Transcriptomic and Cellular Reorganization of the Human Prefrontal Cortex

Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Sestan, Nenad

Abstract

The expansion and evolutionary specializations of the cerebral cortex, and especially the prefrontal cortex (PFC), are thought to underlie the rich and complex nature of primate and human cognition. The PFC is larger and anatomically more complex in anthropoid primates compared to other analyzed mammals, covering the entire dorsolateral two-thirds of the frontal lobe with a well-defined granular layer 4. The granular dorsolateral PFC (dlPFC) exhibits a broad connectivity with other brain regions. In this setting, dysfunction of the dlPFC also has been implicated in the etiology of many neuropsychiatric disorders. Accordingly, nonhuman primates have been used as model species because their complex cognition, expanded PFC, and genetic makeup best approximate that of humans. Single-cell transcriptomics has emerged as a central tool in understanding cell taxonomy and evolution of the brain, but prior efforts to characterize human PFC were not extensive in the scope of cell type classification and nonhuman primates compared. To better understand the cellular repertoire of the dlPFC and its conserved and divergent features, we assessed over 600,000 single-nucleus transcriptomes from human, chimpanzee, macaque, and marmoset adult dlPFC, representing multiple phylogenetic groups of anthropoid primates. While major subclasses of transcriptomically-defined cell types (t-types) are shared across these species, I detected several neuronal, glial and non-neural t-types present only in some species and substantial species-specific molecular differences across homologous t-types. The latter are exemplified by human-specific expression of retinoic acid signaling genes, human-specific switching between translation of the neuropeptide somatostatin (SST) and tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine production, in certain interneurons, and also by expression of the neuropsychiatric risk gene FOXP2, which is human-specific in microglia and primate-specific in layer-4 granular neurons. Altogether, this represents a comprehensive dlPFC cellular taxonomy and delineates changes underlying its evolutionary divergence in anthropoids.

This document is currently not available here.

Share

COinS