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Medini, Paolo
Publications (10 of 23) Show all publications
Lorenzon, P., Antos, K., Tripathi, A., Vedin, V., Berghard, A. & Medini, P. (2023). In vivo spontaneous activity and coital-evoked inhibition of mouse accessory olfactory bulb output neurons. iScience, 26(9), Article ID 107545.
Open this publication in new window or tab >>In vivo spontaneous activity and coital-evoked inhibition of mouse accessory olfactory bulb output neurons
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2023 (English)In: iScience, E-ISSN 2589-0042 , Vol. 26, no 9, article id 107545Article in journal (Refereed) Published
Abstract [en]

Little is known about estrous effects on brain microcircuits. We examined the accessory olfactory bulb (AOB) in vivo, in anesthetized naturally cycling females, as model microcircuit receiving coital somatosensory information. Whole-cell recordings demonstrate that output neurons are relatively hyperpolarized in estrus and unexpectedly fire high frequency bursts of action potentials. To mimic coitus, a calibrated artificial vagino-cervical stimulation (aVCS) protocol was devised. aVCS evoked stimulus-locked local field responses in the interneuron layer independent of estrous stage. The response is sensitive to α1-adrenergic receptor blockade, as expected since aVCS increases norepinephrine release in AOB. Intriguingly, only in estrus does aVCS inhibit AOB spike output. Estrus-specific output reduction coincides with prolonged aVCS activation of inhibitory interneurons. Accordingly, in estrus the AOB microcircuit sets the stage for coital stimulation to inhibit the output neurons, possibly via high frequency bursting-dependent enhancement of reciprocal synapse efficacy between inter- and output neurons.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Behavioral neuroscience, Cell biology, Neuroscience, Sensory neuroscience
National Category
Neurosciences Physiology
Identifiers
urn:nbn:se:umu:diva-214504 (URN)10.1016/j.isci.2023.107545 (DOI)37664596 (PubMedID)2-s2.0-85170288229 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2014.0051The Kempe Foundations
Available from: 2023-09-27 Created: 2023-09-27 Last updated: 2023-09-27Bibliographically approved
Papaioannou, S. & Medini, P. (2022). Advantages, Pitfalls, and Developments of All Optical Interrogation Strategies of Microcircuits in vivo. Frontiers in Neuroscience, 16, Article ID 859803.
Open this publication in new window or tab >>Advantages, Pitfalls, and Developments of All Optical Interrogation Strategies of Microcircuits in vivo
2022 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 16, article id 859803Article, review/survey (Refereed) Published
Abstract [en]

The holy grail for every neurophysiologist is to conclude a causal relationship between an elementary behaviour and the function of a specific brain area or circuit. Our effort to map elementary behaviours to specific brain loci and to further manipulate neural activity while observing the alterations in behaviour is in essence the goal for neuroscientists. Recent advancements in the area of experimental brain imaging in the form of longer wavelength near infrared (NIR) pulsed lasers with the development of highly efficient optogenetic actuators and reporters of neural activity, has endowed us with unprecedented resolution in spatiotemporal precision both in imaging neural activity as well as manipulating it with multiphoton microscopy. This readily available toolbox has introduced a so called all-optical physiology and interrogation of circuits and has opened new horizons when it comes to precisely, fast and non-invasively map and manipulate anatomically, molecularly or functionally identified mesoscopic brain circuits. The purpose of this review is to describe the advantages and possible pitfalls of all-optical approaches in system neuroscience, where by all-optical we mean use of multiphoton microscopy to image the functional response of neuron(s) in the network so to attain flexible choice of the cells to be also optogenetically photostimulated by holography, in absence of electrophysiology. Spatio-temporal constraints will be compared toward the classical reference of electrophysiology methods. When appropriate, in relation to current limitations of current optical approaches, we will make reference to latest works aimed to overcome these limitations, in order to highlight the most recent developments. We will also provide examples of types of experiments uniquely approachable all-optically. Finally, although mechanically non-invasive, all-optical electrophysiology exhibits potential off-target effects which can ambiguate and complicate the interpretation of the results. In summary, this review is an effort to exemplify how an all-optical experiment can be designed, conducted and interpreted from the point of view of the integrative neurophysiologist.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
all-optical circuit interrogation, holographic optogenetics, in vivo electrophysiology, multiphoton microscopy, network functional imaging
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-198224 (URN)10.3389/fnins.2022.859803 (DOI)000824516600001 ()35837124 (PubMedID)2-s2.0-85133922424 (Scopus ID)
Funder
Swedish Research Council, 2014-02350
Available from: 2022-07-21 Created: 2022-07-21 Last updated: 2023-03-24Bibliographically approved
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
Open this publication in new window or tab >>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 (English)In: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 46, no 3, p. E371-E387Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Canadian Medical Association (CMA), 2021
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-184452 (URN)10.1503/jpn.200131 (DOI)000743686000007 ()2-s2.0-85107241570 (Scopus ID)
Available from: 2021-06-17 Created: 2021-06-17 Last updated: 2023-09-05Bibliographically approved
Kuznetsova, T., Antos, K., Malinina, E., Papaioannou, S. & Medini, P. (2021). Visual stimulation with blue wavelength light drives V1 effectively eliminating stray light contamination during two-photon calcium imaging. Journal of Neuroscience Methods, 362, Article ID 109287.
Open this publication in new window or tab >>Visual stimulation with blue wavelength light drives V1 effectively eliminating stray light contamination during two-photon calcium imaging
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2021 (English)In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 362, article id 109287Article in journal (Refereed) Published
Abstract [en]

