De plus, les cellules nerveuses de la rétine neurale, sauf les photorécepteurs, sont déplacées vers le pourtour de la fovea, en particulier au niveau de la foveola. La lumière atteignant cette région de la rétine ne subit donc pas de diffusion, ce qui favorise la vision des détails par les cônes. Click here to see the Library ] pour plus de détails. La structure des bâtonnets et des cônes est globalement très similaire.
Les cônes se distinguent toutefois des bâtonnets par la forme de leur segment externe Figure 2. Ces cellules ont donc une structure et une composition qui sont optimisées pour absorber la lumière et la transformer en un signal électrique analysable par le cerveau.
Un cil connecteur permet de relier les segments externe et interne. Le segment interne contient la machinerie métabolique nécessaire au fonctionnement de ces cellules nerveuses. Le schéma montre aussi le noyau et la terminaison synaptique. Les bâtonnets servent à la vision scotopique, ou en conditions de faible éclairage, alors que les cônes permettent la vision photopique ou diurne.
Phototransduction in rods and cones Vertebrate photoreceptors. Dans la majorité de la rétine, les signaux provenant des cônes et des bâtonnets convergent vers les mêmes cellules ganglionnaires par le biais de cellules nerveuses qui leur sont spécifiques. Les cellules bipolaires des bâtonnets font synapse avec une classe spécifique de cellules amacrines qui font synapse avec les cellules bipolaires des cônes. Il est orienté de façon optimale dans la rhodopsine et les photorécepteurs pour absorber la lumière.
Structure de la rhodopsine et son organisation dans la membrane des disques des bâtonnets. Structure de la rhodopsine, obtenue à partir de ses coordonnées structurales, dans la membrane de phospholipides des disques des bâtonnets rhodopsine vue de côté. Structure de la rhodopsine vue du dessus. Structure du cis rétinal les tirets montrent sa position dans la structure de la rhodopsine. Le cis rétinal des pigments visuels des cônes est aussi lié à une lysine de leur hélice alpha VII par le même type de lien chimique.
Le mécanisme de phototransduction visuelle est beaucoup mieux connu chez les bâtonnets que les cônes. Les connaissances sur la phototransduction visuelle des bâtonnets ont en très grande majorité été acquises avec la rhodopsine bovine.
La transducine est une protéine G hétérotrimérique, i. The cGMP phosphodiesterase-transducin complex of retinal rods. Activated cGMP phosphodiesterase of retinal rods.
La rhodopsine est donc inactivée par ce mécanisme. A fifth member of the mammalian G-protein beta-subunit family. La phototransduction peut donc de nouveau être stimulée par la lumière. Les rétinoïdes sont des molécules très hydrophobes.
Mécanisme du cycle visuel des rétinoïdes pour régénérer la rhodopsine des bâtonnets. La lécithine rétinol acyltransférase LRAT va alors transformer le tout-trans rétinol en rétinyl ester qui sera ensuite isomérisé et clivé pour produire le cis rétinol par la RPE Les cônes répondent donc bien à des variations transitoires beaucoup plus rapides de lumière que les bâtonnets. Des protéines similaires sont impliquées dans la phototransduction des cônes et des bâtonnets.
Regeneration of cis-retinal in visual systems with monostable and bistable visual pigments Vertebrate photoreceptors. Les cellules de Müller peuvent aussi recevoir le tout-trans rétinol en provenance des bâtonnets pour satisfaire les besoins importants des cônes en pigments perte de poids terrebonne 14 régénérés en considérant la quantité importante de lumière absorbée par ces cellules.
Français Español Italiano. Poli, P. Denis, C. Dot, J. Journal page Archives Sommaire. Santos-Bueso, J. Vinuesa-Silva, J. Article Article Outline. Access to the text HTML. Access to the PDF text If you experience reading problems with Firefox, please follow this procedure. Recommend this article. Save as favorites. Service d'aide à la décision clinique Votre service d'aide à la décision clinique. We further evaluated the neurotoxic changes in the striatum by electron microscopy.
