Neuronal ensembles in cortical function and disease.

Neuronal ensembles, defined as groups of coactive neurons, are physiological modules of the cerebral cortex. Calcium imaging and optogenetics have enabled mapping and manipulating ensembles with single-cell resolution in mouse visual cortex, providing evidence of their importance. Ensembles dominate cortical activity and are generated endogenously or by sensory stimulation. Ensembles are imprinted by activating neurons synchronously and can be reactivated by "pattern completion" trigger cells. Intrinsic excitability mediates ensemble coactivation and reactivation, while UP states shield ongoing ensembles from external inputs. Neurons can belong to different ensembles, forming a combinatorial system that encodes visual stimuli accurately and stably. Ensembles contain pyramidal neurons and interneurons and inhibited "offsemble" cells. Cross inhibition makes ensembles orthogonal to one another, while astrocytic activation increases ensemble occurrence. Ensembles can last for weeks, providing a substrate for long-term information storage, and they also capture the recent history of stimulus presentation, implementing short-term memory. Optogenetic manipulation of ensembles demonstrates that they are necessary and sufficient for visual discrimination and perceptual states. Ensembles are altered in mouse models of epilepsy, schizophrenia, Alzheimer's disease, autism spectrum disorders, and medically induced loss of consciousness. An ensemble model of the cortex is proposed in which ensembles are functional units that activate each other via trigger cells and silence nondesired ensembles by cross-inhibition. This generates a map of orthogonal attractor states, forming a computationally powerful memory and processing system. Ensembles are likely involved in many brain diseases, so manipulating them could offer avenues for new therapeutics.