Carrillo-Segura, S. | Search bioRxiv

bioRxiv2023

On the results of causal optogenetic engram manipulations

Hippocampal neurons encoding memories discharge in sparsely-distributed patterns; they can be optogenetically tagged, then photostimulated to elicit conditioned behavior, potentially generating a synthetic memory trace, "engram". We investigated mouse hippocampal population responses to the photostimulation of memory-tagged neurons to determine if memory-associated discharge is mimicked in hippocampus, a network with non-linear and homeostatic interactions. Both memory-tagged and not-tagged CA1 cells adjusted firing during photostimulation without altering place cell firing fields. Cell-pair cofiring relationships also maintain during photostimulation, indicating a low-dimensional, dynamical structure-preserving, homeostatic network response instead of the photostimulated pattern. Photostimulating neurons that were tagged during place-avoidance memory elicits similar place-avoidance memory in control conditions. Thus artificial photostimulation elicits natural, stored, homeostatic neuronal network cofiring patterns to elicit memory, establishing mimicry evidence for the engram.

neuroscience↗

bioRxiv2022

Phencyclidine disrupts neural coordination and cognitive control by dysregulating translation

BackgroundPhencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist impairs cognition remains unknown. MethodsThe effects of PCP were investigated i) on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice; ii) on synaptic responses in ex vivo mouse hippocampus slices; iii) in mice on a hippocampus-dependent active place avoidance task that requires cognitive control; and iv) on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects to the effects of inhibitors of protein synthesis, group-1-type metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. ResultsConsistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity, and impaired active place avoidance, despite learning the task before PCP. Consistent with metabotropic actions, PCP exaggerated protein-synthesis dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression (LTD). Pretreatment with anisomycin or the mGluR1/5-antagonist MPEP, both of which repress translation, prevented the PCP-induced discoordination, and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR-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. ConclusionsPCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, leading to the neural discoordination that is central to the cognitive and sensorimotor impairments.

neuroscience↗