Doses refer to the base. Control mice received saline. Mice were housed in groups of 4—6 per cage during treatment. Animals were killed 1 or 3 days after treatment. One hemisphere of each brain was cut in sagital and the other in coronal sections to study the anatomical neurodegeneration. Neuronal degeneration was analyzed by the A-Cu-Ag stain, which stains degenerating perikarya, dendrites, stem axons, and their terminal ramifications synaptic endings de Olmos et al; Switzer, Immunostaining was carried out on free-floating sections with standard avidin—biotin immunocytochemical protocols Granado et ala ; Ortiz et al This step was avoided if immunostaining was performed in silver-stained tissue.
An image analysis system Analytical Imaging Station; Imaging Research, Linton, UK was used to convert color intensities into a gray scale and to quantify the area of staining in the striatum as a proportion of pixels in the striatum that show staining stained area in relation to total pixels in the striatum scanned area.
We refer to this as proportional stained area Darmopil et al, The threshold was chosen in saline animals and applied to all animals. Degeneration of striatal fibers was confirmed at the ultrastructural level by EM following the protocol described previously Rivera et al Cryoprotected tissue was frozen with liquid nitrogen and thawed in cold 0. Selected areas of the caudate—putamen were dissected out, re-embedded in Durcupan, and cut in ultrathin sections 1—0. The optical fractionator, Stereoinvestigator program Microbrightfield Bioscience, Colchester, VTwas used as described Ares-Santos et al; Espadas et alby an experienced observer unaware of treatment conditions.
To avoid double counting, neurons were counted when their nuclei were optimally visualized, which occurred only in one focal plane. Only A-Cu-Ag-stained particles with the size and morphology of degenerating cells or apoptotic bodies were counted.
Although this criterion may have excluded some dopaminergic degenerating neurons, it should have reliably excluded all non-dopaminergic degenerating cells. Some neurons with extremely faint signs of TH expression were not counted as TH-expressing neurons see Figure 4f.
Results are expressed as bilateral estimations. Nissl staining was performed on SNpc sections after TH immunohistochemistry. Motor coordination was measured at the same time points in the same animals, right after the locomotor activity evaluation, using an accelerating rotarod apparatus Hugo Basile, Rome, Italy as described previously Rodrigues et al Relevant differences were analyzed pair-wise by post hoc comparisons with Student—Newman—Keuls and Tukey's test, to determine specific group differences.
All statistical analyses and graphical representations were performed using Sigma Plot Animals treated with methamphetamine in all three different administration protocols showed significant increases in rectal temperature compared with saline-treated animals Figure 1a.
Arrows indicate drug injection. Statistical analysis was performed by two-way analysis of variance and post hoc Newman—Keuls analysis.
One day after methamphetamine administration, a marked overall decrease in the density of TH-ir terminals in the striatum was evident compared with the intense TH staining in saline-treated animals Figure 1b and d. In the single high-dose regimen, striosomes of the dorsolateral part of the caudoputamen were the most affected areas, with severe TH-ir loss compared with the rest of the striatum.
This tendency to recover TH-ir levels was not observed in the single high-dose group Figure 1b and d. TH-ir was performed on A-Cu-Ag-stained striatal sections to see if the signals of the two techniques were inversely associated. The increase in A-Cu-Ag-stained degenerating terminals in the striatum was complementary to the loss of TH-ir, strongly suggesting that dopaminergic fibers are the ones that degenerate after methamphetamine. Methamphetamine produced degeneration of striatal neurons.
This high dose produced a stronger silver deposition in the striosomes and in the dorsolateral part of the caudoputamen than in the rest of the striatal areas Figure 1c and d. However, the intensity of A-Cu-Ag signal in the striatum was reduced compared with 1 day after treatment Figure 1c and d. This degeneration was accompanied by microgliosis assessed by Ibair and astrogliosis GFAP-irpeaking 1 and 3 days after treatment, respectively data not shownin agreement with previous reports Ares-Santos et al; O'Callaghan and Miller, ; LaVoie et al A-Cu-Ag-stained neurons were observed in the striatum of methamphetamine-treated animals Figure 2.
