Genes, neurons and cortical architecture supporting human cognitive ability

Chapter 1 of this thesis introduces the question of why some individuals possess higher cognitive abilities than others. The chapter discusses traditional strategies employed to study the neurobiology of intelligence: brain imaging to investigate brain structure and function and genome-wide association studies to identify genes associated with intelligence. However, there is little information on how neuronal properties relate to intelligence. We propose that single-cell transcriptomics combined with functional and morphological analysis of neurons in the human neocortex may provide an opportunity to understand how genes of intelligence can act on cortical structure and function contributing to human cognitive ability. In chapter 2 we investigated the association between human intelligence and the structural and physiological properties of neurons. The study utilized electrophysiological recordings of neurosurgically resected temporal cortex in combination with presurgical IQ scores. The results demonstrate that high IQ scores associate with larger temporal cortical thickness and larger, more complex dendrites of pyramidal neurons. In silico analysis reveals that these dendritic trees allow pyramidal neurons to track activity of synaptic inputs with higher temporal precision, due to fast action potential kinetics. The study concludes that human intelligence is associated with neuronal complexity, action potential kinetics, and efficient information transfer from inputs to output within cortical neurons. Chapter 3 investigates whether cortical laminar architecture and cellular properties of the left temporal lobe relate to verbal intelligence by extending our previous findings with histological data and more detailed analysis. The findings indicate that individuals with higher general and verbal IQ scores have thicker left temporal cortex due to the selective increase in layer 2 and 3 thickness, accompanied by lower neuron densities and larger dendrites and cell body size of pyramidal neurons in these layers. These neurons also maintain faster action potential kinetics under pressure, which improves information processing. The study concludes that verbal mental ability associates with selective adaptations of supragranular layers and their cellular micro-architecture and function in the left, but not right, temporal cortex. Chapter 4 explores the genetic basis of human intelligence and how it relates to human brain evolution. The study investigates whether genes associated with human cognition and human accelerated regions (HARs) implicated in human brain evolution are expressed in adult human cortical neurons and brain areas of cognition and how their expression relates to neuronal function and structure. The findings reveal that these gene sets are preferentially expressed in layer 3 excitatory neurons in the middle temporal gyrus (MTG). The study also identifies a subset of genes associated with dendritic length, with predominantly synaptic functions and high abundance of HARs. The results suggest that the mechanisms underlying human brain evolution and interindividual differences in intelligence might share genetic origin and manifest in specific neuronal types. In conclusion, this thesis provides novel insights into the neurobiological basis of intelligence. By investigating the cellular and molecular mechanisms underlying differences in cognitive ability, we have identified specific adaptations in neuronal structure and function that associate with higher IQ scores and verbal mental ability. Our findings suggest that genes implicated in human brain evolution and cognitive function may act on the same biological processes, manifesting in specific neuronal types. This work highlights the potential of integrating single-cell transcriptomics, functional and morphological analysis of neurons, and brain imaging to better understand the complex neurobiology of higher brain functions.