1) The study assessed changes in hippocampal dendritic spines of APP/PS1 transgenic mice, a model of Alzheimer's disease.
2) It found a substantial decrease in the frequency of large dendritic spines in plaque-free regions of the dentate gyrus in these mice compared to controls.
3) Dendrites passing through amyloid plaques also showed alterations in spine density and morphology, with lower spine density within plaques and higher density on dendrites contacting plaques.
This study analyzed dendritic spine morphology in the CA1 region of the hippocampus in a mouse model of Alzheimer's disease (AD). Three key findings were observed:
1) Dendritic spine necks in the stratum oriens layer were significantly shorter in AD mice compared to controls.
2) The frequency of dendritic spines with small head volumes increased in the stratum radiatum layer of AD mice.
3) These layer-specific changes to spine morphology in an AD mouse model may underlie the synaptic dysfunction and cognitive impairments seen in the disease. The changes reflect the effects of amyloid-beta overexpression on excitatory synapses in the hippocampus.
1) The study compared two motor learning paradigms - increasing and decreasing the gain of the vestibulo-ocular reflex (VOR) - that both elicited robust activity in climbing fibers, which are thought to encode performance errors.
2) During VOR gain increase training, climbing fiber activity predicted changes in cerebellar output on the next trial and optogenetic activation of climbing fibers was sufficient to induce learning. However, during VOR gain decrease training, climbing fiber activity did not correlate with changes in cerebellar output and their activation did not induce learning.
3) The results suggest that even when climbing fibers are strongly activated by performance errors, the cerebellum can dynamically gate whether that activity
This article reviews studies on transgenic Alzheimer's disease (AD) mouse models that investigate dendritic spine structure, synaptic function, and cognition. These studies show that soluble amyloid-beta initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. In vivo imaging reveals plaque-associated spine loss and structural plasticity deficits in AD mouse models. Synaptic plasticity is also severely impaired in AD mouse models, with deficits in basal synaptic transmission and long-term potentiation emerging with age. Together, these changes in synapse structure and function are thought to underlie the cognitive deficits observed in AD.
Spines, plasticity, and cognition in alzheimer model mice.shiraknafo
This review article discusses research on transgenic Alzheimer's disease (AD) mouse models and how they are used to investigate dendritic spine structure, synaptic function, and cognition. Studies show that soluble amyloid-beta initiates synaptic dysfunction and loss, as well as tau pathology, contributing to both synaptic and neuronal loss. These changes in synapse structure and function, as well as outright synapse and neuron loss, underlie the neural system dysfunction that causes cognitive deficits in AD. Understanding how dementia develops in AD is crucial for developing effective therapies.
This document summarizes a study investigating how the gene encoding the nogo-66 receptor 1 (ngr1) regulates plasticity in the visual cortex during the critical period of development. The study found that mice lacking ngr1 retained characteristics of critical period plasticity into adulthood, including shifts in ocular dominance following brief monocular deprivation. In both juvenile wild-type mice and adult ngr1-deficient mice, monocular deprivation led to a loss of excitatory synaptic input onto inhibitory interneurons that express parvalbumin, indicating increased disinhibition. The study proposes that ngr1 acts to close the critical period by preventing this disinhibitory effect of monocular deprivation in adulthood.
This document summarizes research on the effects of misexpressing the Dip3 gene in Drosophila eye-antennal discs. The key findings are:
1. Dip3 misexpression leads to two distinct outcomes - antennal duplication, where the antennal disc splits into multiple domains each forming an antenna, and eye-to-antenna transformation, where the eye disc adopts an antennal fate and forms antenna-like structures.