There was no significant difference between numbers of stained neurons at 1 and 3 days for either dosing paradigm Figure 2b. In sagital brain sections from animals treated with methamphetamine, but not in saline animals, some A-Cu-Ag-stained axons were observed in the nigrostriatal pathway leading from the SNpc, via medial forebrain bundle MFBto the striatum Figure 3.
However, A-Cu-Ag staining was not as abundant as in the striatum. Some degenerating nigrostriatal axons are observed in sagital sections of methamphetamine-treated animals. As reported previously Ares-Santos et al; Granado et alabmethamphetamine administration resulted in significant loss of TH-expressing neurons in the SNpc.
The number of TH-expressing neurons in this area remained stable 3 days after treatment with each of the different regimens of the drug Figure 4a and b. Methamphetamine induces degeneration of dopaminergic neurons in substantia nigra pars compacta SNpc. Statistical analysis was performed by Student's t -test.
Photomicrographs of neurons in the SNpc of mice show normal neurons in a saline control upper rowand degenerating neurons 1 day after treatment with methamphetamine lower row. The percentage of double-stained neurons at 1 day after treatment with methamphetamine represented 7.
The percentage of double-stained neurons remained similar 3 days after treatment in all the protocols Figure 4c. The estimated percentage of double-stained neurons was lower than the percentage of TH-ir neuron loss, which could indicate that some neurons do lose TH expression before degenerating or without degeneration see Figure 4f.
Some degenerating or apoptotic cell bodies stained for A-Cu-Ag but not for TH were seen in this area Figure 4d, h, and i. These could be dopaminergic neurons that degenerate after the loss of TH expression or non-dopaminergic degenerating neurons. No significant changes in the estimate of non-dopaminergic-A-Cu-Ag-positive neurons A-Cu-Ag were observed at 3 days vs 1 day after reatment Figure 4d.
Bar indicates 0. Motor coordination returned to normal at 3 and 7 days after treatment with methamphetamine f, right. The persistence of reduced TH-ir at 30 days indicates that recovery was not complete, at this time point. To confirm that increases in A-Cu-Ag staining in the striatum after methamphetamine were due to fiber degeneration, evidence for neurodegeneration was obtained by EM.
Normal looking neuropil with typical dendritic and axonal striatal profiles were observed in saline-treated animals Figure 5bSAL. At 1 day after treatment, several fibers had a characteristic degenerating morphology, similar to that reported after MPTP treatment Cochiolo et al These fibers exhibited an abnormal collection of altered membranous structures Figure 5bbottom row, left.
Some nitrated terminals were observed at this time point Figure 5bbottom row, middle. In addition, vacuolated TH-ir fibers with characteristic degenerating morphology were observed 1 day after the treatment. Seven days after drug injection, the morphology of most striatal axons and synaptic terminals was similar to that seen in saline-treated animals.
At this time, terminals containing densely packed small synaptic vesicles and establishing typical synaptic contacts were observed Figure 5b. These results indicate that the degeneration wave peaks 1—3 days after methamphetamine, although a small number of dopaminergic neurons degenerate at later times Figure 5e.
At 7 days after treatment with methamphetamine, both horizontal crossings and vertical crossings locomotor activity had returned to normal levels. These results indicate that motor behavior is drastically impaired at 1 and 3 days after methamphetamine and then recovers, consistent with the time course of TH loss in the striatum. We found that multiple low doses of methamphetamine produced a greater, but still dose-dependent, loss of dopaminergic terminals than a single higher dose.
There was also degeneration of striatal neurons after treatment with methamphetamine, with degenerating neurons equally divided between direct pathway MSNs, indirect pathway MSNs, and other striatal neurons.
We show for the first time that methamphetamine kills dopaminergic neurons in the SNpc of mice, which can be detected 1 day after the treatment. Despite the significant differences between the effects of the three regimens on the striatum, similar toxicity was observed in the SNpc following all three delivery paradigms. EM confirmed fiber degeneration, first showing degenerating dopamine fibers and nitrated terminals 1 day after the treatment with the drug.
The number of TH-ir neurons did not change at 3, 7, or 30 days after drug administration, indicating long-lasting loss of TH-ir neurons. These neurotoxic changes had functional consequences: animals showed deficits in locomotor activity and motor coordination with a time course consistent with the observed dopaminergic terminal degeneration, peaking at 1—3 days after methamphetamine and returning to normal levels by 7 days after the treatment.
