised of heterogenous cell types and understanding the gene expression patterns and chromatin states within each of these cell types can provide important insights into both brain evolution as well as the development of cognitive disorders. We have used single cell genomics to compare human and nonhuman primate brains to uncover human brain innovations including changes in the proportions of immature oligodendrocytes and cell type specific expression patterns of key genes such as FOXP2. We have also applied this approach to brain tissue surgically resected from living humans to determine the cell type specific patterns of genes relevant to human memory encoding. Together, these data highlight the complex intersection of cellular genomics with brain evolution and function.

Carmel Lab

Talk Title: Picking into the Neanderthal brain using ancient DNA methylation

Abstract: Paleoepigenetics, the computational reconstruction of premortem DNA methylation of ancient individuals, provides a glimpse into recent evolutionary changes in gene regulation along the human lineage. As DNA methylation is tissue-specific, reconstructed ancient methylation maps usually represent methylation patterns in the skeletal system. A key challenge in paleoepigenetics is to identify changes in DNA methylation in tissues that are not represented in the paleontological record. Here, we combine parsimony principles with the understanding that tissue-specific DNA methylation patterns are built up during embryonic development, to show that DNA methylation patterns in one tissue may, under certain conditions, be informative on DNA methylation patterns in other tissues of the same individual. We devised an algorithm for such cross-tissue inference and used data of extant species to show that we reach precisions of up to 92%. We then applied the algorithm to prefrontal cortex neurons of archaic humans, and detected more than 1,850 genomic positions with differential methylation across modern humans, archaic humans and chimpanzees. These positions are associated with hunderds of genes, many of which are related to the nervous system, and are related to disorders such as autism spectrum disorder, Alzheimer’s disease and intellectual disability. Three of these genes belong to the NBPF gene family, which likely played a significant role in human brain evolution. This work demonstrates the potential of paleoepigenetics to provide insights on evolutionary changes that occurred in many different biological systems, even in systems that are poorly preserved after death.

Talk Title: Leveraging the Allen Ancient DNA Resource to provide insights into the evolution of the human brain

Abstract: We present a method for detecting evidence of natural selection in ancient DNA time series data that leverages an opportunity not utilized in previous scans: testing for a consistent trend in allele frequency change over time. By applying this to a dataset of 8433 West Eurasians who lived over the past 14000 years and 6510 contemporary people developed with the support of the Allen Discover Center for Human Brain Evolution, we find an order of magnitude more genome-wide significant signals than previous studies: 347 independent loci with >99% probability of selection. We find that cognitive traits are much less important as a target of natural selection than blood and immune ones. Nevertheless, when we search for evidence of coordinated selection on alleles affecting the same trait, we find selection for combinations of alleles that today decrease risk for schizophrenia and bipolar disease, and also for combinations of alleles that today increase some measures of cognitive performance (scores on intelligence tests, household income, and years of schooling). Multiple lines of evidence show these results are not artifacts of confounding factors such as uncorrected population structure. For example for years of schooling, there is significant positive correlation of West Eurasian selection coefficients over the last 14000 years not only to allelic effect sizes measured in modern West Eurasians but also to effect sizes in East Asians with completely uncorrelated population structure (P=1.9×10-10). Although the statistical signals are compelling, these phenotypes would have been undefined in prehistoric societies, so what traits were the targets of selection is not clear. Our analysis also shows that Human Accelerated Regions (HARs) including ones associated with the brain and that we experimentally validate as biologically functional, are roughly 100-times enriched for signals of positive directional selection in the last 14000 years (p<0.05) compared to random regions, providing insight into HARs which are often thought to have experienced strong selection on the human lineage hundreds of thousands of years ago but are not generally viewed as rapidly evolving in different groups of people today.

Max Planck Institute, Leipzig

Talk Title: A Neandertal Perspective on Recent Human Brain Evolution

Abstract: Our laboratory has generated high-quality genome sequences from Neandertals and Denisovans, archaic hominins who shared a common ancestor with present-day humans about half a million years ago. These genomes allow genetic variants that appeared and rose to high frequencies in modern humans since their divergence from a common ancestor shared with the archaic hominins. I will describe our current knowledge about some such modern-human-specific changes that affect proteins that may be of importance for brain development. For example, amino acid substitutions in KNL1 and KIF18A increase the length of metaphase and decrease the number of chromosomal segregation errors in apical progenitors during neocortex development, while a single amino acid substitution in the enzyme TKTL1 increases the numbers of basal-radial-glia cells and thus the number of neurons generated. Another amino acid substitution in the enzyme ADSL affect purine biosynthesis, particularly in the brain, and behavior in a mouse model and in humans. I will suggest that the genetic basis of the modern human phenotype is likely to be a combination of several or many genetic features, where not every feature is present in every present-day human.