Deep posteromedial cortical rhythm in dissociation
AbstractAdvanced 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 states1,2,3,4,5,6,7,8,9,10,11,12. 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.
Data availabilityThe datasets generated and analysed are available from the corresponding author upon reasonable request and at https://www.optogenetics.org. Source data are provided with this paper.Code availabilityCode used for data processing and analysis is available from the corresponding author upon reasonable request.References1.Ferezou, I. et al. Spatiotemporal dynamics of cortical sensorimotor integration in behaving mice. Neuron 56, 907–923 (2007).PubMed
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Download referencesAcknowledgementsThis work was supported by grants to K.D. from the National Institute on Drug Abuse (NIDA P50 Center), NIMH, DARPA, the Tarlton Foundation, the AE Foundation Borderline Research Fund, the NOMIS Foundation and the Else Kroner Fresenius Foundation. K.D. and L.L. were additionally supported by the NSF NeuroNex program. S.V., I.V.K. and E.R. are supported by a National Science Foundation Graduate Research Fellowship. F.G. is supported by a Walter V. and Idun Berry Postdoctoral Fellowship, a NARSAD Young Investigator Award, and a K99/R00 award from NIDA. J.H. and P.N. are supported by a Stanford Bio-X Interdisciplinary Initiatives Seeds Grants Program. P.N. received funding from the Wu Tsai Neurosciences Institute. J.P. is supported by R01MH109954 from the National Institutes of Mental Health. We thank J. H. Lui (Rbp4-Cre), S. Franco (Cux2-CreER), K. Masuda and L. Giocomo (HCN1), and W. E. Allen for contributing to widefield imaging and Neuropixels systems; C. Ramakrishnan for virus assistance; and S. Pak, A. Chibukhchyan, N. Pichamoorthy, C. Lee and C. Delacruz for administrative support and animal husbandry. We acknowledge L. Williams and L. Tozzi for detailed discussions regarding human imaging; and L. Giocomo, B. Heifets, B. Knutson, L. Fenno, E. Sylwestrak, Y. Chen, X. Sun, T. Machado and J. Kochalka for discussion. We thank members of the Stanford Comprehensive Epilepsy Center, including H. Kaur, T. Pham, L. Schumacher, D. Sebrell, A. Valderde, A. Joshi, M. Market, C. Halpern and B. Razavi. We also thank the Clinical Imaging and Stimulation subgroup in our laboratory for discussion and collaboration.Author informationAuthor notesThese authors contributed equally: Sam Vesuna, Isaac V. KauvarAffiliationsDepartment of Bioengineering, Stanford University, Stanford, CA, USASam Vesuna, Isaac V. Kauvar, Ethan Richman, Felicity Gore, Tomiko Oskotsky, Paul Nuyujukian & Karl DeisserothDepartment of Electrical Engineering, Stanford University, Stanford, CA, USAIsaac V. Kauvar & Paul NuyujukianDepartment of Neurosurgery, Stanford University, Stanford, CA, USATomiko Oskotsky, Jaimie M. Henderson & Paul NuyujukianDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USAClara Sava-Segal & Josef ParviziDepartment of Biology, Stanford University, Stanford, CA, USALiqun LuoHoward Hughes Medical Institute, Stanford University, Stanford, CA, USALiqun Luo & Karl DeisserothDepartment of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USAFelicity Gore, Robert C. Malenka & Karl DeisserothContributionsS.V., I.V.K. and K.D. designed experiments and wrote the paper. S.V. and I.V.K. collaborated closely to perform all mouse experiments, analyse all datasets and make all figures. E.R. constructed the Neuropixels rig, designed Neuropixels experiments, performed recordings and processed data under the guidance of K.D. and L.L. S.V., I.V.K. and E.R. analysed Neuropixels data and made figures. F.G. performed electrophysiological recordings, analysis and made figures under the guidance of K.D. and R.C.M. J.M.H. performed the implantation of the epilepsy monitoring electrodes in the human research patient. J.P., J.M.H., P.N., T.O. and C.S.-S. collected human iEEG data. T.O. and P.N. performed human iEEG data curation and processing. J.P. performed the human electrical stimulation procedure. All authors made comments on the manuscript. K.D. supervised all aspects of the work.Corresponding authorCorrespondence to
Karl Deisseroth.Ethics declarations
Competing interests
All tools and protocols used during this study are freely available for non-profit use from the corresponding author upon request. Stanford University is in the process of submitting a patent application to further facilitate therapeutic translation of the findings reported in this study.
Additional informationPeer review information Nature thanks Thomas J. McHugh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Time course of ketamine-induced retrosplenial rhythm.a, Prominent 1–3 Hz retrospenial activity after ketamine injection seen in a frequency response from Thy1-GCaMP6s (top) but not control (Thy1–GFP) mice (bottom). b, Expansion of the first 15 min of the recording shown in Fig. 1g. c, Power in 1–3 Hz band in motor (MOT), somatosensory (SS), visual (VIS), posterior parietal (PP) and retrosplenial (RSP) cortices (mean ± s.e.m., n = 6 mice). d, Example 410-nm channel-corrected trace of RSP and SS activity from 3 min before to 12 min after intraperitoneal injection of 50 mg kg−1 ketamine. Vertical lines indicate injection time. e, Magnifications of 30 s of data demonstrating oscillatory rhythm in the RSP but not the SS at ten minutes after injection, or before injection. f, PSD in the RSP during five consecutive days of 50 mg kg−1 ketamine injection (mean ± s.e.m., n = 6 mice). g, Summary of power in the 1–3 Hz band in the RSP during five consecutive days of 50 mg kg−1 ketamine injection (ns, corrected paired t-test comparison with first day, P = 0.10, 0.10, 0.80, 0.75, Hedge’s g=0.73, 0.49, 0.12, 0.15). h, Direct comparison of oscillation in similarly aged male and female mice. PSD in the RSP and summary of power in the 1–3 Hz band. Both sexes have significant increase in power relative to pre-injection, but the magnitude is not significantly different between male and female mice (P
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