The A-Cu-Ag technique is highly sensitive detecting degenerating neurons soma, dendrites, axons, and synaptic terminals de Olmos et al; de Olmos et al; Switzer Degeneration is seen as black stained objects against a pale unstained background of normal unaffected components. Staining is thought to result from the precipitation of ionic silver around chemical reducing groups present in damaged subcellular structures, like proteins dismantled by proteolitic mechanism Beltramino et al; Switzer, This technique has the advantage of selectively identifying degenerating nerve cell components while producing a high contrast image that is relatively easy to observe and can be combined with immunohistochemistry, facilitating identification of the phenotype of degenerating neurons de Olmos et al Results from this study agree with previous reports with other suppressive silver methods that indicated that methamphetamine produces destruction and loss of dopaminergic terminals in the striatum Ricaurte et al, This is also evidenced by the presence of degenerating striatal terminals detected by EM.
This difference could be due to the different effects of these regimens on blockade of DAT or VMAT2, resulting in cytosolic accumulation of dopamine, which have been shown to be greater and longer lasting for multiple administrations of methamphetamine than for a single injection Fleckenstein et al; Metzger et al In addition, the hyperthermic response was greater and had more peaks for multiple administration regimens than for single administration Figure 1awhich may potentiate the neurotoxic effects of methamphetamine although hyperthermia is not solely responsible for methamphetamine-induced neuropathology Albers and Sonsalla, ; Ares-Santos et al, b ; Granado et ala ; Urrutia et al Consistent with previous reports, methamphetamine induced degeneration of striatal cells 1 day after treatment Zhu et alab and degenerating neurons were still visible 3 days later Figure 2a and b.
Notably, this is the first study to report that the degenerating neurons that appear in the striatum following methamphetamine treatment are equally distributed between direct and indirect projection pathways neurons. In line with this, previous work showed that projection neurons are less vulnerable to methamphetamine neurotoxicity than parvalbumin interneurons or cholinergic interneurons, although somatostatin interneurons are refractory to methamphetamine neurotoxicity Zhu et alb.
Alternatively, it is possible that the loss of striatal projection neurons is due to systemic rather than specific toxicity as opposed to that of the interneurons. This is also the first study to provide direct evidence of degeneration of dopaminergic neurons in the SN pars compacta and pars lateralis after exposure to methamphetamine Figure 4confirming previous studies that reported a decrease of TH-ir neurons, Ares-Santos et al; Granado et alab ; Sonsalla et al Although it has been proposed that axonal degeneration, rather than neuronal loss, has the dominant causative role in the clinical manifestations of PD Burke and O'Malley,the permanent loss of a small fraction regimental fire and fury basing the dopaminergic cells in the SNpc significantly diminishes the capacity for protective compensation following future insults.
Ricaurte et al previously used a silver technique and found no evidence of TH-soma loss after methamphetamine. The discrepancy between our studies is likely the result of timing: they looked at 6 weeks after methamphetamine and our time-course experiment showed the biggest cell body degeneration at 1—3 days after methamphetamine. This is consistent with silver-suppressive studies with other neurotoxic agents Switzer, that indicate that degenerating cell bodies can only be detected shortly after the injury.
However, degenerating axons and dopaminergic neurons in the SNpc after methamphetamine exposure represent a small percentage compared with the massive terminal damage observed in the striatum. The mechanisms mediating methamphetamine-induced degeneration of dopaminergic neurons in the SNpc seem to include more than one known death pathway. We have reported previously the appearance of Nissl-stained apoptotic cell bodies in the SNpc 1 day after treatment with methamphetamine Ares-Santos et al On the other hand, we have also observed necrotic eosinophilic neurons following methamphetamine.
Necrosis and apoptosis can occur either as distinct conditions, in combination, or as sequential events Davidson et al Results from in vitro research with dopaminergic cell culture models point to activation of the apoptotic cascade involving caspase-3 and DNA fragmentation in neurodegeneration of these cells and suggest that other factors may contribute to cell death, including ER stress, ubiquitin dysfunction, and autophagic impairment Kanthasamy et al; Larsen et al From this time onwards, the number of silver-stained cell bodies decreased, but remained significant 7 and 30 days after treatment compared with saline-treated animals.
