Lab-grown human neuron assembloids effectively model synaptic plasticity

The ability to study human neurological systems depends on having viable, accurate models of brain function. St. Jude researchers have created a model for such research by combining thalamic cells and cortical cells derived from human induced pluripotent stem cells. The thalamocortical system mediates multiple sensory and cognitive processes, such as perception, learning and memory. The researchers developed a model of a primitive human thalamocortical system by maintaining thalamic and cortical cell masses known as organoids in close proximity in a culture dish. In this model, the neurons in both organoids develop and grow long-ranging processes (axons) that extend to the opposite organoid and form functional connections (synapses). The researchers determined that when these synapses are stimulated, they undergo long-term strengthening and weakening of their electrical signals, which is the hallmark of synaptic plasticity, a process that underlies certain forms of learning and memory. The new human model was successfully validated against established animal models, demonstrating species differences in underlying mechanisms and emphasizing the importance of accurate human models. These findings were published this week in Cell Reports.

To study neuronal function in human models, scientists have historically relied on low-resolution methods that measure responses from a group of neurons, because high-resolution methods that measure single-cell or synaptic responses in humans were not available. St. Jude researchers wanted to address this. “Our goal is to not only study neural circuits but also truly understand communication between neurons in the human brain,” said corresponding author Stanislav Zakharenko, MD, PhD, St. Jude Department of Developmental Neurobiology. “Therefore, we need to measure the activity between individual neurons at the sub-micron synaptic level.”

Studying synapses at the sub-micron level

Synaptic plasticity is based on the long-term strengthening and weakening of synapses as our brains develop and encode new information, but the minute scale at which this takes place means studying synapses in humans has been a long-standing dilemma in the field.

To address this, the researchers leveraged the recent surge in brain organoid research. “The technology has reached such a level where we can grow specific neurons, such as cortical or thalamic cells,” explained Zakharenko. “Once the cells are grown, they self-organize into a mass called an organoid and start to develop long-range processes (axons) with pre- and post-synaptic specializations.”

Researchers figured out that if two different types of organoids fuse together, they create an “assembloid” in which the two types of neurons continue to develop, send processes toward each other, and then begin to communicate.

However, for the researchers, that was only the first step. “We clumped thalamic and cortical cells together, and they began to self-organize and make connections,” Zakharenko explained. “But this could have just been a random, disorganized process. We needed to see if they could exhibit the synaptic plasticity characteristics of thalamocortical and corticothalamic synapses.”