2. Antennal duplication occurs when Dip3 causes underproliferation of the eye disc and overproliferation of the antennal disc, leading to its splitting. Eye-to-antenna transformation involves downregulation of eye
This document summarizes a study on developing a novel protein interaction platform to study neurodegeneration. The study cultured neuronal stem cells to form neurospheres, which were used as a model system. Lentiviral transfection was optimized to introduce target genes stably into the neurospheres. The goal was to analyze protein interactions of Alzheimer's disease proteins by co-immunoprecipitation of neurosphere cultures expressing tagged target proteins. This model aims to further the understanding of molecular mechanisms in neurodegenerative disorders like Alzheimer's disease.
1) Inactivation of all four alleles of Msx1 and Msx2 in neural crest cells leads to an unexpected formation of ectopic bone in the frontal bone region of mouse embryos.
2) This ectopic bone develops from neural crest cells that normally do not form bone and are located in the layer through which the frontal bone normally expands.
3) The formation of ectopic bone is associated with upregulation of Bmp signaling in this normally non-osteogenic neural crest cell layer. Inhibition of Bmp signaling prevents ectopic bone formation.
This study analyzed dendritic spine morphology in the CA1 region of the hippocampus in a mouse model of Alzheimer's disease (AD). Three key findings were observed:
1) Dendritic spine necks in the stratum oriens layer were significantly shorter in AD mice compared to controls.
2) The frequency of dendritic spines with small head volumes increased in the stratum radiatum layer of AD mice.
3) These layer-specific changes to spine morphology in an AD mouse model may underlie the synaptic dysfunction and cognitive impairments seen in the disease. The changes reflect the effects of amyloid-beta overexpression on excitatory synapses in the hippocampus.
1) The study compared two motor learning paradigms - increasing and decreasing the gain of the vestibulo-ocular reflex (VOR) - that both elicited robust activity in climbing fibers, which are thought to encode performance errors.
2) During VOR gain increase training, climbing fiber activity predicted changes in cerebellar output on the next trial and optogenetic activation of climbing fibers was sufficient to induce learning. However, during VOR gain decrease training, climbing fiber activity did not correlate with changes in cerebellar output and their activation did not induce learning.
3) The results suggest that even when climbing fibers are strongly activated by performance errors, the cerebellum can dynamically gate whether that activity
This article reviews studies on transgenic Alzheimer's disease (AD) mouse models that investigate dendritic spine structure, synaptic function, and cognition. These studies show that soluble amyloid-beta initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. In vivo imaging reveals plaque-associated spine loss and structural plasticity deficits in AD mouse models. Synaptic plasticity is also severely impaired in AD mouse models, with deficits in basal synaptic transmission and long-term potentiation emerging with age. Together, these changes in synapse structure and function are thought to underlie the cognitive deficits observed in AD.
Spines, plasticity, and cognition in alzheimer model mice.shiraknafo
This review article discusses research on transgenic Alzheimer's disease (AD) mouse models and how they are used to investigate dendritic spine structure, synaptic function, and cognition. Studies show that soluble amyloid-beta initiates synaptic dysfunction and loss, as well as tau pathology, contributing to both synaptic and neuronal loss. These changes in synapse structure and function, as well as outright synapse and neuron loss, underlie the neural system dysfunction that causes cognitive deficits in AD. Understanding how dementia develops in AD is crucial for developing effective therapies.
This document summarizes a study investigating how the gene encoding the nogo-66 receptor 1 (ngr1) regulates plasticity in the visual cortex during the critical period of development. The study found that mice lacking ngr1 retained characteristics of critical period plasticity into adulthood, including shifts in ocular dominance following brief monocular deprivation. In both juvenile wild-type mice and adult ngr1-deficient mice, monocular deprivation led to a loss of excitatory synaptic input onto inhibitory interneurons that express parvalbumin, indicating increased disinhibition. The study proposes that ngr1 acts to close the critical period by preventing this disinhibitory effect of monocular deprivation in adulthood.
This document summarizes research on the effects of misexpressing the Dip3 gene in Drosophila eye-antennal discs. The key findings are:
1. Dip3 misexpression leads to two distinct outcomes - antennal duplication, where the antennal disc splits into multiple domains each forming an antenna, and eye-to-antenna transformation, where the eye disc adopts an antennal fate and forms antenna-like structures.
