Neural plasticity in the adult central nervous system involves the adaptation of myelination, including the formation of novel myelin sheaths by adult-born oligodendrocytes. Yet, mature oligodendrocytes slowly but con...Neural plasticity in the adult central nervous system involves the adaptation of myelination, including the formation of novel myelin sheaths by adult-born oligodendrocytes. Yet, mature oligodendrocytes slowly but constantly turn over their pre-existing myelin sheaths, thereby establishing an equilibrium of replenishment and degradation that may also be subject to adaptation with consequences for nerve conduction velocity. In this short review we highlight selected approaches to the normal turnover of adult myelin in vivo, from injecting radioactive precursors of myelin constituents in the 1960s to current strategies involving isotope labeling and tamoxifen-induced gene targeting.展开更多
Schwann cells, the myelinating glial cells of the peripheral nervous system are remarkably plastic after nerve trauma. Their transdifferentiation into specialized repair cells after injury shares some features with th...Schwann cells, the myelinating glial cells of the peripheral nervous system are remarkably plastic after nerve trauma. Their transdifferentiation into specialized repair cells after injury shares some features with their development from the neural crest. Both processes are governed by a tightly regulated balance between activators and inhibitors to ensure timely lineage progression and allow re-maturation after nerve injury. Functional recovery after injury is very successful in rodents, however, in humans, lack of regeneration after nerve trauma and loss of function as the result of peripheral neuropathies represents a significant problem. Our understanding of the basic molecular machinery underlying Schwann cell maturation and plasticity has made significant progress in recent years and novel players have been discovered. While the transcriptional activators of Schwann cell development and nerve repair have been well defined, the mechanisms counteracting negative regulation of（re-）myelination are less well understood. Recently, transcriptional inhibition has emerged as a new regulatory mechanism in Schwann cell development and nerve repair. This mini-review summarizes some of the regulatory mechanisms controlling both processes and the novel concept of ＂inhibiting the inhibitors＂ in the context of Schwann cell plasticity.展开更多
We report 19 patients with a previously undelineated neurodegenerative syndrome characterized by episodic acute onset of irritability or neurological deficits between 2 months and 3.5 years of age, followed by steady ...We report 19 patients with a previously undelineated neurodegenerative syndrome characterized by episodic acute onset of irritability or neurological deficits between 2 months and 3.5 years of age, followed by steady or intermittent clinical deterioration. Seven children died between 11 months and 14 years of age. Cranial magnetic resonance imaging (MRI) shows patchy leukoencephalopathy with cavities, and vascular permeability, in actively affected regions. Early lesions affect corpus callosum and centrum semiovale, with or without cerebellar or cord involvement. After repeated episodes, areas of tissue loss coalesce with older lesions to become larger cystic regions in brain or spinal cord. Diffuse spasticity, dementia, vegetative state, or death ensues. Gray matter is spared until late in the course. In some, incomplete clinical or MRI recovery occurs after episodes. The clinical course varies from rapid deterioration to prolonged periods of stability that are unpredictable by clinical or MRI changes. Elevated levels of lactate in brain, blood, and cerebrospinal fluid, abnormal urine organic acids, and changes in muscle respiratory chain enzymes are present but inconsistent, without identifiable mitochondrial DNA mutations or deletions. Pathological studies show severe loss of myelin sparing U-fibers, axonal disruption, and cavitary lesions without inflammation. Familial occurrence and consanguinity suggest autosomal recessive inheritance of this distinct entity.展开更多
In a study published in Cell,Hu and colleagues discovered that the signaling activity of the intestinal hormone Cholesin leads to the attenuation of hepatic cholesterol synthesis in response to intestinal absorption t...In a study published in Cell,Hu and colleagues discovered that the signaling activity of the intestinal hormone Cholesin leads to the attenuation of hepatic cholesterol synthesis in response to intestinal absorption thereby maintaining homeostatic levels of circulating cholesterol.1 These findings have major translational implications as they provide a potential new target for the management of hypercholesterolemia and associated disorders.展开更多
Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows...Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows cells to adapt to lower O2 and limited energy metabolism.This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors.Remarkably,this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise,leading to a relative decrease in O2 supply,compared to the acutely augmented O2 requirement.We have coined the term“functional hypoxia”for this important demand-responsive,relative reduction in O2 availability.Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial“brain hardware upgrade,”underlying advanced performance.Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes,which can be imitated by recombinant human erythropoietin treatment.This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function.It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease.Finally,it sketches a planned multistep pilot study in healthy volunteers and first patients,about to start,aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.展开更多
Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is ...Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks,provoking a relative decrease in O_(2) in relation to the acutely augmented requirement.We termed this fundamental,demand-dependent drop in O_(2) availability"functional hypoxia."Major players in the hypoxia response are hypoxia-inducible factors(HIFs)and associated prolyl-hydroxylases.HIFs are transcription factors,stabilized by low O_(2) accessibility,and control expression of a multitude of genes.Changes in oxygen,however,can also be sensed via other pathways,among them the thiol-oxidase(2-aminoethanethiol)dioxygenase.Considering the far-reaching biological response to hypoxia,hitherto mostly observed in rodents,we initiated a translational project,combining mild to moderate inspiratory with functional hypoxia.We had identified this combination earlier to benefit motor-cognitive attainment in mice.A total of 20 subjects were included:13 healthy individuals and 7 patients with depression and/or autism spectrum disorder.Here,we show that motor-cognitive training under inspiratory hypoxia(12%O_(2))for 3.5 h daily over 3 weeks is optimally tolerated.We present first signals of beneficial effects on general well-being,cognitive performance,physical fitness and psychopathology.Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia.To obtain reliable information regarding the"add-on"value of inspiratory on top of functional hypoxia,induced by motor-cognitive training,a single-blind study—with versus without inspiratory hypoxia—is essential and outlined here.展开更多
基金supported by the Deutsche Forschungsgemeinschaft(DFG,WE2720/2-2 and WE2720/4-1,both to HBW)
文摘Neural plasticity in the adult central nervous system involves the adaptation of myelination, including the formation of novel myelin sheaths by adult-born oligodendrocytes. Yet, mature oligodendrocytes slowly but constantly turn over their pre-existing myelin sheaths, thereby establishing an equilibrium of replenishment and degradation that may also be subject to adaptation with consequences for nerve conduction velocity. In this short review we highlight selected approaches to the normal turnover of adult myelin in vivo, from injecting radioactive precursors of myelin constituents in the 1960s to current strategies involving isotope labeling and tamoxifen-induced gene targeting.
