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The neuroscience of tickling: cerebellar mechanisms and sensory prediction

Periodic Reporting for period 1 - NeuroTick (The neuroscience of tickling: cerebellar mechanisms and sensory prediction)

Reporting period: 2019-09-01 to 2021-08-31

This fellowship has contributed to three research topics:
1. Cerebellar contribution to cognition and autism
2. Cell-type classification in the cerebellum
3. Kin-avoidance in cannibalistic homicides
4. Cerebellar contribution to tickling
The exact aim of each research topic is explained in more detail below.

The cerebellum (‘the little brain’, a region in the back of the brain containing more than half of all brain cells) plays an important role in the coordination of movement as well as cognitive functions. In humans, damage to the cerebellum around birth is associated with a higher risk of developing autism spectrum disorder (ASD). However, how exactly the cerebellum coordinates cognitive functions and how it can be involved in the development of ASD is still unclear.

First, we aim to get a better understanding of the neuronal mechanisms by which the cerebellum plays a role in cognition, and specifically in ASD. We train mice to perform a complex cognitive task in which they need to accumulate evidence and execute a decision as a measure of their information processing. Using mice allows us to manipulate activity in specific brain regions as well as perform detailed high-quality recordings of brain activity which are not feasible in humans, thus getting a better insight into the exact neuronal mechanisms during specific behaviours. Understanding the neuronal mechanisms by which the cerebellum can coordinate and improve cognition and is involved in ASD can help us to better understand and highlight specific enhanced abilities in people with ASD.

Second, we aim to develop a tool to improve analysis of recordings from the cerebellar cortex, and provide this tool open-access to the cerebellar community. Currently, high-density silicon probes are commonly used to record brain activity. The advantage of these probes is that hundreds of cells can be recorded simultaneously. However, the downside is that it is currently not possible to determine the exact cell type these cells belong to. With the tool we aim to address that issue by providing automatic cell-type classification in the cerebellar cortex.

Third, we had a less conventional and more creative approach to study the brain. We aim to address the question of how humans are able to recognize kin, and how preserved kin-recognition is in the most severe criminals of our society. Our assumption is that many mental faculties will be disrupted in offenders of cannibalistic homicides. Knowing whether kin recognition is disrupted or preserved, as in other cannibalistic animal species, helps us to understand how important and evolutionary preserved kin recognition is for humans.

Fourth, ultimately we aim to combine cerebellar mechanisms of cognition and social behaviour such as kin-recognition by studying tickling in rats. The cerebellum is the reason you cannot tickle yourself: it already predicts your movements, removing the element of surprise which is essential for tickling. Play-fight behaviour such as tickling is naturalistic behaviour in rats. By combining all three previous aims, we can better understand the neuronal mechanisms by which the cerebellum controls cognitive and social behaviours.
1. Cerebellar contribution to cognition and autism
The results from this aim have now been published as a pre-print (Oostland et al., BioRxiv, 2021), and presented in a short video format which was prepared for the Society for Neuroscience 2021 meeting which is now available online (https://scholar.princeton.edu/sites/default/files/oostland_sfn_2021_withcc.mp4). In this preprint, we report that a cerebellum-specific transgenic mouse model of ASD, the L7-Tsc1 mutant mice, shows increased sensory sensitivity as well as faster learning on a sensory evidence-accumulation task (see figure). We are able to replicate these findings in wild-type mice with optogenetic perturbation of the cerebellum. We conclude that cerebellar perturbation can activate neocortex via complex spike activity and reduce reliance on prior experience, consistent with a weak-global-coherence account in which ASD traits arise from enhanced detail-oriented processing.

2. Cell-type classification in the cerebellum
We are currently still developing the toolbox for automatic cell-type classification in the cerebellar cortex. This is part of a larger team effort, consisting of neuroscience experimentalists as well as computer scientists.

3. Kin-avoidance in cannibalistic homicides
The results from this aim have now been published in a peer-reviewed paper (Oostland & Brecht, Frontiers in Psychology, 2020) and more information for the general public about this topic as well as the full data set is now available on www.cannibalismresearch.org for anyone to browse. To investigate whether kin recognition is still in place in offenders of cannibalistic homicides, we generated a unique data set of information about 121 cannibals with approximately 631 victims, operating worldwide since 1900. We found that cannibalistic homicides are a distinct category of homicides with a unique pattern of murder methods, offenders, and victims, and only rarely ate kin. The preserved kin-recognition and kin-protection in offenders of cannibalistic homicides is not unlike the behaviour of cannibalistic fish or tadpoles, and points to anti-kin-ingestion mechanisms evolved from kin-selection many hundred millions of years ago.

4. Cerebellar contribution to tickling
I have learned how to tickle rats, and how to use this as a form of naturalistic behaviour to study neuronal mechanisms. In the future, I can use all of the techniques and insights I gained from this fellowship to fully explore the cerebellar contributions to tickling and other naturalistic behaviours.
1. Cerebellar contribution to cognition and autism
Here, we used a unique combination of in vivo electrophysiology in awake behaving animals, genetic manipulations, optogenetic manipulations, and computational latent-state analysis of behaviour to gain new insights in how the activity in the cerebellum can lead to enhanced functions and improved learning, including in a cerebellum-specific mouse model of ASD. This recasts ASD not so much as a disorder but as a variation that, in particular niches, can be adaptive.

2. Cell-type classification in the cerebellum
We will continue the development of this toolbox and make it freely available for other researchers to use. Once widely implemented, this will improve and accelerate many research projects and contribute to advanced understanding of the cerebellum. Overall, this will have implications for our understanding of the cerebellum in health and disease.

3. Kin-avoidance in cannibalistic homicides
This project had a very unique approach to studying kin recognition. By making the dataset about the cannibalistic homicides freely available on the public website www.cannibalismresearch.org with all data easy to use and browse for the general public, anyone interested in true crime can use this dataset to advance our understanding of the behaviour of offenders of cannibalistic homicides.

4. Cerebellar contribution to tickling
This fellowship has put me in a perfect position to study the cerebellar contribution to tickling and other naturalistic behaviours when I start my own line of research as an independent investigator.
Islands of enhanced functions in a cerebellum-specific mouse model of autism spectrum disorder (ASD)