There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 poly...There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.展开更多
Louis Pierre Gratiolet (1815-1865) was one of the first modern anatomists to pay attention to cerebral convolutions. Born in Sainte-Foy-la-Grande (Gironde), he moved to Paris in 1834 to study medicine, as well as comp...Louis Pierre Gratiolet (1815-1865) was one of the first modern anatomists to pay attention to cerebral convolutions. Born in Sainte-Foy-la-Grande (Gironde), he moved to Paris in 1834 to study medicine, as well as comparative anatomy under Henri de Blainville (1777-1850). In 1842, he accepted de Blainville’s offer to become his assistant at the Muséum d’histoire naturelle and progressively abandoned medicine for comparative anatomy. He undertook a detailed study of brains of human and nonhuman primates and soon realized that the organizational pattern of cerebral convolutions was so predictable that it could serve as a criterion to classify primate groups. He noted that only the deepest sulci exist in lower primate forms, while the complexity of cortical folding increases markedly in great apes and humans. Gratiolet provided the first cogent description of the lobular organization of primate cerebral hemispheres. He saw the insula as a central lobe around which revolved the frontal, parietal, temporal (temporo-sphenoidal) and occipital lobes. He correctly identified most gyri and sulci on all brain surfaces, introduced the term “plis de passage” for some interconnecting gyri, and provided the first description of the optic radiations. In the early 1860s, Gratiolet fought a highly publicized battle against Paul Broca (1824-1880) on the relationship between brain and intelligence. Gratiolet agreed that the brain was most likely the seat of intelligence, but he considered human cognition far too subtle to have any direct relationship with brain size. He argued that a detailed study of the human brain architecture would be more profitable than Broca’s vain speculations on the relationship between brain weight and intelligence, which he considered a monolithic entity. Despite remarkable scientific achievements and a unique teaching capacity, Gratiolet was unable to secure any academic position until three years before his sudden death in Paris at age 49.展开更多
It took many centuries for the basal ganglia (BG) to be recognized as specific brain entities involved in the control of psychomotor behavior. Andreas Vesalius (1514-1564) was the first to delineate this set of struct...It took many centuries for the basal ganglia (BG) to be recognized as specific brain entities involved in the control of psychomotor behavior. Andreas Vesalius (1514-1564) was the first to delineate this set of structures, but he did not name them nor payany attention to their functional significance. This was left to the English physician Thomas Willis (1621-1675), who used the term corpus striatum (striated or chamfered body) to designate the largest BG constituent, which he considered a major sensorimotor integration center. Willis’s pioneering description influenced markedly some 18th and 19th centuries scholars, particularly the German physician and anatomist Karl Friedrich Burdach (1776-1847). Burdach’s insightful studies of the human brain are summarized in a three-volume treatise entitled Vom Baue und Leben des Gehirns (1819-1826). This landmark opus provides a description of the BGwhose originality has largely been overlooked. Burdach’s careful investigation allowed him to differentiate the caudate nucleus from the putamen, which he respectively termed Streifenhügel (elongated hillock) and Schale (shell). He also called the putamen Linsenkern (lens-shaped nucleus), a term that he admittedly borrowed from his compatriot Johann Christian Reil (1759-1813). He further identified a paler structure (blasser Klumpen) within the inner portion of the lentiform nucleus that he called globus pallidus, and correctly identified its inner and outer segments (innern und ?ussern Theil). He aptly pointed out that the major BG nuclei are separated from one another by fibers fascicles that he termed inner and ?ussre Capsel (internal and external capsules). Burdach also referred to the substantia nigra (schwarzgraue Schicht or stratum nigrum) and claustrum (Vormauer), but gave full credit to the French anatomist Félix Vicq-d’Azyr (1748-1794) for their discovery. Although Burdach did not comment much on BG function, his anatomical description was sufficiently cogent to be still in use two centuries after its inception.展开更多
