Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits

Abstract

Cortical processing depends on finely tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here we test the effect of reduced somatostatin interneuron-mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrate human cellular, circuit, and gene expression data to generate detailed models of human cortical microcircuits in health and depression. We simulate microcircuit baseline and response activity and find a reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. We thus apply models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

EEG biomarkers of reduced inhibition in human cortical microcircuits in depression

“…We used our previous detailed models of human cortical L2/3 microcircuits[32] (Fig 1a) as canonical cortical microcircuit models for simulating resting state spiking and EEG signals. The model microcircuits included the four key neuron types: Pyr neurons, SST interneurons, Parvalbumin-expressing interneurons (PV), and Vasoactive intestinal polypeptide-expressing interneurons (VIP).…”

“…Human cortical microcircuit models. We used our previous models of human cortical L2/3 microcircuits [32], consisting of 1000 neurons distributed in a 500x500x950μm 3 volume (250 to 1200μm below pia [93]). The model microcircuits included the four key neuron types in cortical L2/3: Pyramidal (Pyr), Somatostatin-expressing (SST), Parvalbumin-expressing (PV), and Vasoactive Intestinal Peptide-expressing (VIP) neurons.…”

“…The background input was generated by random Orstein-Uhlenbeck (OU) point processes [99] placed on all neurons at the halfway point of each dendritic arbor, and 5 additional OU processes placed along the apical trunk of Pyr neurons in equal intervals, from 10% to 90% apical dendritic length. This enabled the circuit to generate recurrent activity with neuronal firing rates as measured in vivo [31,32,100,101]. For both healthy and depression microcircuit models (see below) we simulated 60 randomized microcircuits, for 28 seconds each.…”

“…We used our previous detailed models of human cortical L2/3 microcircuits [32] (Fig 1a ) as canonical cortical microcircuit models for simulating resting state spiking and EEG signals.…”

Multiscale and Extended Retrieval of Associative Memory Structures in a Cortical Model of Local-Global Inhibition Balance

“…But more recent work has shown inhibitory neurons are tuned to specific external stimuli ( Okun and Lampl, 2008 ; Xue et al, 2014 ), have specific associations with behavior ( Dudok et al, 2021 ), have a large diversity of forms and functions within and across brain areas ( Gouwens et al, 2020 ; Burns and Rajan, 2021 ), and form inhibitory assemblies ( Zhang et al, 2017 ), often jointly with excitatory subnetworks ( Otsuka and Kawaguchi, 2009 ; Koolschijn et al, 2019 ). A hallmark of many neuropathologies is inhibitory dysfunction ( Amieva et al, 2004 ; Baroncelli et al, 2011 ; Burns and Rajan, 2022 ; Yao et al, 2022 ). If specific inhibitory dysfunction alone is sufficient for explaining these pathologies, then we could expect subtle inhibitory changes to cause dramatic changes in global function in complex tasks like those involving learning and memory.…”