Deep posteromedial cortical rhythm in dissociation

Sam Vesuna, Isaac V. Kauvar, Ethan Richman, Felicity Gore, Tomiko Oskotsky, Clara Sava-Segal, Liqun Luo, Robert C. Malenka, Jaimie M. Henderson, Paul Nuyujukian, Josef Parvizi and Karl Deisseroth ()
Additional contact information
Sam Vesuna: Stanford University
Isaac V. Kauvar: Stanford University
Ethan Richman: Stanford University
Felicity Gore: Stanford University
Tomiko Oskotsky: Stanford University
Clara Sava-Segal: Stanford University
Liqun Luo: Stanford University
Robert C. Malenka: Stanford University
Jaimie M. Henderson: Stanford University
Paul Nuyujukian: Stanford University
Josef Parvizi: Stanford University
Karl Deisseroth: Stanford University

Nature, 2020, vol. 586, issue 7827, 87-94

Abstract: Abstract Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states1–12. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use13,14, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1–3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed—including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.

Date: 2020
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DOI: 10.1038/s41586-020-2731-9

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