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      Activation of the spinal and brainstem locomotor networks during free treadmill stepping in rats lacking dopamine transporter

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          Abstract

          Dopamine is extremely important for the multiple functions of the brain and spinal cord including locomotor behavior. Extracellular dopamine levels are controlled by the membrane dopamine transporter (DAT), and animals lacking DAT (DAT-KO) are characterized by hyperdopaminergia and several alterations of locomotion including hyperactivity. Neuronal mechanisms of such altered locomotor behavior are still not fully understood. We believe that in hyperdopaminergic animals both the spinal and brain neuronal networks involved in locomotion are modified. Using the c-fos technique, we studied activated neuronal networks of the spinal cord and two brainstem structures related to locomotor control and being under the strong dopaminergic influence, the cuneiform nucleus (CnF) and ventrolateral periaqueductal gray (VLPAG), in wild-type (DAT-WT) and DAT-KO rats. In the spinal cord, most c-fos-positive cells were located in the dorsal laminae II-IV and in the central gray matter (laminae V-VI). No differences were revealed for the central areas. As for the dorsal areas, in the DAT-WT group, labeled cells mostly occupied the lateral region, whereas, in the DAT-KO group, c-fos-positive cells were observed in both medial and lateral regions in some animals or in the medial regions in some animals. In the brainstem of the DAT-WT group, approximately the same number of labeled cells were found in the CnF and VLPAG, but in the DAT-KO group, the VLPAG contained a significantly smaller number of c-fos-positive cells compared to the CnF. Thereby, our work indicates an imbalance in the sensorimotor networks located within the dorsal horns of the spinal cord as well as a disbalance in the activity of brainstem networks in the DAT-deficient animals.

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          Fiji: an open-source platform for biological-image analysis.

          Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
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            NeuN, a neuronal specific nuclear protein in vertebrates.

            A battery of monoclonal antibodies (mAbs) against brain cell nuclei has been generated by repeated immunizations. One of these, mAb A60, recognizes a vertebrate nervous system- and neuron-specific nuclear protein that we have named NeuN (Neuronal Nuclei). The expression of NeuN is observed in most neuronal cell types throughout the nervous system of adult mice. However, some major cell types appear devoid of immunoreactivity including cerebellar Purkinje cells, olfactory bulb mitral cells, and retinal photoreceptor cells. NeuN can also be detected in neurons in primary cerebellar cultures and in retinoic acid-stimulated P19 embryonal carcinoma cells. Immunohistochemically detectable NeuN protein first appears at developmental timepoints which correspond with the withdrawal of the neuron from the cell cycle and/or with the initiation of terminal differentiation of the neuron. NeuN is a soluble nuclear protein, appears as 3 bands (46-48 x 10(3) M(r)) on immunoblots, and binds to DNA in vitro. The mAb crossreacts immunohistochemically with nervous tissue from rats, chicks, humans, and salamanders. This mAb and the protein recognized by it serve as an excellent marker for neurons in the central and peripheral nervous systems in both the embryo and adult, and the protein may be important in the determination of neuronal phenotype.
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              Organization of mammalian locomotor rhythm and pattern generation.

              Central pattern generators (CPGs) located in the spinal cord produce the coordinated activation of flexor and extensor motoneurons during locomotion. Previously proposed architectures for the spinal locomotor CPG have included the classical half-center oscillator and the unit burst generator (UBG) comprised of multiple coupled oscillators. We have recently proposed another organization in which a two-level CPG has a common rhythm generator (RG) that controls the operation of the pattern formation (PF) circuitry responsible for motoneuron activation. These architectures are discussed in relation to recent data obtained during fictive locomotion in the decerebrate cat. The data show that the CPG can maintain the period and phase of locomotor oscillations both during spontaneous deletions of motoneuron activity and during sensory stimulation affecting motoneuron activity throughout the limb. The proposed two-level CPG organization has been investigated with a computational model which incorporates interactions between the CPG, spinal circuits and afferent inputs. The model includes interacting populations of spinal interneurons and motoneurons modeled in the Hodgkin-Huxley style. Our simulations demonstrate that a relatively simple CPG with separate RG and PF networks can realistically reproduce many experimental phenomena including spontaneous deletions of motoneuron activity and a variety of effects of afferent stimulation. The model suggests plausible explanations for a number of features of real CPG operation that would be difficult to explain in the framework of the classical single-level CPG organization. Some modeling predictions and directions for further studies of locomotor CPG organization are discussed.
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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/310343/overviewRole: Role: Role: Role: Role: Role:
                URI : http://loop.frontiersin.org/people/963364/overviewRole: Role:
                URI : http://loop.frontiersin.org/people/2569652/overviewRole: Role: Role: Role: Role:
                URI : http://loop.frontiersin.org/people/2569643/overviewRole:
                URI : http://loop.frontiersin.org/people/902130/overviewRole:
                URI : http://loop.frontiersin.org/people/37484/overviewRole: Role:
                URI : http://loop.frontiersin.org/people/282055/overviewRole: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                21 November 2023
                2023
                : 16
                : 1299297
                Affiliations
                [1] 1Neuromorphology Laboratory, Pavlov Institute of Physiology, Russian Academy of Sciences , Saint Petersburg, Russia
                [2] 2Institute of Translational Biomedicine, Saint Petersburg State University , Saint Petersburg, Russia
                [3] 3Saint Petersburg University Hospital, Saint Petersburg State University , Saint Petersburg, Russia
                Author notes

                Edited by: Volker Eulenburg, University of Augsburg, Germany

                Reviewed by: Varun B. Chokshi, Johns Hopkins University, United States; Swetha K. Godavarthi, University of California, San Diego, United States

                *Correspondence: Natalia Merkulyeva, mer-natalia@ 123456yandex.ru
                Article
                10.3389/fnmol.2023.1299297
                10702542
                38076209
                709194b9-e1fa-445a-a882-d7cbea8e9b57
                Copyright © 2023 Veshchitskii, Shkorbatova, Mikhalkin, Fesenko, Efimova, Gainetdinov and Merkulyeva.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 September 2023
                : 26 October 2023
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 89, Pages: 13, Words: 9128
                Funding
                The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Russian Science Foundation grant number 21-15-00235.
                Categories
                Neuroscience
                Original Research
                Custom metadata
                Neuroplasticity and Development

                Neurosciences
                dopamine transporter,treadmill locomotion,c-fos,spinal cord,mesencephalic locomotor area,ventrolateral periaqueductal gray

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