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

• Published in: Molecular psychiatry Vol. 22; no. 5; pp. 647 - 655
• Main Authors: Parker, K L, Kim, Y C, Kelley, R M, Nessler, A J, Chen, K-H, Muller-Ewald, V A, Andreasen, N C, Narayanan, N S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2017; Nature Publishing Group
• Subjects: 631/378; 692/699/476/1799; Adult; Aged; Animal models; Animals; Behavioral Sciences; Biological Psychology; Brain research; Case-Control Studies; Cerebellum; Cerebellum - pathology; Cerebellum - physiopathology; Cognition - physiology; Cognitive ability; Cortex (frontal); Disease Models, Animal; Dopamine; Electroencephalography - methods; Feedback; Female; Frontal Lobe - pathology; Frontal Lobe - physiopathology; Humans; immediate-communication; Information processing; Male; Medicine; Medicine & Public Health; Memory; Mental disorders; Middle Aged; Neural Pathways - pathology; Neural Pathways - physiopathology; Neurons - pathology; Neurosciences; Pharmacotherapy; Prefrontal Cortex - pathology; Prefrontal Cortex - physiopathology; Psychiatry; Rats; Rats, Long-Evans; Schizophrenia; Schizophrenia - pathology; Schizophrenia - physiopathology; Schizophrenia - therapy; Thalamus; Thalamus - physiopathology; Transcranial Direct Current Stimulation - methods; United States > US; Iowa City Iowa
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2017.50

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.