As the A-Cu-Ag staining only labels cells actively undergoing degeneration, these later appearing silver-stained cells may be damaged neurons that initially survive methamphetamine, but eventually degenerate and die Figure 5e.
In line with this, there was no recovery of TH-ir neuron numbers in the SNpc even 30 days after the treatment, confirming the idea that, unlike the partial recovery of terminals in the striatum, the loss of striatal neurons is permanent. It is likely that the major source of TH terminal regrowth is the spared dopaminergic neurons in the SNpc. Neurodegeneration in the striatum and SNpc were accompanied by strong glial activation, in agreement with previous results Ares-Santos et al; O'Callaghan and Miller, ; LaVoie et botox permanente labios Although non-selective systemic methamphetamine toxicity might contribute to the selective loss of dopamine Halpin and Yamamoto,the motor impairment we observed is due to the loss of dopamine terminals in the striatum as has been shown in drug abusers Volkow et alab ; McCann et al Thus, the loss of dopamine markers after methamphetamine neurotoxicity may be the cause of the motor impairment we observed: a drastic, but transient, decrease in horizontal and vertical movement and motor coordination.
The timing of these changes paralleled the degeneration and partial recovery of dopamine terminals, and complete recovery of these motor indicators suggested they were not related to the permanent loss of nigral neurons.
Our results with methamphetamine further confirm the requirement for certain dopamine levels in the striatum for motor activity and motor coordination Rodrigues et al The dying-back axonopathy hypothesis in PD suggest that degeneration begins in the distal axon and proceeds toward the cell body Burke and O'Malley, In contrast, our finding that degenerative processes in the terminal and neuronal body occurred simultaneously suggest a direct effect of methamphetamine administration on SNpc neurons and terminals, as opposed to retrograde degeneration.
A large body of evidence indicates that the molecular mechanisms of terminal degeneration are separate and distinct from those of neuron somatic degeneration Burke and O'Malley, ; Coleman, ; Raff et al; Ries et al This idea is further supported by the fact that genetic inactivation of Nrf2 potentiates dopamine terminal loss without affecting survival of dopamine neurons in the SNpc Granado et alb.
In line with this, we observe no significant differences between the effects of single high dose and multiple lower doses on methamphetamine-induced dopaminergic neuronal loss, despite the clear dose dependence of dopamine terminal loss in the striatum.
Further investigation is required to characterize the process leading to neurodegeneration and to define the distinct mechanisms that may mediate terminal and somatic neurodegeneration. Our results are consistent with the recent report that methamphetamine abusers have higher risk for future development of PD Callaghan et aland with other reports of neurotoxic effects of methamphetamine in human abusers that indicate poor motor performance associated with DAT loss in the caudate nucleus and putamen Volkow et alab ; McCann et al Similar partial recovery of dopaminergic markers in the striatum has been reported in human methamphetamine abusers after periods of abstinence Volkow et ala.
Persistent dopamine terminal loss has been also documented after 11 months Volkow et ala or 3 years of abstinence McCann et alin line with the loss we see at 30 days.
However, to date, there are no published reports of anatomical evidence of dopamine neuronal destruction in SNpc of human methamphetamine abusers. Some evidence of neurodegenerative changes exists: for example, a specific decrease in pigmented neurons in SN of human abusers, similar to that seen in PD patients Büttner and Weis, ; Büttner, Moreover, the morphology of the SN as measured by transcranial sonography in individuals with a history of stimulant abuse, including methamphetamine, is abnormal, and is associated with reduced dopamine uptake in the striatum and increased risk for development of PD Todd et al Our results indicating very low, but significant, rates, around 0.
In summary, the data presented here provide anatomical evidence of dopamine cell body degeneration and a persistent loss of dopaminergic cell soma after exposure to methamphetamine in mice, making it clear that some neurotoxic effects of this drug are long-lasting despite partial regeneration of dopaminergic terminals in the striatum.