Transcriptome and epigenome landscape of human cortical development modeled in organoids


The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids' epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs).

Towards a Quantum-Like Cognitive Architecture for Decision-Making Artificial Intelligence

We propose an alternative and unifying framework for decision-making that, by using quantum mechanics, provides more generalised cognitive and decision models with the ability to represent more information than classical models. This framework can accommodate and predict several cognitive biases reported in Lieder & Griffiths without heavy reliance on heuristics nor on assumptions of the computational resources of the mind. Expected utility theory and classical probabilities tell us what people should do if employing traditionally rational thought, but do not tell us what people do in reality (Machina, 2009). Under this principle, L&G propose an architecture for cognition that can serve as an intermediary layer between Neuroscience and Computation. Whilst instances where large expenditures of cognitive resources occur are theoretically alluded to, the model primarily assumes a preference for fast, heuristic-based processing.

Expanding a Standard Theory of Action Selection to Produce a More Complete Model of Cognition

AAAI Conferences

A standard model of how brains produce natural cognition would provide a framework for organizing cognitive neuroscience research. A recent effort (Laird et al., in press) to build on consensus views of cognitive operations and produce a standard model of natural cognition started with common aspects of well-established cognitive architectures ACT-R, Sigma, and SOAR. The model captures scientific consensus on “how” the brain works, but it does not offer a coherent story for “why” the component modules (i.e., working memory, long-term memory, visual and motor areas) exist and interact in the ways described. This manuscript starts with background information on a well-cited theory of action selection, and extends that theory to a fuller explanation of decision-making, action and perception that includes a framework for the elements of cognition.

Introduction to Computational Neuroscience

AITopics Original Links

This course gives a mathematical introduction to neural coding and dynamics. Topics include convolution, correlation, linear systems, game theory, signal detection theory, probability theory, information theory, and reinforcement learning. Applications to neural coding, focusing on the visual system are covered, as well as Hodgkin-Huxley and other related models of neural excitability, stochastic models of ion channels, cable theory, and models of synaptic transmission.