2. Antennal duplication occurs when Dip3 causes underproliferation of the eye disc and overproliferation of the antennal disc, leading to its splitting. Eye-to-antenna transformation involves downregulation of eye
This document summarizes a study on developing a novel protein interaction platform to study neurodegeneration. The study cultured neuronal stem cells to form neurospheres, which were used as a model system. Lentiviral transfection was optimized to introduce target genes stably into the neurospheres. The goal was to analyze protein interactions of Alzheimer's disease proteins by co-immunoprecipitation of neurosphere cultures expressing tagged target proteins. This model aims to further the understanding of molecular mechanisms in neurodegenerative disorders like Alzheimer's disease.
1) Inactivation of all four alleles of Msx1 and Msx2 in neural crest cells leads to an unexpected formation of ectopic bone in the frontal bone region of mouse embryos.
2) This ectopic bone develops from neural crest cells that normally do not form bone and are located in the layer through which the frontal bone normally expands.
3) The formation of ectopic bone is associated with upregulation of Bmp signaling in this normally non-osteogenic neural crest cell layer. Inhibition of Bmp signaling prevents ectopic bone formation.
This study examined motor learning in the vestibulo-ocular reflex (VOR) in mice deficient in the γ isoform of protein kinase C (PKCγ−/− mice). PKCγ−/− mice have multiple climbing fiber inputs to individual Purkinje cells in the cerebellum, whereas wild-type mice normally have a single climbing fiber input per Purkinje cell. The study found that PKCγ−/− mice showed no adaptive increases or decreases in VOR gain after training at frequencies of 2 Hz or 0.5 Hz, indicating profound impairment in VOR motor learning. This suggests that single climbing fiber innervation of Purkinje cells is critical for VOR motor learning.
This document summarizes a study that used picosecond optical tomography with a white laser and streak camera to measure changes in oxyhemoglobin and deoxyhemoglobin concentration in the brains of zebra finches in response to auditory stimulation. The technique showed submicromolar sensitivity and was able to resolve fast changes in the hippocampus and auditory forebrain with 250 μm resolution. Stimulation resulted in an early decrease in hemoglobin and oxyhemoglobin levels, followed by an increase in blood oxygen availability and pronounced vasodilation after stimulus end. The findings provide direct evidence linking blood oxygen level-dependent signals to changes in oxygen transport in birds.
This document discusses the relationship between angiogenesis, neurogenesis, and learning/memory in the context of aerobic exercise. It notes that exercise promotes both angiogenesis (growth of new blood vessels) and neurogenesis (growth of new neurons) in brain areas involved in learning and memory. However, the specific contributions of angiogenesis versus neurogenesis to improved cognitive performance with exercise are unclear. The study aimed to investigate this by pharmacologically blocking angiogenesis or neurogenesis separately in exercising animals, and then assessing spatial memory performance. Results showed that blocking angiogenesis impaired memory, while blocking neurogenesis unexpectedly enhanced memory, suggesting angiogenesis may be more important than neurogenesis for normal learning and memory with exercise.
This study examined the effects of oxygen-glucose deprivation (OGD), a model of stroke, on microglial mobility and viability in developing mouse hippocampal tissue slices. The key findings were:
1) Prolonged OGD (2+ hours) induced microglial cell death, as shown by loss of GFP expression and gain of a cell death marker, while hypoxia alone did not induce death over similar time periods.
2) OGD, but not hypoxia, significantly reduced microglial motility based on quantitative analysis of time-lapse imaging.
3) Some microglia retained or recovered motility during OGD and were able to engulf dead cells, while others
Kouvaros S. et al (2015). Hippocampal sharp waves and ripples. Effects of agi...Stylianos Kouvaros
1) The study found that aging in rats is accompanied by changes in hippocampal sharp wave ripple activity, including a lower frequency of ripples and a higher tendency to generate long sequences of sharp wave ripple events in aged hippocampal slices.
