Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction

Abstract

Schizophrenia involves abnormalities in the medial frontal cortex that lead to cognitive deficits. Here we investigate a novel strategy to normalize medial frontal brain activity by stimulating cerebellar projections. We used an interval timing task to study elementary cognitive processing that requires both frontal and cerebellar networks that are disrupted in patients with schizophrenia. We report three novel findings. First, patients with schizophrenia had dysfunctional delta rhythms between 1–4 Hz in the medial frontal cortex. We explored cerebellar-frontal interactions in animal models and found that both frontal and cerebellar neurons were modulated during interval timing and had delta-frequency interactions. Finally, delta-frequency optogenetic stimulation of thalamic synaptic terminals of lateral cerebellar projection neurons rescued timing performance as well as medial frontal activity in a rodent model of schizophrenia-related frontal dysfunction. These data provide insight into how the cerebellum influences medial frontal networks and the role of the cerebellum in cognitive processing.

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Acknowledgements

We thank members of the Narayanan Lab, Erik Carlson, MD, PhD, John Freeman, PhD and Vince Magnotta, PhD for scientific discussion and Alane Tranel and Tom Wassink, MD, PhD for assistance with patient recruitment. KLP has received generous funding to complete this research from the Brain and Behavior Foundation Young Investigator NARSAD Award, The Nellie Ball Research Trust and NIMH K01 MH106824. NSN has received funding from an NIND R01 NS089470.

Author contributions

KLP and NN designed research, analyzed data and wrote the manuscript. KLP performed rodent research. NCA facilitated access to and provided expertise in working with the human schizophrenia population, KLP and K-HC performed human studies, RMK conducted Granger Causality analyses, KLP, YCK, AJN and VAM-E conducted histological analyses, and all authors provided feedback on manuscript.

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Correspondence to N S Narayanan.

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Parker, K., Kim, Y., Kelley, R. et al. Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction. Mol Psychiatry 22, 647–655 (2017). https://doi.org/10.1038/mp.2017.50

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