Circuit Diagrams

Abstract The goal of this proposal is to develop robust in vitro human cell-derived microphysical systems which faithfully represent key features of the developing human neocortex in vivo. Our work addresses three key challenges that have limited the development of these systems to date: (1) Building robust and reproducible organoids at high throughput. To obtain meaningful, statistically significant results from genetic and non-genetic perturbations, it is necessary to develop organoid systems which are robust and can be reproducibly assayed in large numbers.

PROJECT SUMMARY Understanding of many aspects of the human brain is currently limited due to the lack of appropriate model systems that recapitulate the heterogenous nature of the human brain and the ethical and practical limitations of working with human brain tissue from patients. To overcome these challenges, we employ three-dimensional brain organoids, derived from human pluripotent stem cells, that recapitulate key features of human cortical development.

Experimental models of the human developing brain are needed to investigate human-specific aspects of brain development, evolution, and neurological disease. Progress in the field has been hampered by the lack of models, considering that the endogenous developing human brain cannot be directly investigated; animal models often fail to recapitulate human disorders and cannot feasibly be used to study complex polygenic states spanning many genes.

The human induced pluripotent stem cell (hiPSC) technology promises major advances in disease modeling and personalized medicine. Using hiPSCs, organoid systems have been generated in recent years that resemble the identity of several brain regions, including cortex, basal ganglia, cerebellum and spinal cord. Major shortfalls of these models are the lack of a reproducible topography of the cell types and tissue architecture that are generated, and the failure to recapitulate the full range of cellular and molecular diversity that characterizes in vivo systems.

SUMMARY The modular organization of the cerebral cortex is defined by anatomically and functionally segregated cortical columns, as well as layer-specific anatomical and functional connections that span multiple columns. Dysregulation of the developmental processes governing cortical formation can result in dysmorphic features that have been implicated in numerous neurological and psychiatric disorders.

Project Summary/Abstract Over the past decade, serial-section electron microscopy has come into its own as a method to study the connectivity of neural circuits, from local circuits in mammals to entire invertebrate brains. Recently, the emphasis in the field has been to create increasingly large data sets, while comparatively little effort has been spent on making the tools of EM connectomics available to a large number of circuit neuroscientists. Obstacles exist at multiple levels.

SUMMARY Electrical synapses, also known as gap junctions, occur frequently in all nervous systems, including the human brain. They are composed of connexins, arranged to form intercellular channels between adjacent, coupled cells. Connexin36 (Cx36) is the predominant connexin in the CNS. In many brain and retinal circuits, gap junctions provide direct and specific connections between cells. In addition, electrical synapses mediate network properties such as signal averaging, noise reduction and synchronization.

Project Summary This proposal seeks to investigate sex hormone effects on reward and aversion-related behaviors through mapping of Lateral Habenula (LHb) circuits. The LHb is a central hub important for encoding aversive information and coordinating motivated behaviors, actions critical for survival. Dysfunction in LHb-dependent circuits contribute to a diverse set of disordered behaviors, such as aberrant processing of positive and negative valence, anhedonia, depressive symptomology, and maladaptive stress response, to name a few.

PROJECT SUMMARY To flexibly execute behavior, choices are made based on previous outcomes that will maximize reward. Crucially, learning the value of each action to obtain a reward is thought to drive this decision making process. In a value-based decision making framework, these values are first computed and then used to select and execute actions. Dysfunction in this decision making process is evident in many neuropsychiatric disorders including addiction and in patients with frontal cortical damage who show an inability to flexibly adjust or adapt their behavior.

The brain uses the combined physiology of many cells to transform incoming sensory signals into internal representations. This process is critical for the animal’s survival because it underlies the animal’s ability to identify environmental cues and associate them with the condition of their situation. While sensory representation at the somatic level is well-studied, exploration of this phenomenon at the synaptic level is lacking.