Background: Brain visual circuits are often studied in vivo by imaging Ca2+ indicators with green-shifted emission spectra. Polychromatic white visual stimuli have a spectrum that partially overlaps indicators´ emission spectra, resulting in significant contamination of calcium signals.

New method: To overcome light contamination problems we choose blue visual stimuli, having a spectral composition not overlapping with Ca2+ indicator´s emission spectrum. To compare visual responsiveness to blue and white stimuli we used electrophysiology (visual evoked potentials –VEPs) and 3D acousto-optic two-photon (2P) population Ca2+ imaging in mouse primary visual cortex (V1).

Results: VEPs in response to blue and white stimuli had comparable peak amplitudes and latencies. Ca2+ imaging in a Thy1 GP4.3 line revealed that the populations of neurons responding to blue and white stimuli were largely overlapping, that their responses had similar amplitudes, and that functional response properties such as orientation and direction selectivities were also comparable.

Comparison with existing methods: Masking or shielding the microscope are often used to minimize the contamination of Ca2+ signal by white light, but they are time consuming, bulky and thus can limit experimental design, particularly in the more and more frequently used awake set-up. Blue stimuli not interfering with imaging allow to omit shielding.

Conclusions: Together, our results show that the selected blue light stimuli evoke responses comparable to those evoked by white stimuli in mouse V1. This will make complex designs of imaging experiments in behavioral set-ups easier, and facilitate the combination of Ca2+ imaging with electrophysiology and optogenetics.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
3D acousto-optic two-photon imaging, In vivo population Ca2+ imaging, Light contamination, Mouse primary visual cortex, Visual stimulation, Visually-evoked potentials
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-191170 (URN)10.1016/j.jneumeth.2021.109287 (DOI)000688443100003 ()34256082 (PubMedID)2-s2.0-85111216618 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2014.0051Swedish Research Council, VR 2014.02350
Available from: 2022-01-11 Created: 2022-01-11 Last updated: 2022-01-11Bibliographically approved
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
Open this publication in new window or tab >>Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
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2020 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, no 6, p. 2876-2888Article in journal (Refereed) 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.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:umu:diva-169314 (URN)10.1021/jacs.9b11232 (DOI)000514255300025 ()31990532 (PubMedID)2-s2.0-85079045732 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Kempe Foundations, SMK-1632Åke Wiberg FoundationSwedish Cancer SocietyVästerbotten County Council, VLL-643451Västerbotten County Council, VLL-832001EU, Horizon 2020, 751474
Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2023-03-24Bibliographically approved
Tran, P., Wanrooij, P. H., Lorenzon, P., Sharma, S., Thelander, L., Nilsson, A. K., . . . Chabes, A. (2019). De novo dNTP production is essential for normal postnatal murine heart development. Journal of Biological Chemistry, 394(44), 15889-15897, Article ID jbc.RA119.009492.
Open this publication in new window or tab >>De novo dNTP production is essential for normal postnatal murine heart development
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2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 394, no 44, p. 15889-15897, article id jbc.RA119.009492Article in journal (Refereed) Published
Abstract [en]

