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Active dendrites and cortical associations

Periodic Reporting for period 2 - ActiveCortex (Active dendrites and cortical associations)

Reporting period: 2017-07-01 to 2018-12-31

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:
Workpackage 1 – Active dendrites and behavior
The main hypothesis of this grant proposal is that active dendritic properties contribute to cognition. This Workpackage aims to confront this topic head-on by investigating the causal link between dendritic activity and animal behavior. Our laboratory has developed a set of techniques for addressing these issues that the current proposal is ideally timed to utilize. The assumption underlying the main hypothesis (Hypothesis 1) is that Ca2+ spikes serve as a central mechanism for detecting the coincident activation of feed-forward and feedback information streams. It is therefore of great interest to examine the correlation of Ca2+ with behavior. On the other hand, NMDA-dependent electrogenesis has also been shown to underlie various forms of spiking activity in vivo and is known to mediate the influence of feedback information. From these data and from our previous in vitro study we propose that Ca2+ spike initiation is dependent on NMDA electrogenesis in the tuft dendrite. From this it would follow that cognitive tasks involving feedback are dependent on NMDA-dependent electrogenesis and that this in turn is correlated with Ca2+-dependent electrogenesis. In this Workpackage we will therefore probe the influence of Ca2+- and NMDA-dependent electrogenesis in behavior.
Workpackage 2: Dendritic electrogenesis in the pyramidal cell tuft and influence of long-range connections to L1
In this workpackage we will investigate 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. So far, there has been no systematic stud
The main hypothesis (Hypothesis 1) that we aim to investigate in ActiveCortex is “that the circuitry of the neocortex combined with the active dendritic properties of pyramidal neurons allow the cortex to associate feed-forward and feedback information arriving within a specific time window”. The assumption underlying the main hypothesis (Hypothesis 1) is that Ca2+ spikes serve as a central mechanism for detecting the coincident activation of feed-forward and feedback information streams.

WorkPackage 1 “Active dendrites and behavior” - Summary: We have completed 4 of the 5 aims of this WorkPackage resulting in 5 publications so far. The 5th unfinished aim should be completed in the next phase of the project. All projects have therefore been completed according to schedule (or faster).
Details: The first aim of Workpackage 1 was: “1.1 Ca2+ spikes and the perceptual threshold” in which we aimed to test the first conjecture that Ca2+ spikes are central to perception. This has been extremely successful bearing out our initial predictions. In a set of experiments that were recently published in the journal Science (Takahashi et al., 2016), we examined the activity of the apical dendrites of L5 pyramidal neurons around the “perceptual threshold” and showed that Ca2+ activity in the apical dendrites of layer 5 pyramidal neurons is correlated with the threshold for perceptual detection of whisker deflections. Furthermore, by manipulating the activity of apical dendrites we could shift the perceptual threshold, demonstrating that an active dendritic mechanism is causally linked to perceptual detection. This has therefore been a major success already for the project as a whole. Also, this last part constitutes the first step to achieving the aim “1.2 Direct modulation of dendritic activity during freely-moving behavior requiring top-down control”. We have also developed a head-fixed floating environment (“AirTrack”) published in the journals Journal of Physiology (Nashaat et al., 2016) and eNeuro (Nashaat et al., 2017). This approach has been taken up by many laboratories around the world and we currently using to further this goal.
We have completed and are currently preparing the manuscript for the aim “1.3 Dendritic feedback responses during awake state and anesthesia” of WorkPackage 1. Here, we obtained the unexpected finding that anesthesia downregulates the coupling between the distal and proximal dendritic compartments of L5 pyramidal neurons. The experiments for aim “1.4 Non-invasive modulation of dendritic activity during behavior” have been completed and published in the journal eLife (Murphy et al., 2016). Here, we showed that TMS modulation downregulates dendritic activity via a GABAb mechanism. Lastly, aim “1.5 Dendritic spikes and LFP/EEG” have also been successfully completed and published in the journal Nature Communications (Suzuki and Larkum, 2017). Here, we showed that dendritic spikes are clearly detectable in the EEG signal which is a major breakthrough finding, in our opinion, and clears the way for using this old and standard technology for investigating dendritic activity in humans.

WorkPackage 2 - Dendritic electrogenesis in the pyramidal cell tuft and influence of long-range connections to L1 Summary: We have completed 2 of the 7 aims of this WorkPackage. All projects are underway and are running according to schedule.
Details: The first 3 aims of WorkPackage 2, “2.1 The contribution of NMDA spikes to neuronal output”, “2.2 GABAergic control of dendritic electrogenesis in vitro” and “2.3. NMDA spikes in the dendrites of L1 interneurons” are still underway. These aims have required the development of a new approach to investigating synaptic integration in vitro using a new optogenetic approach we have dubbed “optoclamp” (see below) in collaboration with Prof. Peter Hegemann and Prof. Valentina Emiliani. We are very excited about this new approach that we ex
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