4.5 years and 2 different versions later @yingzhang777
and I are thrilled to share our new study in @Nature
. As always this was a team effort across many labs. Link: nature.com/articles/s4158… @broadinstitute
@mcgovernmit
A brief summary...
For starters, the editorial team kindly invited us to write a Research Briefing, which is a lot easier to read than the main article :). Link: nature.com/articles/d4158…
For context, our work builds on many previous studies about parafascicular thalamus (PF) including from the Kreitzer Lab at UCSF, Surmeier Lab at Northwestern, Sabatini Lab at HMS, and Yin Lab at Duke.
In Fig 1 we simply start by characterizing projection-specific PF subpopulations and their physiological properties ex vivo. In short, there are at least 3 distinct subpopulations.
In Fig 2 we show that CPu- and STN-projecting PF ensembles contribute to locomotion or motor learning. For the motor learning function, we revealed an understudied PV+ excitatory cell type in mouse STN.
Fig 3 extends the behavioral observations to a role for NAc-projecting PF neurons in reward processing and depression-like states. Also, there is some nice fiber photometry data supporting the various PF subnetworks.
When thinking about these motor and non-motor circuits in PF, like others, Parkinson's disease (PD) applications came to mind. In Fig 4, we show that the different PF circuits are altered in an acute PD model and that circuit manipulations can rescue some PD deficits in mice.
For the above Fig 4 work, we generated a Cre-dependent SOUL AAV that could be useful for minimally invasive optogenetics. It can be ordered from @Addgene. Link: addgene.org/177577/
In the final Fig 5, we extend the rescue experiments to distinct nicotinic acetylcholine receptors (nAChRs) expressed by the PF subpopulations. Modulating these nAChRs in PD mice is another way to alleviate some motor and non-motor deficits.
And finally, we end the study by showing that the nAChRs are not only expressed by PF neurons/circuits in mice but is also the case in macaques. We hope that in the future non-human primate experiments can test these therapeutic candidates. Thank you for reading about our work!
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