The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in wild-type postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in wildtype hearts.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2019
Keywords
cardiac function, cardiac muscle, dNTP metabolism, dNTP salvage, deoxyribonucleoside kinases, desmin, heart development, nucleoside/nucleotide biosynthesis, nucleoside/nucleotide metabolism, ribonucleotide reductase
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161767 (URN)10.1074/jbc.RA119.009492 (DOI)000499478600002 ()31300555 (PubMedID)2-s2.0-85074444850 (Scopus ID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2023-03-24Bibliographically approved
Kokinovic, B. & Medini, P. (2018). Loss of GABAB-mediated interhemispheric synaptic inhibition in stroke periphery. Journal of Physiology, 596(10), 1949-1964
Open this publication in new window or tab >>Loss of GABAB-mediated interhemispheric synaptic inhibition in stroke periphery
2018 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 596, no 10, p. 1949-1964Article in journal (Refereed) Published
Abstract [en]

Recovery after stroke is mediated by plastic changes largely occurring in the lesion periphery. However, little is known about the microcircuit changes underlying recovery, the extent to which perilesional plasticity occurs at synaptic input vs. spike output level, and the connectivity behind such synaptic plasticity. We combined intrinsic imaging with extracellular and intracellular recordings and pharmacological inactivation in a focal stroke in mouse somatosensory cortex (S1). In vivo whole-cell recordings in hindlimb S1 (hS1) showed synaptic responses also to forelimb stimulation in controls, and such responses were abolished by stroke in the neighbouring forelimb area (fS1), suggesting that, under normal conditions, they originate via horizontal connections from the neighbouring fS1. Synaptic and spike responses to forelimb stimulation in hS1 recovered to quasi-normal levels 2weeks after stroke, without changes in intrinsic excitability and hindlimb-evoked spike responses. Recovered synaptic responses had longer latencies, suggesting a long-range origin of the recovery, prompting us to investigate the role of callosal inputs in the recovery process. Contralesional S1 silencing unmasked significantly larger responses to both limbs in controls, a phenomenon that was not observed when GABAB receptors were antagonized in the recorded area. Conversely, such GABAB-mediated interhemispheric inhibition was not detectable after stroke: callosal input silencing failed to change hindlimb responses, whereas it robustly reduced recovered forelimb responses. Thus, recovery of subthreshold responsiveness in the stroke periphery is accompanied by a loss of interhemispheric inhibition and this is a result of pathway-specific facilitatory action on the affected sensory response from the contralateral cortex.

National Category
Physiology Neurosciences
Identifiers
urn:nbn:se:umu:diva-149023 (URN)10.1113/JP275690 (DOI)000433597200019 ()29508394 (PubMedID)2-s2.0-85045387876 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Mazzaro, N., Barini, E., Spillantini, M. G., Goedert, M., Medini, P. & Gasparini, L. (2016). Tau-driven neuronal and neurotrophic dysfunction in a mouse model of early tauopathy. Journal of Neuroscience, 36(7), 2086-2100
Open this publication in new window or tab >>Tau-driven neuronal and neurotrophic dysfunction in a mouse model of early tauopathy
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2016 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 7, p. 2086-2100Article in journal (Refereed) Published
Abstract [en]

