CNS*2026 Halifax

Introduction
Major depressive disorder (depression) is associated with reduced cortical inhibition from somatostatin-expressing (SST) interneurons, as indicated by decreased SST expression in human post-mortem studies^[1]. We previously showed in simulations of human cortical layer 2/3 that reduced SST interneuron inhibition would increase baseline cortical activity (noise) to significantly reduce the signal-to-noise ratio in signal processing and contribute to cognitive deficits observed in depression^[2]. However, as SST interneuron proportion and connectivity vary across cortical layers, it is unclear how reduced SST interneuron inhibition in depression differentially affects processing and signal propagation across cortical layers^[3].


Methods
In this study, we generated biophysical models of multilayered human cortical microcircuits that encompass 4000 neurons with detailed morphologies spanning 12 neuron types across layers 2-5. Our models integrated human cellular, synaptic, neuron proportion, and connectivity data, such as human paired recordings and electron-microscopy reconstruction of a human cortical column^[4]. To better capture biological variability, we incorporated heterogeneity in synaptic strengths, transmission delays, and connection probabilities. We simulated electroencephalography (EEG) signals arising from the microcircuit using NEURON and LFPy, and reproduced properties of the power spectrum density (PSD) using thalamic drive and adjusting connectivity.


Results
We reproduced healthy baseline firing rates across cell types and oscillatory dynamics (1/f decay and peak power in alpha frequency band) as seen in human resting-state EEG. By systematically reducing SST inhibition within and across layers, we quantified the difference in layer-specific contributions to circuit-level dysfunction and altered EEG power spectral density during resting state.


Discussion
Our study characterizes the effect of reduced inhibition in depression on cortical activity and signal processing across layers, and thereby furthering current understanding of the role dendritic inhibition plays in signal processing in health and depression. Furthermore, our characterization of the signatures of reduced SST inhibition across layers on resting-state EEG due refine our previous biomarkers, and may serve to improve current stratification of depression patients. Finally, our models of multilayers human cortical microcircuits can be used by the scientific community to study cortical processing in health and other diseases.


References


1.         Seney, M. L., Tripp, A., … Sibille, E. (2015). Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression. Neurobiology of Disease, 73(Complete), 213–219.
2.          Yao, H. K., Guet-McCreight, A., … Hay, E. (2022). Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits. Cell Reports, 38(2).
3.          Tremblay, R., Lee, S., & Rudy, B. (2016). GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits. Neuron, 91(2), 260–292.
4.          Shapson-Coe, A., Januszewski, M., A., … Lichtman, J. W. (2024). A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution. Science, 384(6696), eadk4858.

Acknowledgement
This study was supported by a fellowship grant from the Labatt Family Network for Research on the Biology of Depression