Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Neonicotionoid pesticides are insecticides which have been thought to be one of the causes of Colony Collapse Disorder. They were considered to be less toxic to mammals than insects, but some of the recent studies suggested their association with disruption of higher brain fuction in mammals. Nevertheless, it is still unclear how neonicotionoids affect on the central nervous system. Here, we propose the use of in vivo Ca²⁺ imaging with two-photon microscope to detect abnormal activity of neuronal circuits in brain with the application of neonicotionoids.</p><p>In this study, a less than the no-observed-adverse-effect level (NOAEL) of acetamiprid (20 mg/kg bw); and a tenth or half of the median lethal doses of nicotine (0.33 or 1.65 mg/kg bw respectively) were orally administered to mice. They were subjected to elevated plus maze test and Ca²⁺ imaging by two-photon microscope in the somatosensory cortex. We further detected acetamiprid and metabolites in brain and blood an hour after the administration.</p><p>Mice exposed to acetamiprid or nicotine exhibited an increase in anxiety-like behavior that associated with the altered activities of the neuronal population in the somatosensory cortex. Although the dose of acetamiprid used in the current study was below the NOAEL, both acetamiprid and nicotine affected the behavior and the neuronal activity in the somatosensory cortex. The results suggested that in vivo Ca²⁺ imaging using two-photon microscope enabled highly sensitive detection of brain neurodisruption by neurotoxicants.</p>

DOI： 10.14869/toxpt.48.1.0_p-37e

CiNii Research

Publisher：Scientific Reports  

DOI： 10.1038/s41598-020-78294-2

Web of Science

Scopus

PubMed

Publishing type：Research paper (scientific journal)  

Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.

DOI： 10.1002/glia.23713

Scopus

PubMed

Publishing type：Research paper (scientific journal)  

Subcortical white matter infarction causes ischemic demyelination and loss of brain functions, as the result of disturbances of the blood flow. Although angiogenesis is one of the recovery processes after cerebral infarction, the dynamics of revascularization after white matter infarction still remains unclear. We induced white matter infarction in the internal capsule of Flk1-GFP::Flt1-tdsRed double transgenic mice by injection of endothelin-1 (ET-1), a vasoconstrictor peptide, together with N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and followed the changes in Flk1 and Flt1 expression in the vascular system in the infarct area. Reduction of Flt1-tdsRed-positive blood vessels 1 day after the injection and increase of Flk1-GFP-strongly-positive blood vessels 3 days after the injection were apparent. PDGFRβ-strongly-positive (PDGFRβ+) cells appeared in the infarct area 3 days after the injection and increased their number thereafter. Three days after the injection, most of these cells were in close contact with Flk1-GFP-positive endothelial cells, indicating these cells are bona fide pericytes. Seven days after the injection, the number of PDGFRβ+ cells increased dramatically, and the vast majority of these cells were not in close contact with Flk1-GFP-positive endothelial cells. Taken together, our results suggest revascularization begins early after the ischemic insult, and the emerging pericytes first ensheath blood vessels and then produce fibroblast-like cells not directly associated with blood vessels.

DOI： 10.1016/j.neulet.2018.10.057

PubMed

DOI： 10.1111/jnc.14486

PubMed

Using region-specific injection of hyaluronic acid, we developed a mouse model of acute retinal detachment (RD) to investigate molecular mechanisms of photoreceptor cell death triggered by RD. We focused on the transient receptor potential vanilloid 4 (TRPV4) ion channel, which functions as a thermosensor, osmosensor, and/or mechanosensor. After RD, the number of apoptotic photoreceptors was reduced by ∼50% in TRPV4KO mice relative to wild-type mice, indicating the possible involvement of TRPV4 activation in RD-induced photoreceptor cell death. Furthermore, TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Together, our results suggest that RD adversely impacts photoreceptor viability via TRPV4-dependent cytokine release from Müller glial cells and that TRPV4 is part of a novel molecular pathway that could exacerbate the effects of hypoxia on photoreceptor survival after RD.SIGNIFICANCE STATEMENT Identification of the mechanisms of photoreceptor death in retinal detachment is required for establishment of therapeutic targets for preventing loss of visual acuity. In this study, we found that TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Hence, TRPV4 inhibition could suppress cell death in RD pathological conditions and suggests that TRPV4 in Müller glial cells might be a novel therapeutic target for preventing photoreceptor cell death after RD.

