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Leão, Richardson N
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Publications (10 of 22) Show all publications
de Oliveira, R. B., Petiz, L. L., Lim, R., Lipski, J., Gravina, F. S., Brichta, A. M., . . . van Helden, D. F. (2019). Crosstalk between mitochondria, calcium channels and actin cytoskeleton modulates noradrenergic activity of locus coeruleus neurons. Journal of Neurochemistry, 149(4), 471-487
Open this publication in new window or tab >>Crosstalk between mitochondria, calcium channels and actin cytoskeleton modulates noradrenergic activity of locus coeruleus neurons
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2019 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 149, no 4, p. 471-487Article in journal (Refereed) Published
Abstract [en]

Locus coeruleus (LC) is the name of a group of large sized neurons located at the brain stem, which provides the main source of noradrenaline to the central nervous system, virtually, innervating the whole brain. All noradrenergic signalling provided by this nucleus is dependent on an intrinsic pacemaker process. Our study aims to understand how noradrenergic neurons finely tune their pacemaker processes and regulate their activities. Here we present that mitochondrial perturbation in the LC from mice, inhibits spontaneous firing by a hyperpolarizing response that involves Ca2+ entry via L-type Ca2+ channels and the actin cytoskeleton. We found that pharmacological perturbation of mitochondria from LC neurons using the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP), induced a dominant hyperpolarizing response when electrophysiological approaches were performed. Surprisingly, the CCCP-induced hyperpolarizing response was dependent on L-type Ca2+ channel-mediated Ca2+ entry, as it was inhibited by: the removal of extracellular Ca2+; the addition of Cd2+; nifedipine or nicardipine; but not by the intracellular dialysis with the Ca2+ chelator 1,2-Bis(2-Aminophenoxy)ethane-N,N,N ',N '-tetraacetic acid, the latter indicating that the response was not because of a global change in [Ca2+](c) but does not exclude action at intracellular microdomains. Further to this, the incubation of slices with cytochalasin D, an agent that depolymerises the actin cytoskeleton, inhibited the hyperpolarizing response indicating an involvement of the actin cytoskeleton. The data are consistent with the hypothesis that there is a crosstalk between mitochondria and L-type Ca2+ channels leading to modulation of noradrenergic neuronal activity mediated by the actin cytoskeleton. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
actin cytoskeleton, calcium channels, locus coeruleus, mitochondria, neuronal activity, noradrenergic
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-386166 (URN)10.1111/jnc.14692 (DOI)000468834600004 ()30828804 (PubMedID)
Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Winne, J., Franzon, R., de Miranda, A., Malfatti, T., Patriota, J., Mikulovic, S., . . . Leão, R. N. (2019). Salicylate induces anxiety-like behavior and slow theta oscillation and abolishes the relationship between running speed and fast theta oscillation frequency. Hippocampus, 29(1), 15-25
Open this publication in new window or tab >>Salicylate induces anxiety-like behavior and slow theta oscillation and abolishes the relationship between running speed and fast theta oscillation frequency
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2019 (English)In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 29, no 1, p. 15-25Article in journal (Refereed) Published
Abstract [en]

Salicylate intoxication is a cause of tinnitus in humans and it is often used to produce tinnitus-like perception in animal models. Here, we assess whether salicylate induces anxiety-like electrophysiological and behavioral signs. Using microwire electrode arrays, we recorded local field potential in the ventral and, in some experiments dorsal hippocampus, in an open field arena 1 hr after salicylate (300 mg/kg) injection. We found that animals treated with salicylate moved dramatically less than saline treated animals. Salicylate-treated animals showed a strong 4-6 Hz (type 2) oscillation in the ventral hippocampus (with smaller peaks in dorsal hippocampus electrodes). Coherence in the 4-6 Hz-theta band was low in the ventral and dorsal hippocampus when compared to movement-related theta coherence (7-10 Hz). Moreover, movement related theta oscillation frequency decreased and its dependency on running speed was abolished. Our results suggest that salicylate-induced theta is mostly restricted to the ventral hippocampus. Slow theta has been classically associated to anxiety-like behaviors. Here, we show that salicylate application can consistently generate low frequency theta in the ventral hippocampus. Tinnitus and anxiety show strong comorbidity and the increase in ventral hippocampus low frequency theta could be part of this association.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
anxiety, salicylate, theta, tinnitus, ventral hippocampus
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-373310 (URN)10.1002/hipo.23021 (DOI)000454153200002 ()30152905 (PubMedID)
Available from: 2019-01-16 Created: 2019-01-16 Last updated: 2019-01-16Bibliographically approved
Lima da Cruz, R. V., Moulin, T. C., Petiz, L. L. & Leão, R. N. (2018). A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus. Frontiers in Molecular Neuroscience, 11, Article ID 312.
Open this publication in new window or tab >>A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus
2018 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 312Article in journal (Refereed) Published
Abstract [en]