2) Blocking NMDA receptors increased the amplitude and interval between sharp wave ripple events in both adult and aged slices, but reduced the probability of sequences more in adult slices. Blocking L-type calcium channels only increased amplitudes in adult slices.
3) Aged slices showed alterations in complex spike cell firing, including more spikes and longer intervals per burst, which may underlie changes in ripple activity with aging.
1. The document summarizes three research papers on the effects of nanoparticles, memory tests in mice, and axonal transport deficits.
2. One study found that intracellular gold nanoparticles can increase neuronal excitability and aggravate seizures. Another developed an automated maze to assess hippocampus-dependent memory without human interference.
3. The third study used MRI to show age-dependent axonal transport deficits in a mouse model of tauopathy, linking the deficits to hyperphosphorylated tau protein in the brain.
Kouvaros S and Papatheodoropoulos C, (2016). Major dorsoventral differences i...Stylianos Kouvaros
1) The study examines differences in modulation of the local hippocampal CA1 network between the dorsal and ventral hippocampus by NMDA, mGlu5, adenosine A2A, and cannabinoid CB1 receptors.
2) Activation of NMDA receptors reduced excitatory transmission more in the ventral hippocampus than in the dorsal hippocampus by an adenosine A1 receptor-independent mechanism. In the dorsal hippocampus, NMDA receptors reduced inhibition and enhanced postsynaptic excitability.
3) Co-activation of mGlu5 and NMDA receptors strongly potentiated their effects in the dorsal hippocampus but had no potentiating effect in the ventral hippocampus. This potentiation in the dorsal hippocampus required adenos
1) The study found that traumatic brain injury (TBI) caused a transient upregulation of the protein ephrin-B1 in astrocytes in the hippocampus. This upregulation coincided with a decline in glutamatergic synapses in the CA1 region at 3 days post-injury.
2) Ablating ephrin-B1 specifically from astrocytes accelerated the recovery of glutamatergic synapses after TBI, suggesting ephrin-B1 plays a role in injury-induced synapse remodeling.
3) The study provides evidence that astrocytic ephrin-B1 may act through activating STAT3 signaling in astrocytes, as ephrin-B1 activation in cultured
Pten Deletion in Adult Neural Stem/Progenitor Cells Enhances Constitutive Neu...johnohab
Here we show that conditional deletion of Pten in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to constitutive neurogenesis in the olfactory bulb. As a result, Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, in contrast to the olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis.
1) The study analyzed MRI findings of Wallerian degeneration in the spinal cords of 11 patients with traumatic spinal injuries.
2) The most common pattern observed was degeneration in both the posterior and lateral tracts of the spinal cord.
3) The signal changes observed on MRI, including hyperintensity on T1 and T2 weighted images, likely correspond to later stages (3 and 4) of Wallerian degeneration as described in the brain.
Efficiency of Stem Cell After Spinal Cord Injury with Clip-Compression_ Crims...Crimsonpublisherssmoaj
Efficiency of Stem Cell After Spinal Cord Injury with Clip-Compression by Tae Hoon Lee* in Crimson Publishers: Surgery Journal Impact Factor
Our experiment grafted mouse embryonic stem cell (mESC) to influence behavioral deficiency in rodent animal models of clip compressive surgery inducing spinal cord injury (SCI) of central nervous system. Our research proved the effect of grafted stem cells to the injured spinal cord region, focusing the application of mouse embryonic stem cells for regeneration of spinal cord nervous injury. Therefore, our research suggests manifest results that implantation of mouse embryonic stem cell could show behavioral improvement after severe spinal cord damage.
https://crimsonpublishers.com/smoaj/fulltext/SMOAJ.000533.php
For more open access journals in Crimson Publishers
Please click on: https://crimsonpublishers.com/
For more articles on Surgery Journal Impact Factor
Please click on link: https://crimsonpublishers.com/smoaj/index.php
Please follow the below link for our LinkedIn page
https://www.linkedin.com/company/crimsonpublishers
This document contains a bibliography listing references related to the development of the brain and neural structures in various vertebrate and invertebrate species, including mice, frogs, lampreys, and zebrafish. The references cover topics such as gene expression patterns, brain regionalization, organization of subdivisions in the diencephalon and hypothalamus, and the evolution of the basal ganglia and forebrain connectivity across tetrapods. Most references are journal articles, but one web page is also included.
