Cortico-thalamic development and disease: From cells, to circuits, to schizophrenia

Abstract

The human brain is the most complex structure generated during development. Unveiling the ontogenesis and the intrinsic organization of specific neural networks may represent a key to understanding the physio-pathological aspects of different brain areas. The cortico-thalamic and thalamo-cortical (CT-TC) circuits process and modulate essential tasks such as wakefulness, sleep and memory, and their alterations may result in neurodevelopmental and psychiatric disorders. These pathologies are reported to affect specific neural populations but may also broadly alter physiological connections and thus dysregulate brain network generation, communication, and function. More specifically, the CT-TC system is reported to be severely affected in disorders impacting superior brain functions, such as schizophrenia (SCZ), bipolar disorder, autism spectrum disorders or epilepsy. In this review, the focus will be on CT development, and the models exploited to uncover and comprehend its molecular and cellular mechanisms. In parallel to animal models, still fundamental to unveil human neural network establishment, advanced in vitro platforms, such as brain organoids derived from human pluripotent stem cells, will be discussed. Indeed, organoids and assembloids represent unique tools to study and accelerate fundamental research in CT development and its dysfunctions. We will then discuss recent cutting-edge contributions, including in silico approaches, concerning ontogenesis, specification, and function of the CT-TC circuitry that generates connectivity maps in physiological and pathological conditions.

Keywords: cerebral cortex; neurodevelopment; organoids; schizophrenia; thalamus.

FIGURE 1

Schematics of human neurodevelopment. (A) Neuromere formation according to the prosomeric model at 3 brain vesicle stage (3–4 pcw). (B) Schematics at 5 brain vesicle stage, illustrating the expression pattern of relevant neurodevelopmental genes with special emphasis on the diencephalon (6 pcw). (C) Schematics of the cortico-thalamic (CT) and thalamo-cortical (TC) projections in the developing human brain (9–10 pcw). In blue and green representative CT and TC neurons, respectively, cross PSPB and DTB to reach their target area. In red TRN GABAergic neurons projecting to specific thalamic nuclei. P1, P2, P3, prosomere 1, 2, 3; ZLI, zona limitans intrathalamica; IsO, isthmic organizer; PSPB, pallial-subpallial boundary; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; DTB, diencephalic-telencephalic boundary; TH, thalamus; TRN, thalamic reticular nucleus; HT, hypothalamus.

FIGURE 2

Different approaches to study CT-TC network. From animal models to in vitro and in silico systems to understand the development of CT networks and the consequences of their disruption.