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The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer’s disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD., Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .

ObjectiveInterictal discharges (IIDs) and high frequency oscillations (HFOs) are neurophysiologic biomarkers of epilepsy. In this study, we use custom poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) microelectrodes to better understand their microscale dynamics.MethodsElectrodes with spatial resolution down to 50µm were used to record intraoperatively in 30 subjects. For IIDs, putative spatiotemporal paths were generated by peak-tracking, followed by clustering. For HFOs, repeating patterns were elucidated by clustering similar time windows. Fast events, consistent with multi-unit activity (MUA), were covaried with either IIDs or HFOs.ResultsIIDs seen across the entire array were detected in 93% of subjects. Local IIDs, observed across ConclusionsOverall, these data suggest micro-domains of irritable cortex that form part of an underlying pathologic architecture that contributes to the seizure network.SignificanceMicroelectrodes in cases of human epilepsy can reveal dynamics that are not seen by conventional electrocorticography and point to new possibilities for their use in the diagnosis and treatment of epilepsy.HighlightsPEDOT:PSS microelectrodes with at least 50µm spatial resolution uniquely reveal spatiotemporal patterns of markers of epilepsyHigh spatiotemporal resolution allows interictal discharges to be tracked and reveal cortical domains involved in microseizuresHigh frequency oscillations detected by microelectrodes demonstrate localized clustering on the cortical surface

The biophysical properties of neurons are the foundation for computation in the brain. Neuronal size is a key determinant of single neuron input–output features and varies substantially across species1–3. However, it is unknown whether different species adapt neuronal properties to conserve how single neurons process information4–7. Here we characterize layer 5 cortical pyramidal neurons across 10 mammalian species to identify the allometric relationships that govern how neuronal biophysics change with cell size. In 9 of the 10 species, we observe conserved rules that control the conductance of voltage-gated potassium and HCN channels. Species with larger neurons, and therefore a decreased surface-to-volume ratio, exhibit higher membrane ionic conductances. This relationship produces a conserved conductance per unit brain volume. These size-dependent rules result in large but predictable changes in somatic and dendritic integrative properties. Human neurons do not follow these allometric relationships, exhibiting much lower voltage-gated potassium and HCN conductances. Together, our results in layer 5 neurons identify conserved evolutionary principles for neuronal biophysics in mammals as well as notable features of the human cortex. Analyses of layer 5 cortical pyramidal neurons in 10 mammalian species show that human neurons are distinct in that they do not follow the expected allometric relationship between neuron size and membrane conductance.

The ability to regulate emotions in the service of meeting ongoing goals and task demands is a key aspect of adaptive human behavior in our volatile social world. Consequently, difficulties in processing and responding to emotional stimuli underlie many psychiatric diseases ranging from depression to anxiety, the common thread being effects on behavior. Behavior, which is made up of shifting, difficult to measure hidden states such as attention and emotion reactivity, is a product of integrating external input and latent mental processes. Directly measuring, and differentiating, separable hidden cognitive, emotional, and attentional states contributing to emotion conflict resolution, however, is challenging, particularly when only using task-relevant behavioral measures such as reaction time. State-space representations are a powerful method for investigating hidden states underlying complex systems. Using state-space modeling of behavior, we identified relevant hidden cognitive states and predicted behavior in a standardized emotion regulation task. After identifying and validating models which best fit the behavior and narrowing our focus to one model, we used targeted intracranial stimulation of the emotion regulation-relevant neurocircuitry, including prefrontal structures and the amygdala, to causally modulate separable states. Finally, we focused on this one validated state-space model to perform real-time, bidirectional closed-loop adaptive stimulation in a subset of participants. These approaches enable an improved understanding of how to sample and understand emotional processing in a way which could be leveraged in neuromodulatory therapy for disorders of emotional regulation.

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

Inhibitory neuronal activity is critical for the normal functioning of the brain, but is thought to go awry during neurological disorders such as epilepsy. Animal models have suggested both decreased and increased inhibition as possible initiators of epileptic activity, but it is not known if, or how, human inhibitory neurons shape seizures. Here, using large-scale recordings of neocortical single neurons in patients with secondarily generalized tonic-clonic seizures, we show that fast-spiking (FS) inhibitory activity first increases as a seizure spreads across the neocortex, impeding and altering the spatial flow of fast epileptic traveling waves. Unexpectedly, however, FS cells cease firing less than half-way through a seizure. We use biophysically-realistic computational models to show that this cessation is due to FS cells entering depolarization block as a result of extracellular potassium accumulation during the seizure and not because they are inhibited by other inhibitory subtypes. Strikingly, this absence of FS inhibitory activity is accompanied by dramatic increases in local seizure amplitude along with unobstructed traveling waves and is seen during all secondarily generalized seizures examined, independent of etiology or focus. FS cessation also leads to prominent spike-and-wave events, suggesting that FS cell dynamics control the transition between the tonic and clonic phases of these seizures. Thus, it may be possible to curtail human seizures by preventing inhibitory neurons from entering potassium-dependent depolarization block, a novel and potentially powerful therapeutic avenue in treating multiple kinds of epilepsies.