Tauopathies are neurodegenerative diseases characterized by intraneuronal inclusions of hyperphosphorylated tau protein and abnormal expression of brain-derived neurotrophic factor (BDNF), a key modulator of neuronal survival and function. The severity of both these pathological hallmarks correlate with the degree of cognitive impairment in patients. However, how tau pathology specifically modifies BDNF signaling and affects neuronal function during early prodromal stages of tauopathy remains unclear. Here, we report that the mild tauopathy developing in retinal ganglion cells (RGCs) of the P301S tau transgenic (P301S) mouse induces functional retinal changes by disrupting BDNF signaling via the TrkB receptor. In adult P301S mice, the physiological visual response of RGCs to pattern light stimuli and retinal acuity decline significantly. As a consequence, the activity-dependent secretion of BDNF in the vitreous is impaired in P301S mice. Further, in P301S retinas, TrkB receptors are selectively upregulated, but uncoupled from downstream extracellular signal-regulated kinase (ERK) 1/2 signaling. We also show that the impairment of TrkB signaling is triggered by tau pathology and mediates the tau-induced dysfunction of visual response. Overall our results identify a neurotrophin-mediated mechanism by which tau induces neuronal dysfunction during prodromal stages of tauopathy and define tau-driven pathophysiological changes of potential value to support early diagnosis and informed therapeutic decisions.

Place, publisher, year, edition, pages
Society for Neuroscience, 2016
Keywords
BDNF, electroretinography, neuronal dysfunction, retinal ganglion cells, tau protein, TrkB receptor
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-129999 (URN)10.1523/JNEUROSCI.0774-15.2016 (DOI)000370818700003 ()26888921 (PubMedID)2-s2.0-84959420326 (Scopus ID)
Available from: 2017-01-13 Created: 2017-01-11 Last updated: 2024-01-12Bibliographically approved
Medini, P. (2014). Experience-dependent plasticity of visual cortical microcircuits. Neuroscience, 278, 367-384
Open this publication in new window or tab >>Experience-dependent plasticity of visual cortical microcircuits
2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 278, p. 367-384Article, review/survey (Refereed) Published
Abstract [en]

The recent decade testified a tremendous increase in our knowledge on how cell-type-specific microcircuits process sensory information in the neocortex and on how such circuitry reacts to manipulations of the sensory environment. Experience-dependent plasticity has now been investigated with techniques endowed with cell resolution during both postnatal development and in adult animals. This review recapitulates the main recent findings in the field using mainly the primary visual cortex as a model system to highlight the more important questions and physiological principles (such as the role of non-competitive mechanisms, the role of inhibition in excitatory cell plasticity, the functional importance of spine and axonal plasticity on a microscale level). I will also discuss on which scientific problems the debate and controversies are more pronounced. New technologies that allow to perturbate cell-type-specific subcircuits will certainly shine new light in the years to come at least on some of the still open questions. (C) 2014 The Author. Published by Elsevier Ltd. on behalf of IBRO.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
experience-dependent plasticity, microcircuits, layer specificity, cell-type specificity, visual system, barrel cortex
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-94938 (URN)10.1016/j.neuroscience.2014.08.022 (DOI)000342058700033 ()2-s2.0-84909643370 (Scopus ID)
Available from: 2014-11-12 Created: 2014-10-20 Last updated: 2023-03-24Bibliographically approved
Olcese, U., Iurilli, G. & Medini, P. (2013). Cellular and synaptic architecture of multisensory integration in the mouse neocortex. Neuron, 79(3), 579-593
Open this publication in new window or tab >>Cellular and synaptic architecture of multisensory integration in the mouse neocortex
2013 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 79, no 3, p. 579-593Article in journal (Refereed) Published
Abstract [en]

Multisensory integration (MI) is crucial for sensory processing, but it is unclear how MI is organized in cortical microcircuits. Whole-cell recordings in a mouse visuotactile area located between primary visual and somatosensory cortices revealed that spike responses were less bimodal than synaptic responses but displayed larger multisensory enhancement. MI was layer and cell type specific, with multisensory enhancement being rare in the major class of inhibitory interneurons and in the output infragranular layers. Optogenetic manipulation of parvalbumin-positive interneuron activity revealed that the scarce MI of interneurons enables MI in neighboring pyramids. Finally, single-cell resolution calcium imaging revealed a gradual merging of modalities: unisensory neurons had higher densities toward the borders of the primary cortices, but were located in unimodal clusters in the middle of the cortical area. These findings reveal the role of different neuronal subcircuits in the synaptic process of MI in the rodent parietal cortex.

National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-79153 (URN)10.1016/j.neuron.2013.06.010 (DOI)23850594 (PubMedID)
Available from: 2013-08-17 Created: 2013-08-09 Last updated: 2018-06-08Bibliographically approved
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