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Sulis Sato, Sebastian
Publikationer (2 of 2) Visa alla publikationer
Tripathi, A., Sulis Sato, S. & Medini, P. (2021). Cortico-cortical connectivity behind acoustic information transfer to mouse orbitofrontal cortex is sensitive to neuromodulation and displays local sensory gating: relevance in disorders with auditory hallucinations?. Journal of Psychiatry & Neuroscience, 46(3), E371-E387
Öppna denna publikation i ny flik eller fönster >>Cortico-cortical connectivity behind acoustic information transfer to mouse orbitofrontal cortex is sensitive to neuromodulation and displays local sensory gating: relevance in disorders with auditory hallucinations?
2021 (Engelska)Ingår i: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 46, nr 3, s. E371-E387Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Canadian Medical Association (CMA), 2021
Nationell ämneskategori
Neurovetenskaper Neurologi
Identifikatorer
urn:nbn:se:umu:diva-184452 (URN)10.1503/jpn.200131 (DOI)000743686000007 ()2-s2.0-85107241570 (Scopus ID)
Tillgänglig från: 2021-06-17 Skapad: 2021-06-17 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Jamroskovic, J., Doimo, M., Chand, K., Obi, I., Kumar, R., Brännström, K., . . . Sabouri, N. (2020). Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization. Journal of the American Chemical Society, 142(6), 2876-2888
Öppna denna publikation i ny flik eller fönster >>Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
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2020 (Engelska)Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, nr 6, s. 2876-2888Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Atom- och molekylfysik och optik
Identifikatorer
urn:nbn:se:umu:diva-169314 (URN)10.1021/jacs.9b11232 (DOI)000514255300025 ()31990532 (PubMedID)2-s2.0-85079045732 (Scopus ID)
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseVetenskapsrådetKempestiftelserna, SMK-1632Åke Wibergs StiftelseCancerfondenVästerbottens läns landsting, VLL-643451Västerbottens läns landsting, VLL-832001EU, Horisont 2020, 751474
Tillgänglig från: 2020-03-31 Skapad: 2020-03-31 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
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