文摘Schwann cells, the myelinating glial cells of the peripheral nervous system are remarkably plastic after nerve trauma. Their transdifferentiation into specialized repair cells after injury shares some features with their development from the neural crest. Both processes are governed by a tightly regulated balance between activators and inhibitors to ensure timely lineage progression and allow re-maturation after nerve injury. Functional recovery after injury is very successful in rodents, however, in humans, lack of regeneration after nerve trauma and loss of function as the result of peripheral neuropathies represents a significant problem. Our understanding of the basic molecular machinery underlying Schwann cell maturation and plasticity has made significant progress in recent years and novel players have been discovered. While the transcriptional activators of Schwann cell development and nerve repair have been well defined, the mechanisms counteracting negative regulation of（re-）myelination are less well understood. Recently, transcriptional inhibition has emerged as a new regulatory mechanism in Schwann cell development and nerve repair. This mini-review summarizes some of the regulatory mechanisms controlling both processes and the novel concept of ＂inhibiting the inhibitors＂ in the context of Schwann cell plasticity.
文摘We report 19 patients with a previously undelineated neurodegenerative syndrome characterized by episodic acute onset of irritability or neurological deficits between 2 months and 3.5 years of age, followed by steady or intermittent clinical deterioration. Seven children died between 11 months and 14 years of age. Cranial magnetic resonance imaging (MRI) shows patchy leukoencephalopathy with cavities, and vascular permeability, in actively affected regions. Early lesions affect corpus callosum and centrum semiovale, with or without cerebellar or cord involvement. After repeated episodes, areas of tissue loss coalesce with older lesions to become larger cystic regions in brain or spinal cord. Diffuse spasticity, dementia, vegetative state, or death ensues. Gray matter is spared until late in the course. In some, incomplete clinical or MRI recovery occurs after episodes. The clinical course varies from rapid deterioration to prolonged periods of stability that are unpredictable by clinical or MRI changes. Elevated levels of lactate in brain, blood, and cerebrospinal fluid, abnormal urine organic acids, and changes in muscle respiratory chain enzymes are present but inconsistent, without identifiable mitochondrial DNA mutations or deletions. Pathological studies show severe loss of myelin sparing U-fibers, axonal disruption, and cavitary lesions without inflammation. Familial occurrence and consanguinity suggest autosomal recessive inheritance of this distinct entity.
文摘In a study published in Cell,Hu and colleagues discovered that the signaling activity of the intestinal hormone Cholesin leads to the attenuation of hepatic cholesterol synthesis in response to intestinal absorption thereby maintaining homeostatic levels of circulating cholesterol.1 These findings have major translational implications as they provide a potential new target for the management of hypercholesterolemia and associated disorders.
基金supported by the Max Planck Society,the Max Planck Förderstiftung,the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),via DFG-Center for Nanoscale Microscopy&Molecular Physiology of the Brain(CNMPB)and DFG-TRR 274/12020–408885537.
文摘Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows cells to adapt to lower O2 and limited energy metabolism.This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors.Remarkably,this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise,leading to a relative decrease in O2 supply,compared to the acutely augmented O2 requirement.We have coined the term“functional hypoxia”for this important demand-responsive,relative reduction in O2 availability.Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial“brain hardware upgrade,”underlying advanced performance.Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes,which can be imitated by recombinant human erythropoietin treatment.This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function.It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease.Finally,it sketches a planned multistep pilot study in healthy volunteers and first patients,about to start,aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.
基金ERC Advanced Grant acronym BREPOCI,Grant/Award Number:101054369ALTIBRAIN,Grant/Award Number:101043416DFG,Grant/Award Number:TRR-274/12020-408885537。
文摘Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks,provoking a relative decrease in O_(2) in relation to the acutely augmented requirement.We termed this fundamental,demand-dependent drop in O_(2) availability"functional hypoxia."Major players in the hypoxia response are hypoxia-inducible factors(HIFs)and associated prolyl-hydroxylases.HIFs are transcription factors,stabilized by low O_(2) accessibility,and control expression of a multitude of genes.Changes in oxygen,however,can also be sensed via other pathways,among them the thiol-oxidase(2-aminoethanethiol)dioxygenase.Considering the far-reaching biological response to hypoxia,hitherto mostly observed in rodents,we initiated a translational project,combining mild to moderate inspiratory with functional hypoxia.We had identified this combination earlier to benefit motor-cognitive attainment in mice.A total of 20 subjects were included:13 healthy individuals and 7 patients with depression and/or autism spectrum disorder.Here,we show that motor-cognitive training under inspiratory hypoxia(12%O_(2))for 3.5 h daily over 3 weeks is optimally tolerated.We present first signals of beneficial effects on general well-being,cognitive performance,physical fitness and psychopathology.Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia.To obtain reliable information regarding the"add-on"value of inspiratory on top of functional hypoxia,induced by motor-cognitive training,a single-blind study—with versus without inspiratory hypoxia—is essential and outlined here.
