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Active dendrites and cortical associations

Periodic Reporting for period 4 - ActiveCortex (Active dendrites and cortical associations)

Reporting period: 2020-07-01 to 2020-12-31

Problem being addressed:
Converging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic.

Why is this study important for society?
Explaining the mechanisms of cognition and the operation of the cerebral cortex at the cellular level is likely to be transformative for neuroscience. We firmly believe that the research done during this project will be decisive in advancing our understanding of the cerebral cortex. This project also looks to the future when we might be able to translate the findings from animal research to human psychophysical studies. We hope to contribute directly with experimental data using non-invasive approaches in humans, however first we need to establish the biophysical details in animals as we are doing in this project. So far, this effort has proved successful, and going forward it should pave the way for modeling the brain and revealing deeper insights about the underlying principles of intelligence itself. This will, in turn, have ramifications in the design of neural networks for accomplishing many tasks that at present are out of the reach of computer science. Additionally, it will open up new possibilities for investigating cognitive deficits that are dependent on dendritic processes and that currently cannot be addressed in the clinical domain.

Overall objectives:
The main hypothesis of this grant proposal is that active dendritic properties contribute to cognition. Workpackage 1 aimed to confront this topic head-on by investigating the causal link between dendritic activity and animal behavior. In this Workpackage we probed the influence of Ca2+- and NMDA-dependent electrogenesis in behavior. In workpackage 2 we investigated the influence of long-range connectivity on dendritic activity in the tuft dendrites of pyramidal neurons and interneurons in L1 focusing on the mechanisms that are likely to underlie the behavior examined in the Workpackage 1. Here, we investigated dendritic nonlinearities in vivo and in vitro in the different dendritic compartments (i.e. subdomains/subarborizations) of single neurons in order to gain a more complete understanding synaptic integration in the dendrites and its impact on the neuronal output and neural computation. In Workpackage 3 we investigated the mechanisms for plasticity in L1 of the neocortex. The related issue of how apical dendritic activity in pyramidal neurons is correlated with plasticity was briefly addressed about a decade ago but has since laid dormant until recently. We proposed that L1 is the locus of important processes that are fundamental to memory formation.
The fourth period was only six months long and suffered somewhat from the severe lockdown imposed in Berlin. Nevertheless, much of what was achieved in this period consisted of consolidating with new publications, new ideas, as well as some residual experiments that could be performed by certain people in the laboratory. There were two major publications that came out during this period that were emblematic hope the success of the whole project.

Overall, the project has been a huge success. The main results of the project were:
1) Dendritic calcium spikes are causally related to conscious perception
2) The deep sub-cortically projecting pyramidal tract (PT) are responsible for carrying out the perceptual detection task
3) Anesthetics decouple pyramidal neurons raising the possibility that this is the reason for loss of consciousness with anesthesia
4) We found a new channel type in the dendrites of human pyramidal neurons that gives them the ability to complete more powerful computations
5) We showed that layer 1 is the locus for long-term memory consolidation in the neocortex

These results have been disseminated mostly in the form of scientific publications in high-profile journals (3 in Science, 1 in Cell, 1 in Cell Reports, 1 Nature Neurosci, and many other publications).
The project has produced conclusive evidence that an active dendritic mechanism is causally linked to conscious perception. The project has also found evidence for the importance of dendritic calcium for memory consolidation. Lastly, we have shown that dendritic calcium spikes are clearly detectable at the cortical surface using EEG. This could possibly be a gateway finding for investigating these important events in humans in the future.

By the end of the project we hope to be able to report the locus of memory consolidation in the neocortex and possibly the underlying synaptic mechanisms.
Artist's impression of dendritic spikes in the cortex