The subgranular zone (SGZ) of dentate gyrus (DG) is one of the few regions in which neurogenesis is maintained throughout adulthood. It is believed that newborn neurons in this region encode temporal information about partially overlapping contextual memories. The 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring compound capable of inducing a powerful psychedelic state. Recently, it has been suggested that DMT analogs may be used in the treatment of mood disorders. Due to the strong link between altered neurogenesis and mood disorders, we tested whether 5-MeO-DMT is capable of increasing DG cell proliferation. We show that a single intracerebroventricular (ICV) injection of 5-MeO-DMT increases the number of Bromodeoxyuridine (BrdU+) cells in adult mice DG. Moreover, using a transgenic animal expressing tamoxifen-dependent Cre recombinase under doublecortin promoter, we found that 5 Meo-DMT treated mice had a higher number of newborn DG Granule cells (GC). We also showed that these DG GC have more complex dendritic morphology after 5-MeO-DMT. Lastly, newborn GC treated with 5-MeO-DMT, display shorter afterhyperpolarization (AHP) potentials and higher action potential (AP) threshold compared. Our findings show that 5-MeO-DMT affects neurogenesis and this effect may contribute to the known antidepressant properties of DMT-derived compounds.

Keywords
5-MeO-DMT, adult neurogenesis, patch clamp, psychedelics, dentate gyrus granule cells
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-364247 (URN)10.3389/fnmol.2018.00312 (DOI)000443650200001 ()30233313 (PubMedID)
Note

Correction in: FRONTIERS IN MOLECULAR NEUROSCIENCE, Volume: 12, Article Number: 79, DOI: 10.3389/fnmol.2019.00079

Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2019-04-24Bibliographically approved
Siwani, S., Franca, A. S. C., Mikulovic, S., Reis, A., Hilscher, M. M., Edwards, S. J., . . . Kullander, K. (2018). OLM alpha 2 Cells Bidirectionally Modulate Learning. Neuron, 99(2), 404-412
Open this publication in new window or tab >>OLM alpha 2 Cells Bidirectionally Modulate Learning
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2018 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 99, no 2, p. 404-412Article in journal (Refereed) Published
Abstract [en]

Inhibitory interneurons participate in mnemonic processes. However, defined roles for identified interneuron populations are scarce. A subpopulation of oriens lacunosum-moleculare (OLM) interneurons genetically defined by the expression of the nicotinic receptor alpha 2 subunit has been shown to gate information carried by either the temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine whether selective modulation of OLM alpha 2 cells in the intermediate CA1 affects learning and memory in vivo. Our data show that intermediate OLM alpha 2 cells can either enhance (upon their inhibition) or impair (upon their activation) object memory encoding in freely moving mice, thus exerting bidirectional control. Moreover, we find that OLM alpha 2 cell activation inhibits fear-related memories and that OLM alpha 2 cells respond differently to nicotine in the dorsoventral axis. These results suggest that intermediate OLM alpha 2 cells are an important component in the CA1 microcircuit regulating learning and memory processes.