An update of wallace´s zoogeographic regions of the worldCarlos Sáenz
This document reports on a study that mapped global zoogeographic regions by integrating data on the distributions and phylogenetic relationships of over 21,000 amphibian, bird, and mammal species. The study identified 20 distinct zoogeographic regions grouped into 11 larger realms. Key findings include:
1) Support was lacking for several regions previously defined based solely on distributional data.
2) Spatial turnover in phylogenetic composition was higher in the Southern Hemisphere than the Northern Hemisphere.
3) Incorporating phylogenetic information provided insight on historical relationships among regions and identified evolutionarily unique regions.
This document summarizes a study that investigated the effects of total knee arthroplasty (TKA) and neuromuscular electrical stimulation (NMES) on mitochondrial subpopulations in skeletal muscle. The study found that TKA caused significant muscle atrophy and loss of both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. NMES prevented muscle atrophy and maintained IMF mitochondrial content but not SS mitochondrial content. Specifically, TKA reduced IMF mitochondrial area by 19% and SS mitochondria per unit of sarcolemma by 64%, while NMES maintained IMF mitochondrial area above baseline and reduced the SS mitochondrial loss to 55%. The results suggest that decreased neural activation following TKA leads to mitochondrial
Hypothesis 1 is supported, as Old World Monkeys have more medially placed zygomaxillare superiors and anteriorly placed zygomaxillare inferiors compared to New World Monkeys. Hypothesis 2 is not fully supported, as only the robust New World Monkey species showed slightly more lateral zygomaxillare inferiors. Hypothesis 3 is also supported, as correlations between the zygomatic module and other landmarks were consistently higher than between the feeding and sensory units, indicating development has a stronger influence than function on integration patterns.
White Paper: In vivo Fiberoptic Fluorescence Microscopy in freely behaving miceFUJIFILM VisualSonics Inc.
Fiberoptic fluorescence microscopy (FFM) employs optical fibers as small as 300 micrometers in diameter and offers the ability to image cellular and subcellular processes in deep brain structures including the Ventral Tegmental Area (VTA) and the substantia nigra (Sn).
Netrin signaling through DCC modulates retinotectal synaptic connectivity in Xenopus laevis by influencing axon branching and synapse formation in the developing brain. Live imaging of retinal ganglion cell axons expressing GFP-synaptobrevin and DsRed showed that injecting netrin-1 into the tectum increased presynaptic site addition, branch addition and total branch number over 24 hours. In contrast, injecting DCC blocking antibodies prevented the normal increase in presynaptic sites and branch number. Dynamic analysis revealed the antibodies specifically decreased new synapse and branch additions without affecting stability of existing structures, indicating netrin is required for branching and synaptic differentiation through DCC signaling.
This document discusses various materials and therapies for peripheral nerve regeneration. It covers guidance therapies using nerve conduits made from natural and synthetic biomaterials. Biomolecular therapies involve delivering growth factors to promote regeneration. Cellular therapies utilize Schwann cells, stem cells, and genetically modified cells. Advanced techniques include nerve conduits fabricated using 3D printing, injection molding and aligned polymer fibers. Future areas of focus are multi-chamber conduits and stem cell therapies to further enhance regeneration.
