Neuronal Encoding of Object‐Type and Object‐Place Memories in Hippocampus and Neocortex of Young and Old Mice

Abstract

Neuronal encoding of environmental information has long been in the focus of neuroscience. Neurophysiological studies show that when animals become familiar with space or objects, neuronal activity changes due to these factors. However, despite a considerable amount of experimental data, the specific neural bases of space and objects encoding, and the nature of their disturbance in aging or pathology remains an open question. In this work, we test the hypothesis that neurons in different regions of the brain, hippocampus and retrosplenial cortex (RSC) encode spatial and object information respectively, and that natural aging impairs these two forms of memory differently. To test this hypothesis, we developed an approach combining optical recording of neuronal activity and assessment of animal behavior during novel object recognition (NOR) and object place recognition (OPR) tasks, as well as cognitive enhancement in young and old animals. First, we examined what forms of memory are affected in old mice, and whether it is possible to restore the age‐impaired memory pharmacologically. We trained young (2–3 months) and old (18–21 months) mice in NOR and OPR tasks and then tested short‐term 120 min memory and long‐term 24 h memory. We showed that both young and old mice demonstrate short‐term NOR and OPR memories, and that P2 cognitive enhancer that belongs to a new class of sAPP‐mimetics did not potentiate this memory. On the other hand, both old and young mice failed to form NOR and OPR long‐term memories. Interestingly, administration of P2 produced long‐term memory manifestation only in the old mice.Next, we recorded the object‐type and object‐place related calcium activity in the RSC and hippocampus CA1 of young mice using genetically encoded YtnC sensor and fiber‐optic photometry (Fig. 1, A). We found an increase in the number of calcium events in the RSC when animals examined new position of the familiar object. We also discovered decrease in the RSC activity during exploration of a novel object.Using multiphoton microscopy and NVista minimicroscopy we registered GCaMP6 calcium activity of identified RSC (Fig. 1, B) and CA1 (Fig. 1, C) neurons in young mice during NOR and OPR tasks performed in the Mobile HomeCage. Different classes of neurons were identified – those demonstrating an increase and decrease of activity during place and objects exploration, as well as cells that were active during specific behavioral acts.Thus, we showed that both object‐type and object‐place memory was specifically expressed in the activity of RSC and CA1 neurons. Both object‐type and object‐place long‐term memories were missing in the old mice but were brought to the surface by administration sAPP‐mimetic cognitive enhancer. In the future, we will test how memory‐related brain activity changes in NOR and OPR tasks in old animals, and whether these changes in neuronal activity could be compensated pharmacologically.Support or Funding InformationSupported by RSF 20‐15‐00283 and RFBR 17‐00‐00215, 19‐315‐80020, 17‐29‐07083, 18‐32‐20212Neuronal calcium activity in novel object recognition and object place recognition tasks. A: fiber‐optic photometry of YtnC calcium signal from retrosplenial cortex (RSC) and hippocampus CA1; red line – baseline. B: two‐photon microscopy of identified GCaMP6S neurons in the retrosplenial cortex; asterisks show calcium events – spikes. Ñ: NVista minimicroscopy of GCaMP6S neurons in hippocampus CA1; arrows show calcium spikes.Figure 1