Place, publisher, year, edition, pages
CELL PRESS, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-387269 (URN)10.1016/j.neuron.2018.06.022 (DOI)000439709900017 ()29983324 (PubMedID)
Funder
Swedish Research Council, 2015-02395
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Mikulovic, S., Restrepo, C. E., Siwani, S., Bauer, P., Johann, S. P., Tort, A. B. L., . . . Leão, R. N. (2018). Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor. Nature Communications, 9, 3638:1-15, Article ID 3638.
Open this publication in new window or tab >>Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, p. 3638:1-15, article id 3638Article in journal (Refereed) Published
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-364241 (URN)10.1038/s41467-018-05907-w (DOI)000444014100013 ()30194386 (PubMedID)
Projects
eSSENCE
Available from: 2018-09-07 Created: 2018-10-29 Last updated: 2018-10-30Bibliographically approved
Hilscher, M. M., Leão, R. N., Edwards, S. J., Leão, K. E. & Kullander, K. (2017). Chrna2-Martinotti Cells Synchronize Layer 5 Type A Pyramidal Cells via Rebound Excitation. PLoS biology, 15(2), Article ID e2001392.
Open this publication in new window or tab >>Chrna2-Martinotti Cells Synchronize Layer 5 Type A Pyramidal Cells via Rebound Excitation
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2017 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, no 2, article id e2001392Article in journal (Refereed) Published
Abstract [en]

Martinotti cells are the most prominent distal dendrite-targeting interneurons in the cortex, but their role in controlling pyramidal cell ( PC) activity is largely unknown. Here, we show that the nicotinic acetylcholine receptor alpha 2 subunit (Chrna2) specifically marks layer 5 (L5) Martinotti cells projecting to layer 1. Furthermore, we confirm that Chrna2-expressing Martinotti cells selectively target L5 thick-tufted type A PCs but not thin-tufted type B PCs. Using optogenetic activation and inhibition, we demonstrate how Chrna2-Martinotti cells robustly reset and synchronize type A PCs via slow rhythmic burst activity and rebound excitation. Moreover, using optical feedback inhibition, in which PC spikes controlled the firing of surrounding Chrna2-Martinotti cells, we found that neighboring PC spike trains became synchronized by Martinotti cell inhibition. Together, our results show that L5 Martinotti cells participate in defined cortical circuits and can synchronize PCs in a frequency-dependent manner. These findings suggest that Martinotti cells are pivotal for coordinated PC activity, which is involved in cortical information processing and cognitive control.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-319126 (URN)10.1371/journal.pbio.2001392 (DOI)000395719500005 ()28182735 (PubMedID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-04-03 Created: 2017-04-03 Last updated: 2017-11-29Bibliographically approved
Mikulovic, S., Pupe, S., Peixoto, H. M., Do Nascimiento, G., Kullander, K., Tort, A. & Leao, R. (2016). On the photovoltaic effect in localfield potential recordings. Neurophotonics, 3(1), Article ID 015002.
Open this publication in new window or tab >>On the photovoltaic effect in localfield potential recordings
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2016 (English)In: Neurophotonics, ISSN 2329-423X, Vol. 3, no 1, article id 015002Article in journal (Refereed) Published
Abstract [en]

ptogenetics allows light activation of genetically defined cell populations and the study of their link to specific brain functions. While it is a powerful method that has revolutionized neuroscience in the last decade, the shortcomings of directly stimulating electrodes and living tissue with light have been poorly characterized. Here, we assessed the photovoltaic effects in local field potential (LFP) recordings of the mouse hippocampus. We found that light leads to several artifacts that resemble genuine LFP features in animals with no opsin expression, such as stereotyped peaks at the power spectrum, phase shifts across different recording channels, coupling between low and high oscillation frequencies, and sharp signal deflections that are detected as spikes. Further, we tested how light stimulation affected hippocampal LFP recordings in mice expressing channelrhodopsin 2 in parvalbumin neurons (PV/ChR2 mice). Genuine oscillatory activity at the frequency of light stimulation could not be separated from light-induced artifacts. In addition, light stimulation in PV/ChR2 mice led to an overall decrease in LFP power. Thus, genuine LFP changes caused by the stimulation of specific cell populations may be intermingled with spurious changes caused by photovoltaic effects. Our data suggest that care should be taken in the interpretation of electrophysiology experiments involving light stimulation.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-279326 (URN)10.1117/1.NPh.3.1.015002 (DOI)000373771200006 ()26835485 (PubMedID)
Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2016-06-20Bibliographically approved
Silveira Broggini, A. C., Esteves, I. M., Romcy-Pereira, R. N., Leite, J. P. & Leao, R. N. (2016). Pre-ictal increase in theta synchrony between the hippocampus and prefrontal cortex in a rat model of temporal lobe epilepsy. Experimental Neurology, 279, 232-242
Open this publication in new window or tab >>Pre-ictal increase in theta synchrony between the hippocampus and prefrontal cortex in a rat model of temporal lobe epilepsy
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2016 (English)In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 279, p. 232-242Article in journal (Refereed) Published
Abstract [en]