Background:In glaucoma and after an ischemic injury of the retina,excessive activation of N-Methyl-D-Aspartate receptors,a type of glutamatergic receptors,induces the death of retinal ganglion cells and an irreversibl...Background:In glaucoma and after an ischemic injury of the retina,excessive activation of N-Methyl-D-Aspartate receptors,a type of glutamatergic receptors,induces the death of retinal ganglion cells and an irreversible vision loss.The painless loss of retinal cells does not allow for a swift diagnostic and treatment of retinal damages.There is no efficient therapy to improve retinal functions in this case.In order to develop new therapeutic approaches for retinal injury,we propose,in this study,to stimulate neuronal plasticity of the visual system by neutralising the glial protein,Nogo-A.The inhibitory action of this protein on axonal regeneration is well known in spinal cord injuries but not in the visual system.We thus studied the function of Nogo-A in vision recovery in mice.Methods:Nogo-A activities were chronically blocked by deleting its gene in KO mice and acutely,by intravitreal injections of an antibody known as 11C7.Inner retina lesions were done by injection of 0.5 or 5 nmol of NMDA in the vitreous humor.A PBS buffer was administered in control animals.The visual system functions were accessed with an optokinetic test in awake mice,by electroretinography(ERG)in the eye and visual evoked potentials in the visual cortex.Cell survival of retinal ganglion cells,amacrine and bipolar cells was evaluated on histological sections by immunofluorescence.Changes in expression of Nogo-A,its receptors and neuronal plasticity associated molecules were observed by Western blot and q-PCR.Results:At NMDA doses of≤0.5 nmol,Nogo-A KO mice show a recovery of optokinetic responses much faster than in WT mice.Surprisingly,a single injection of the antibody,11C7 was sufficient to improve VEPs of NMDA injured animals as compared to control antibody.Furthermore,ERGs showed that a dose of 0.5 nmol induced retinal lesions limited to the ganglion cell layer,with significant changes to the VEPs but without influencing photoreceptors and inner nuclear layer cells functions.However,5 nmol of NMDA affected the survival of inner nuclear layer cells and reduced by~50%their activity.Conclusions:Our results show that the neutralisation of Nogo-A can improve visual functions after injury to the inner retina.Inhibition of Nogo-A could thus be an efficient way to treat pathologies like glaucoma.展开更多
基金supported by funding from Parkinson Canadafunded by a scholarship from Parkinson Canadaa scholarship from Fonds d’Enseignement et de Recherche (FER) (Faculty of Pharmacy, Université Laval)
文摘There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.
文摘Louis Pierre Gratiolet (1815-1865) was one of the first modern anatomists to pay attention to cerebral convolutions. Born in Sainte-Foy-la-Grande (Gironde), he moved to Paris in 1834 to study medicine, as well as comparative anatomy under Henri de Blainville (1777-1850). In 1842, he accepted de Blainville’s offer to become his assistant at the Muséum d’histoire naturelle and progressively abandoned medicine for comparative anatomy. He undertook a detailed study of brains of human and nonhuman primates and soon realized that the organizational pattern of cerebral convolutions was so predictable that it could serve as a criterion to classify primate groups. He noted that only the deepest sulci exist in lower primate forms, while the complexity of cortical folding increases markedly in great apes and humans. Gratiolet provided the first cogent description of the lobular organization of primate cerebral hemispheres. He saw the insula as a central lobe around which revolved the frontal, parietal, temporal (temporo-sphenoidal) and occipital lobes. He correctly identified most gyri and sulci on all brain surfaces, introduced the term “plis de passage” for some interconnecting gyri, and provided the first description of the optic radiations. In the early 1860s, Gratiolet fought a highly publicized battle against Paul Broca (1824-1880) on the relationship between brain and intelligence. Gratiolet agreed that the brain was most likely the seat of intelligence, but he considered human cognition far too subtle to have any direct relationship with brain size. He argued that a detailed study of the human brain architecture would be more profitable than Broca’s vain speculations on the relationship between brain weight and intelligence, which he considered a monolithic entity. Despite remarkable scientific achievements and a unique teaching capacity, Gratiolet was unable to secure any academic position until three years before his sudden death in Paris at age 49.