A Neurovascular Niche for Neurogenesis after Strokejohnohab
Stroke causes cell death but also birth and migration of new neurons within sites of ischemic damage. The cellular environment that induces neuronal regeneration and migration after stroke has not been defined. We have used a model of long-distance migration of newly born neurons from the subventricular zone to cortex after stroke to define the cellular cues that induce neuronal regeneration after CNS injury. Mitotic, genetic, and viral labeling and chemokine/growth factor gain- and loss-of-function studies show that stroke induces neurogenesis from a GFAP-expressing progenitor cell in the subventricular zone and migration of newly born neurons into a unique
neurovascular niche in peri-infarct cortex. Within this neurovascular niche, newly born, immature neurons closely associate with the remodeling vasculature. Neurogenesis and angiogenesis are causally linked through vascular production of stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1). Furthermore, SDF1 and Ang1 promote post-stroke neuroblast migration and behavioral recovery. These experiments define a novel brain environment for neuronal regeneration after stroke and identify molecular mechanisms that are shared between angiogenesis and neurogenesis during functional recovery from brain injury.
Morphological alterations to neurons of the amygdalashiraknafo
This study examined the effects of amyloid-beta (Aβ) accumulation in the amygdala of an Alzheimer's disease mouse model. The mice showed impaired fear conditioning compared to controls. While there was no neuronal loss in the lateral nucleus of the amygdala (LA), the dendritic trees and spines of LA projection neurons were morphologically altered. Specifically, plaque-free neurons in the transgenic mice had decreased large dendritic spines compared to controls. This suggests that Aβ deposition leads to structural changes in the amygdala that may underlie impaired emotional memory seen in Alzheimer's disease.
- The study analyzed Alzheimer's disease pathology and expression of the nuclear receptor Nurr1 in 5XFAD mice, a model of severe amyloidosis and neuronal death.
- In the subiculum region of the hippocampus, amyloid plaques and microgliosis increased with age in 5XFAD mice. Significant neuronal loss occurred by 4 months of age.
- Nurr1 expression, which plays a neuroprotective role, decreased in the hippocampus of 5XFAD mice compared to controls by 4 months. Nurr1 was mainly expressed in neurons.
This study examined motor learning in the vestibulo-ocular reflex (VOR) in mice deficient in the γ isoform of protein kinase C (PKCγ−/− mice). PKCγ−/− mice have multiple climbing fiber inputs to individual Purkinje cells in the cerebellum, whereas wild-type mice normally have a single climbing fiber input per Purkinje cell. The study found that PKCγ−/− mice showed no adaptive increases or decreases in VOR gain after training at frequencies of 2 Hz or 0.5 Hz, indicating profound impairment in VOR motor learning. This suggests that single climbing fiber innervation of Purkinje cells is critical for VOR motor learning.
This document summarizes a study that used picosecond optical tomography with a white laser and streak camera to measure changes in oxyhemoglobin and deoxyhemoglobin concentration in the brains of zebra finches in response to auditory stimulation. The technique showed submicromolar sensitivity and was able to resolve fast changes in the hippocampus and auditory forebrain with 250 μm resolution. Stimulation resulted in an early decrease in hemoglobin and oxyhemoglobin levels, followed by an increase in blood oxygen availability and pronounced vasodilation after stimulus end. The findings provide direct evidence linking blood oxygen level-dependent signals to changes in oxygen transport in birds.
This document discusses the relationship between angiogenesis, neurogenesis, and learning/memory in the context of aerobic exercise. It notes that exercise promotes both angiogenesis (growth of new blood vessels) and neurogenesis (growth of new neurons) in brain areas involved in learning and memory. However, the specific contributions of angiogenesis versus neurogenesis to improved cognitive performance with exercise are unclear. The study aimed to investigate this by pharmacologically blocking angiogenesis or neurogenesis separately in exercising animals, and then assessing spatial memory performance. Results showed that blocking angiogenesis impaired memory, while blocking neurogenesis unexpectedly enhanced memory, suggesting angiogenesis may be more important than neurogenesis for normal learning and memory with exercise.