The pathologically synchronized neuronal activity in temporal lobe epilepsy (TLE) can be triggered by network events that were once normal. Under normal conditions, hippocampus and medial prefrontal cortex (mPFC) work in synchrony during a variety of cognitive states. Abnormal changes in this circuit may aid to seizure onset and also help to explain the high association of TLE with mood disorders. We used a TLE rat model generated by perforant path (PP) stimulation to understand whether synchrony between dorsal hippocampal and mPFC networks is altered shortly before a seizure episode. We recorded hippocampal and mPFC local field potentials (LFPs) of animals with spontaneous recurrent seizures (SRSs) to verify the connectivity between these regions. We showed that SRSs decrease hippocampal theta oscillations whereas coherence in theta increases over time prior to seizure onset. This increase in synchrony is accompanied by a stronger coupling between hippocampal theta and mPFC gamma oscillation. Finally, using Granger causality we showed that hippocampus/mPFC synchrony increases in the pre-ictal phase and this increase is likely to be caused by hippocampal networks. The dorsal hippocampus is not directly connected to the mPFC; however, the functional coupling in theta between these two structures rises pre-ictally. Our data indicates that the increase in synchrony between dorsal hippocampus and mPFC may be predictive of seizures and may help to elucidate the network mechanisms that lead to seizure generation.

Keywords
Temporal lobe epilepsy, Perforant path electrical stimulation, Theta synchrony, Ictal patterns, Neurophysiology
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-297113 (URN)10.1016/j.expneurol.2016.03.007 (DOI)000374612900021 ()26953232 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council, 2012-2622
Available from: 2016-06-22 Created: 2016-06-21 Last updated: 2017-11-28Bibliographically approved
Patra, K., Lyons, D. J., Bauer, P., Hilscher, M. M., Sharma, S., Leão, R. N. & Kullander, K. (2015). A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.. European Journal of Neuroscience, 41(3), 316-327
Open this publication in new window or tab >>A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.
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2015 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 41, no 3, p. 316-327Article in journal (Refereed) Published
Abstract [en]

The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function. NMJs lacking VAAT had fewer branch points, whereas endplates showed an increased number of islands. Whereas the amplitude of spontaneous miniature endplate potentials in VAAT-deficient NMJs was decreased, the amplitude of evoked endplate potentials and the size of the readily releasable pool of vesicles were both increased. Moreover, VAAT-deficient NMJs displayed aberrant short-term synaptic plasticity with enhanced synaptic depression in response to high-frequency stimulation. Finally, the transcript levels of cholinergic receptor subunits in VAAT-deficient muscles were increased, indicating a compensatory postsynaptic sensitization. Our results suggested that VAAT modulates NMJ transmission efficiency and, as such, may represent a novel target for treatment of disorders affecting motor neurons.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-239636 (URN)10.1111/ejn.12790 (DOI)000349150000004 ()25410831 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2018-01-11Bibliographically approved
Nordenankar, K., Smith-Anttila, C. J., Schweizer, N., Viereckel, T., Birgner, C., Mejia-Toiber, J., . . . Wallén-Mackenzie, Å. (2015). Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity. Brain Structure and Function, 220(4), 2171-2190
Open this publication in new window or tab >>Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity
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2015 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 220, no 4, p. 2171-2190Article in journal (Refereed) Published
Abstract [en]

Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-239640 (URN)10.1007/s00429-014-0778-9 (DOI)000356874700020 ()24802380 (PubMedID)
Funder
Swedish Research Council, 2007-5742, 2011-4747
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05Bibliographically approved
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