文摘It took many centuries for the basal ganglia (BG) to be recognized as specific brain entities involved in the control of psychomotor behavior. Andreas Vesalius (1514-1564) was the first to delineate this set of structures, but he did not name them nor payany attention to their functional significance. This was left to the English physician Thomas Willis (1621-1675), who used the term corpus striatum (striated or chamfered body) to designate the largest BG constituent, which he considered a major sensorimotor integration center. Willis’s pioneering description influenced markedly some 18th and 19th centuries scholars, particularly the German physician and anatomist Karl Friedrich Burdach (1776-1847). Burdach’s insightful studies of the human brain are summarized in a three-volume treatise entitled Vom Baue und Leben des Gehirns (1819-1826). This landmark opus provides a description of the BGwhose originality has largely been overlooked. Burdach’s careful investigation allowed him to differentiate the caudate nucleus from the putamen, which he respectively termed Streifenhügel (elongated hillock) and Schale (shell). He also called the putamen Linsenkern (lens-shaped nucleus), a term that he admittedly borrowed from his compatriot Johann Christian Reil (1759-1813). He further identified a paler structure (blasser Klumpen) within the inner portion of the lentiform nucleus that he called globus pallidus, and correctly identified its inner and outer segments (innern und ?ussern Theil). He aptly pointed out that the major BG nuclei are separated from one another by fibers fascicles that he termed inner and ?ussre Capsel (internal and external capsules). Burdach also referred to the substantia nigra (schwarzgraue Schicht or stratum nigrum) and claustrum (Vormauer), but gave full credit to the French anatomist Félix Vicq-d’Azyr (1748-1794) for their discovery. Although Burdach did not comment much on BG function, his anatomical description was sufficiently cogent to be still in use two centuries after its inception.
文摘Background:In glaucoma and after an ischemic injury of the retina,excessive activation of N-Methyl-D-Aspartate receptors,a type of glutamatergic receptors,induces the death of retinal ganglion cells and an irreversible vision loss.The painless loss of retinal cells does not allow for a swift diagnostic and treatment of retinal damages.There is no efficient therapy to improve retinal functions in this case.In order to develop new therapeutic approaches for retinal injury,we propose,in this study,to stimulate neuronal plasticity of the visual system by neutralising the glial protein,Nogo-A.The inhibitory action of this protein on axonal regeneration is well known in spinal cord injuries but not in the visual system.We thus studied the function of Nogo-A in vision recovery in mice.Methods:Nogo-A activities were chronically blocked by deleting its gene in KO mice and acutely,by intravitreal injections of an antibody known as 11C7.Inner retina lesions were done by injection of 0.5 or 5 nmol of NMDA in the vitreous humor.A PBS buffer was administered in control animals.The visual system functions were accessed with an optokinetic test in awake mice,by electroretinography(ERG)in the eye and visual evoked potentials in the visual cortex.Cell survival of retinal ganglion cells,amacrine and bipolar cells was evaluated on histological sections by immunofluorescence.Changes in expression of Nogo-A,its receptors and neuronal plasticity associated molecules were observed by Western blot and q-PCR.Results:At NMDA doses of≤0.5 nmol,Nogo-A KO mice show a recovery of optokinetic responses much faster than in WT mice.Surprisingly,a single injection of the antibody,11C7 was sufficient to improve VEPs of NMDA injured animals as compared to control antibody.Furthermore,ERGs showed that a dose of 0.5 nmol induced retinal lesions limited to the ganglion cell layer,with significant changes to the VEPs but without influencing photoreceptors and inner nuclear layer cells functions.However,5 nmol of NMDA affected the survival of inner nuclear layer cells and reduced by~50%their activity.Conclusions:Our results show that the neutralisation of Nogo-A can improve visual functions after injury to the inner retina.Inhibition of Nogo-A could thus be an efficient way to treat pathologies like glaucoma.
