Intra-individual Physiomic Landscape of Pyramidal Neurons in the Human Neocortex

Computation within cortical microcircuits is determined by functional properties of the neurons and their synaptic interactions. While heterogeneity of inhibitory interneurons is well established, the anatomical, physiological, and molecular differentiation of excitatory pyramidal neurons is not fully resolved. To identify functional subtypes within the pyramidal neuron population, we focused on human layer 2-3 cortex which greatly expanded during evolution. We performed multi-neuron patch-clamp recordings in brain slices from the temporal cortex of 22 epilepsy patients. We characterized the electrophysiological properties of up to 80 pyramidal neurons per patient, enabling us to assess inter- and intra-individual functional variability. Hierarchical clustering of the high-dimensional parameter space yielded functionally distinct clusters of pyramidal neurons which were present across individuals. This may represent a generic organizational principle converging with previously described transcriptomic heterogeneity. We further observed substantial heterogeneity in physiological parameters with intra-individual variability being severalfold larger than inter-individual variability. The phenotypic variability within and across pyramidal neuron subtypes has important implications for the computational capacity of the cortical microcircuit.

Age-dependent increased sag current in human pyramidal neurons dampens baseline cortical activity

Aging involves various neurobiological changes, although their effect on brain function in humans remains poorly understood. The growing availability of human neuronal and circuit data provides opportunities for uncovering age-dependent changes of brain networks and for constraining models to predict consequences on brain activity. Here we found increased sag current in human layer 5 pyramidal neurons from older subjects, and captured this effect in biophysical models of younger and older pyramidal neurons. We used these models to simulate detailed layer 5 microcircuits and found lower baseline firing in older pyramidal neuron microcircuits, with minimal effect on response. We then validated the predicted reduced baseline firing using extracellular multi-electrode recordings from human brain slices of different ages. Our results thus report changes in human pyramidal neuron input integration properties that can sufficiently account for age-dependent decreases in cortical resting state activity and may underpin a clinical relevance in aging.

Key Factors in the Cortical Response to Transcranial Electrical Stimulations—A Multi-Scale Modeling Study

Transcranial electrode stimulation (tES), one of the techniques used to apply non-invasive brain stimulation (NIBS), modulates cortical activities by delivering weak electric currents through scalp-attached electrodes. This emerging technique has gained increasing attention recently; however, the results of tES vary greatly depending upon subjects and the stimulation paradigm, and its cellular mechanism remains uncertain. In particular, there is a controversy over the factors that determine the cortical response to tES. Some studies have reported that the electric field's (EF) orientation is the determining factor, while others have demonstrated that the EF magnitude itself is the crucial factor. In this work, we conducted an in-depth investigation of cortical activity in two types of electrode montages used widely-the conventional (C)-tES and high-definition (HD)-tES-as well as two stimulation waveforms-direct current (DC) and alternating current (AC). To do so, we constructed a multi-scale model by coupling an anatomically realistic human head model and morphologically realistic multi-compartmental models of three types of cortical neurons (layer 2/3 pyramidal neuron, layer 4 basket cell, layer 5 pyramidal neuron). Then, we quantified the neuronal response to the C-/HD-tDCS/tACS and explored the relation between the electric field (EF) and the radial field's (RF: radial component of EF) magnitude and the cortical neurons' threshold. The EF tES induced depended upon the electrode montage, and the neuronal responses were correlated with the EF rather than the RF's magnitude. The electrode montages and stimulation waveforms caused a small difference in threshold, but the higher correlation between the EF's magnitude and the threshold was consistent. Further, we observed that the neurons' morphological features affected the degree of the correlation highly. Thus, the EF magnitude was a key factor in the responses of neurons with arborized axons. Our results demonstrate that the crucial factor in neuronal excitability depends upon the neuron models' morphological and biophysical properties. Hence, to predict the cellular targets of NIBS precisely, it is necessary to adopt more advanced neuron models that mimic realistic morphological and biophysical features of actual human cells.