Anushree Tripathi, PhD; Sebastian Sulis Sato, PhD; Paolo Medini, MD, PhD
Background: Auditory hallucinations (which occur when the distinction between thoughts and perceptions is blurred) are common in psychotic disorders. The orbitofrontal cortex (OFC) may be implicated, because it receives multiple inputs, including sound and affective value via the amygdala, orchestrating complex emotional responses. We aimed to elucidate the circuit and neuromodulatory mechanisms that underlie the processing of emotionally salient auditory stimuli in the OFC — mechanisms that may be involved in auditory hallucinations.
Methods: We identified the cortico-cortical connectivity conveying auditory information to the mouse OFC; its sensitivity to neuromodulators involved in psychosis and postpartum depression, such as dopamine and neurosteroids; and its sensitivity to sensory gating (defective in dysexecutive syndromes).
Results: Retrograde tracers in OFC revealed input cells in all auditory cortices. Acoustic responses were abolished by pharmacological and chemogenetic inactivation of the above-identified pathway. Acoustic responses in the OFC were reduced by local dopaminergic agonists and neurosteroids. Noticeably, apomorphine action lasted longer in the OFC than in auditory areas, and its effect was modality-specific (augmentation for visual responses), whereas neurosteroid action was sex-specific. Finally, acoustic responses in the OFC reverberated to the auditory association cortex via feedback connections and displayed sensory gating, a phenomenon of local origin, given that it was not detectable in input auditory cortices.
Limitations: Although our findings were for mice, connectivity and sensitivity to neuromodulation are conserved across mammals.
Conclusion: The corticocortical loop from the auditory association cortex to the OFC is dramatically sensitive to dopamine and neurosteroids. This suggests a clinically testable circuit behind auditory hallucinations. The function of OFC input–output circuits can be studied in mice with targeted and clinically relevant mutations related to their response to emotionally salient sounds.
Submitted Jul. 6, 2020; Revised Oct. 29, 2020; Accepted Jan. 17, 2021
Acknowledgments: We thank the research engineer Kamil Antos for assistance in programming the TDT auditory stimulator and for IT assistance; the research engineer Per Utsi for excellent mechanical assistance; and Dr Eva Henje Blom (Senior Lecturer, Child and Adolescent Psychiatry, Umeå University) for critically reading the manuscript).
Affiliations: Department of Integrative Medical Biology, Umeå University, 90187 Umeå, Sweden (Tripathi, Sato, Medini).
Competing interests: None declared.
Contributors: P. Medini designed the study and S. Sato designed the chemogenetic protocol. A. Tripathi acquired the data, which A. Tripathi and P. Medini analyzed. A. Tripathi and P. Medini wrote the article, which S. Sato reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BYNC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Correspondence to: P. Medini, Department of Integrative Medical Biology, Umeå University, Johan Bures Väg, 12, 90187, Umeå, Sweden; email@example.com