Hippocampus CA1 place cells express a spatial neural code by discharging action potentials in cell-specific locations (′place fields′), but their discharge timing is also coordinated by multiple mechanisms, suggesting an alternative ′ensemble cofiring′ neural code, potentially distinct from place fields. We compare the importance of these distinct information representation schemes for encoding environments. Using miniature microscopes, we recorded the ensemble activity of mouse CA1 principal neurons expressing GCaMP6f across a multi-week experience of two distinct environments. We find that both place fields and ensemble coactivity relationships are similarly reliable within environments and distinctive between environments. Decoding the environment from cell-pair coactivity relationships is effective and improves after removing cell-specific place tuning. Ensemble decoding relies most crucially on anti-coactive cell pairs distributed across CA1 and is independent of place cell firing fields. We conclude that ensemble cofiring relationships constitute an advantageous neural code for environmental space, independent of place fields.

No abstract

Cellular-resolution manipulation technologies like optogenetics enable so-called causal engram- cell experiments in which learning-activated neurons are tagged with a light-responsive protein (opsin) such that subsequent photostimulation elicits memory behavior. The opsin-tagged neurons are considered key neural circuit elements with photostimulation demonstrating their sufficiency for memory expression. Can the sufficiency interpretation be correct if the brain is a complex dynamical system with adaptive, non-linear, and homeostatic interactions? We find that during photostimulation of place avoidance memory-tagged neurons, mouse CA1 hippocampus activity maintains intrinsic ensemble discharge relationships and the low-dimensional manifold organization of the population dynamics. Although the photostimulation causes spatially-precise conditioned avoidance, such manipulations, are better interpreted as eliciting the endogenous population dynamics of a complex system, rather than the causal demonstration of neural circuit function.

Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery, but how this uncompetitive NMDA-receptor antagonist impairs cognition remains unknown. Using rats and mice, we report that, consistent with ionotropic actions, PCP discoordinated hippocampus CA1 action potential discharge and impaired a well-learned hippocampus-dependent active place avoidance that requires cognitive control. However, consistent with metabotropic actions, PCP exaggerated protein-synthesis dependent DHPG-induced mGluR-LTD. Pretreatment with anisomycin or the group I mGluR antagonist MPEP, both of which repress translation, prevented the discoordination and PCP-induced cognitive and sensorimotor impairments. Both PCP and the NR2A-containing NMDA-receptor antagonist NVP-AAM077 unbalanced translation that engages the AKT, mTOR and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. We conclude that PCP dysregulates translation acting through NR2A receptor subtypes recruiting group 1 mGluR signaling pathways, leading to the neural discoordination that is central to the cognitive and sensorimotor impairments.