Jercog, P. E. | bioRxiv Science

bioRxiv2022

Anti-NMDAR encephalitis antibodies cause long-lasting degradation of the hippocampal neural representation of memory

N-methyl D-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder characterized by a complex neuropsychiatric syndrome together with a reduction of NMDAR. Although in most patients the life-threatening symptoms of the acute stage resolve with immunotherapy, memory and executive functions remain altered for several months or years. A mechanistic explanation for these long-lasting cognitive effects is still lacking and previous animal models have not explored this effect. Here, we combined repeat calcium imaging of the same population of hundreds of hippocampal CA1 neurons for three months along with two behavioral tasks to assess retrograde and anterograde memory loss using a reported mouse model of cerebroventricular transfer of patients CSF antibodies. We measured how memory-related neuronal activity is affected by the presence of NMDAR antibodies during the induction of the model and its long-lasting recovery. In addition, we developed a computational model that provides a mechanistic explanation for the long-term antibody-mediated impairment of memory. The findings show that the presence of antibodies leads to an increase of CA1 neuronal firing rate, resulting in a reduction of the amount of information encoded by these cells. Furthermore, the antibodies cause a degradation of the hippocampal neuronal response stability over time, providing a neural correlate of memory dysfunction. All these neuronal alterations span the 3 months of recordings, and in some cases beyond the last recording point. The computational model shows that a reduction of NMDAR is sufficient to cause the changes observed in neuronal activity, including the different involvement of excitatory and inhibitory inputs to CA1 neurons. Altogether, we show that the antibody-mediated reduction of NMDAR leads to long-term changes in hippocampal neuronal activity which extend far beyond the antibody clearance, providing a mechanism that can account for the cognitive deficits observed in the protracted recovery of patients with anti-NMDAR encephalitis.

neuroscience↗

bioRxiv2019

High-throughput task to study memory recall during spatial navigation in rodents

Spatial navigation is the most frequently used behavioral paradigm to study hippocampal dependent memory formation in rodents. However, commonly used tasks can present some limitations: i) they are labor intensive, preventing the implementation of parallel testing for high-throughput experimentation; ii) yield a low number of repeated trials, curtailing the statistical power; iii) are hard to combine with neural recordings, because tethering sometimes interferes with behavior; iv) are not based on overt behavioral responses that can be precisely timed, making difficult the identification of the underlying neural events; v) produce a low spatial coverage, limiting the characterization of neuronal patterns related to spatial information. To circumvent these limitations, we developed a spatial memory task that required minimal human intervention, allowed simultaneous and unsupervised testing of several mice, and yielded a high number of recall trials per session (up to ~20). Moreover, because recall sessions could be repeated over many days, the task provided enough statistical power to characterize in detail the animals behavior during memory recall, even to quantify the decay in spatial accuracy of memories as they are stacked across days. In addition, the task is compatible with neural activity recordings. Together, these features make our task a valuable tool to start dissecting the neural circuit dynamics underlying spatial memory recall.

neuroscience↗

bioRxiv2018

Heading direction with respect to a reference point modulates place-cell activity

Utilizing electrophysiological recordings from CA1 pyramidal cells in freely moving mice, we find that a majority of neural responses are modulated by the heading-direction of the animal relative to a point within or outside their enclosure that we call a reference point. Our findings identify a novel representation in the neuronal responses in the dorsal hippocampus.

neuroscience↗