Synapse-Level Mapping Could Reveal How Disrupted Brain Circuits Lead to Psychiatric Disorders

Altered communication between brain regions has long been implicated in psychiatric disorders, yet current methods cannot settle connectivity across scales: neuroimaging does not visualize individual neurons, and electron microscopy has been restricted to regions too small for whole circuits.¹ Aaron Kuan, PhD, at the Yale School of Medicine, described the development of high-speed, automated microscopy methods designed to map the smallest connections across entire circuit volumes, which could test whether disrupted regional communication reflects imbalanced region-to-region axonal connections or impaired synaptic integration of long-range inputs with local circuits. Kuan reported that his recent work showed inhibitory neurons play an active role in decision-making by precisely controlling when excitatory neurons are permitted to be active.² He suggested that multiple inhibitory neuron subtypes likely had distinct circuit roles, and that defining these roles in higher-order cognitive functions could clarify impaired decision-making in disorders such as obsessive-compulsive disorder, addiction, and depression. Kuan recently received the NIH New Innovator Award for this area of research.

Psychiatric Times: Your work aims to map brain connections at the level of individual synapses. What can we not currently see that you hope this work will show?

Aaron Kuan, PhD: Currently we are limited in our ability to resolve brain connectivity across scales. With human neuroimaging methods such as MRI, we can obtain whole-brain scans, but can’t see individual neurons. With high-resolution electron microscopy, we can resolve individual neurons and synapses but only for very small regions, too small to encompass whole circuits. It’s a bit like looking at the night sky—by naked eye we can gaze upon whole Milky Way but the stars blur together. With a telescope, we can zoom in to resolve individual stars close to each other but can no longer appreciate the larger view. In our work, we’re developing high-speed, automated microscopy methods that can map the smallest connections across entire circuit volumes.

PT: In psychiatry, disorders are often linked to altered regional communication in the brain. What can we learn from individual synaptic connections that might inform our understanding of these disorders?

Kuan: There are several ways in which regional communication could be disrupted, and we currently don’t have technologies that can reveal exactly what’s happening. (1) There could be imbalances in the region-to-region connections, for example too few or too many neuronal axons connecting regions. (2) There could be disruptions in synaptic connections that integrate long-range inputs with local circuits. Or (3), there could be molecular changes such as neuromodulation or receptor imbalances, that disrupt functional circuit activity without changing connectivity. The structural imaging methods we are developing, and the larger field of connectomics, can test the first 2 hypotheses, and if neither are associated with certain disorders, would suggest that the third may be correct.

PT: Your recent research suggests inhibitory neurons help control decision making by regulating when other neurons can be active. How might that inform our understanding of impaired decision making in disorders such as OCD, addiction, or depression?

Kuan: Psychiatric disorders are often thought to result from “disconnectivity” between brain regions, characterized by disruptions in structural and/or functional connections between brain regions. These long-range connections are typically made through excitatory neurons, whose activity is regulated by local inhibitory neurons in each circuit. Inhibitory neurons for many years have been thought as secondary "support” cells, just regulating overall circuit activity levels. But our recent work showed that inhibitory neurons actually play a critical and active role in decision-making, by precisely controlling when excitatory neurons are permitted to be active. Moreover, there are many subtypes of inhibitory neurons, and it’s likely that have unique circuit roles. Understanding these roles in high-order cognitive functions could be important to reveal what goes wrong in decision-making disorders.

PT: What is the most important aspect of this research that you would highlight for the practicing psychiatric clinician?

Kuan: In our work, we are trying to lower the barriers of entry for connectomic technologies. We want to make technologies for mapping brain circuits increasingly available and convenient for translational research. These approaches can inform clinical applications in several ways, ranging from examining animal models to organoids to human tissue samples, and we are soon going to be able to do large-scale comparative studies across multiple samples and circuits. So I hope that clinicians can become familiar and enthusiastic about engaging with these techniques bringing their insights from the clinic to help advance our understanding of how circuit-level structural changes relate to psychiatric and neurological diseases.

PT: What do you hope the future of this research looks like?

Kuan: I am very hopeful that connectomics, and circuit neuroscience research more generally, will enable us to link the bottom-up molecular and cellular views of the brain with top-down systems and psychological views. We want to advance the technology and conceptual approaches that allow us to investigate from the ground up how brain circuits give rise to behavior and function and how they're disrupted in disease. Essentially, we want to discover the secret of how the brain becomes so much more the sum of its parts.

Dr Kuan is an assistant professor of neuroscience and of applied physics and of biomedical engineering and of physics. He is the 2026 recipient of the NIH New Innovator Award.

References

1. van den Heuvel MP, Fornito A. Brain networks in schizophrenia. Neuropsychol Rev. 2014;24(1):32-48.

2. Kuan AT, Bondanelli G, Driscoll LN, et al. Synaptic wiring motifs in posterior parietal cortex support decision-making. Nature. 2024;627(8003):367-373.