This study examined the effects of oxygen-glucose deprivation (OGD), a model of stroke, on microglial mobility and viability in developing mouse hippocampal tissue slices. The key findings were:
1) Prolonged OGD (2+ hours) induced microglial cell death, as shown by loss of GFP expression and gain of a cell death marker, while hypoxia alone did not induce death over similar time periods.
2) OGD, but not hypoxia, significantly reduced microglial motility based on quantitative analysis of time-lapse imaging.
3) Some microglia retained or recovered motility during OGD and were able to engulf dead cells, while others
Kouvaros S. et al (2015). Hippocampal sharp waves and ripples. Effects of agi...Stylianos Kouvaros
1) The study found that aging in rats is accompanied by changes in hippocampal sharp wave ripple activity, including a lower frequency of ripples and a higher tendency to generate long sequences of sharp wave ripple events in aged hippocampal slices.
2) Blocking NMDA receptors increased the amplitude and interval between sharp wave ripple events in both adult and aged slices, but reduced the probability of sequences more in adult slices. Blocking L-type calcium channels only increased amplitudes in adult slices.
3) Aged slices showed alterations in complex spike cell firing, including more spikes and longer intervals per burst, which may underlie changes in ripple activity with aging.
1. The document summarizes three research papers on the effects of nanoparticles, memory tests in mice, and axonal transport deficits.
2. One study found that intracellular gold nanoparticles can increase neuronal excitability and aggravate seizures. Another developed an automated maze to assess hippocampus-dependent memory without human interference.
3. The third study used MRI to show age-dependent axonal transport deficits in a mouse model of tauopathy, linking the deficits to hyperphosphorylated tau protein in the brain.
Kouvaros S and Papatheodoropoulos C, (2016). Major dorsoventral differences i...Stylianos Kouvaros
1) The study examines differences in modulation of the local hippocampal CA1 network between the dorsal and ventral hippocampus by NMDA, mGlu5, adenosine A2A, and cannabinoid CB1 receptors.
2) Activation of NMDA receptors reduced excitatory transmission more in the ventral hippocampus than in the dorsal hippocampus by an adenosine A1 receptor-independent mechanism. In the dorsal hippocampus, NMDA receptors reduced inhibition and enhanced postsynaptic excitability.
3) Co-activation of mGlu5 and NMDA receptors strongly potentiated their effects in the dorsal hippocampus but had no potentiating effect in the ventral hippocampus. This potentiation in the dorsal hippocampus required adenos
1) The study found that traumatic brain injury (TBI) caused a transient upregulation of the protein ephrin-B1 in astrocytes in the hippocampus. This upregulation coincided with a decline in glutamatergic synapses in the CA1 region at 3 days post-injury.
2) Ablating ephrin-B1 specifically from astrocytes accelerated the recovery of glutamatergic synapses after TBI, suggesting ephrin-B1 plays a role in injury-induced synapse remodeling.
3) The study provides evidence that astrocytic ephrin-B1 may act through activating STAT3 signaling in astrocytes, as ephrin-B1 activation in cultured
Pten Deletion in Adult Neural Stem/Progenitor Cells Enhances Constitutive Neu...johnohab
Here we show that conditional deletion of Pten in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to constitutive neurogenesis in the olfactory bulb. As a result, Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, in contrast to the olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis.
1) The study analyzed MRI findings of Wallerian degeneration in the spinal cords of 11 patients with traumatic spinal injuries.
2) The most common pattern observed was degeneration in both the posterior and lateral tracts of the spinal cord.
3) The signal changes observed on MRI, including hyperintensity on T1 and T2 weighted images, likely correspond to later stages (3 and 4) of Wallerian degeneration as described in the brain.