DOI： 10.1523/JNEUROSCI.0897-18.2018

PubMed

Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

We have previously reported that transient receptor potential vanilloid 2 (TRPV2) can be activated by mechanical stimulation, which enhances axonal outgrowth in developing neurons; however, the molecular mechanisms that govern the contribution of TRPV2 activation to axonal outgrowth remain unclear. In the present study, we examined thismechanismby using PC12 cells as a neuronalmodel. Overexpression of TRPV2 enhanced axonal outgrowth in a mechanical stimulus-dependent manner. Accumulation of TRPV2 at the cell surface was 4-fold greater in the growth cone compared with the soma. In the growth cone, TRPV2 is not static, but dynamically accumulates (within similar to 100ms) to the site ofmechanical stimulation. The dynamic and acute clustering ofTRPV2 can enhance very weak mechanical stimuli via focal accumulation of TRPV2. Focal application of mechanical stimuli dramatically increasedgrowth conemotility andcausedactin reorganization via activationofTRPV2. Wealso found that TRPV2 physically interacts with actin and that changes in the actin cytoskeleton are required for its activation. Here, we demonstrated for the first time to our knowledge that TRPV2 clustering is induced by mechanical stimulation generated by axonal outgrowth and that TRPV2 activation is triggered by actin rearrangements that result frommechanical stimulation. Moreover, TRPV2activationenhances growthcone motility andactinaccumulationto promote axonal outgrowth. Sugio, S., Nagasawa, M., Kojima, I., Ishizaki, Y., Shibasaki, K. Transient receptor potential vanilloid 2 activation by focal mechanical stimulation requires interaction with the actin cytoskeleton and enhances growth cone motility.

DOI： 10.1096/fj.201600686RR

Web of Science

PubMed

Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Astrocytes have recently been shown to provide physiological support for various brain functions, although little is known about their involvement in white matter integrity. Several inherited infantile-onset leukoencephalopathies, such as Alexander disease and megalencephalic leukoencephalopathy with subcortical cysts (MLC), implicate astrocytic involvement in the formation of white matter. Several mouse models of MLC had been generated by knocking out the Mlc1 gene; however, none of those models was reported to show myelin abnormalities prior to formation of the myelin sheath. Here we generated a new Mlc1 knockout mouse and a Mlc1 overexpressing mouse, and demonstrate that astrocyte-specific Mlc1 overexpression causes infantile-onset abnormalities of the white matter in which astrocytic swelling followed by myelin membrane splitting are present, whereas knocking out Mlc1 does not, and only shows myelin abnormalities after 12 months of age. Biochemical analyses demonstrated that MLC1 interacts with the Na+/K+ ATPase and that overexpression of Mlc1 results in decreased activity of the astrocytic Na+/K+ pump. In contrast, no changes in Na+/K+ pump activity were observed in Mlc1 KO mice, suggesting that the reduction in Na+/K+ pump activity resulting from Mlc1 overexpression causes astrocytic swelling. Our infantile-onset leukoencephalopathy model based on Mlc1 overexpression may provide an opportunity to further explore the roles of astrocytes in white matter development and structural integrity. We established a novel mouse model for infantile-onset leukoencephalopathy by the overexpression of Mlc1. Mlc1 overexpression reduced activity of the astrocytic sodium pump, which may underlie white matter edema followed by myelin membrane splitting.

DOI： 10.1002/glia.23084

Web of Science

PubMed

Language：Japanese  

J-GLOBAL