Efficiency of Stem Cell After Spinal Cord Injury with Clip-Compression_ Crims...Crimsonpublisherssmoaj
Efficiency of Stem Cell After Spinal Cord Injury with Clip-Compression by Tae Hoon Lee* in Crimson Publishers: Surgery Journal Impact Factor
Our experiment grafted mouse embryonic stem cell (mESC) to influence behavioral deficiency in rodent animal models of clip compressive surgery inducing spinal cord injury (SCI) of central nervous system. Our research proved the effect of grafted stem cells to the injured spinal cord region, focusing the application of mouse embryonic stem cells for regeneration of spinal cord nervous injury. Therefore, our research suggests manifest results that implantation of mouse embryonic stem cell could show behavioral improvement after severe spinal cord damage.
https://crimsonpublishers.com/smoaj/fulltext/SMOAJ.000533.php
For more open access journals in Crimson Publishers
Please click on: https://crimsonpublishers.com/
For more articles on Surgery Journal Impact Factor
Please click on link: https://crimsonpublishers.com/smoaj/index.php
Please follow the below link for our LinkedIn page
https://www.linkedin.com/company/crimsonpublishers
This document contains a bibliography listing references related to the development of the brain and neural structures in various vertebrate and invertebrate species, including mice, frogs, lampreys, and zebrafish. The references cover topics such as gene expression patterns, brain regionalization, organization of subdivisions in the diencephalon and hypothalamus, and the evolution of the basal ganglia and forebrain connectivity across tetrapods. Most references are journal articles, but one web page is also included.
An update of wallace´s zoogeographic regions of the worldCarlos Sáenz
This document reports on a study that mapped global zoogeographic regions by integrating data on the distributions and phylogenetic relationships of over 21,000 amphibian, bird, and mammal species. The study identified 20 distinct zoogeographic regions grouped into 11 larger realms. Key findings include:
1) Support was lacking for several regions previously defined based solely on distributional data.
2) Spatial turnover in phylogenetic composition was higher in the Southern Hemisphere than the Northern Hemisphere.
3) Incorporating phylogenetic information provided insight on historical relationships among regions and identified evolutionarily unique regions.
This document summarizes a study that investigated the effects of total knee arthroplasty (TKA) and neuromuscular electrical stimulation (NMES) on mitochondrial subpopulations in skeletal muscle. The study found that TKA caused significant muscle atrophy and loss of both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. NMES prevented muscle atrophy and maintained IMF mitochondrial content but not SS mitochondrial content. Specifically, TKA reduced IMF mitochondrial area by 19% and SS mitochondria per unit of sarcolemma by 64%, while NMES maintained IMF mitochondrial area above baseline and reduced the SS mitochondrial loss to 55%. The results suggest that decreased neural activation following TKA leads to mitochondrial
Hypothesis 1 is supported, as Old World Monkeys have more medially placed zygomaxillare superiors and anteriorly placed zygomaxillare inferiors compared to New World Monkeys. Hypothesis 2 is not fully supported, as only the robust New World Monkey species showed slightly more lateral zygomaxillare inferiors. Hypothesis 3 is also supported, as correlations between the zygomatic module and other landmarks were consistently higher than between the feeding and sensory units, indicating development has a stronger influence than function on integration patterns.
White Paper: In vivo Fiberoptic Fluorescence Microscopy in freely behaving miceFUJIFILM VisualSonics Inc.
Fiberoptic fluorescence microscopy (FFM) employs optical fibers as small as 300 micrometers in diameter and offers the ability to image cellular and subcellular processes in deep brain structures including the Ventral Tegmental Area (VTA) and the substantia nigra (Sn).
Netrin signaling through DCC modulates retinotectal synaptic connectivity in Xenopus laevis by influencing axon branching and synapse formation in the developing brain. Live imaging of retinal ganglion cell axons expressing GFP-synaptobrevin and DsRed showed that injecting netrin-1 into the tectum increased presynaptic site addition, branch addition and total branch number over 24 hours. In contrast, injecting DCC blocking antibodies prevented the normal increase in presynaptic sites and branch number. Dynamic analysis revealed the antibodies specifically decreased new synapse and branch additions without affecting stability of existing structures, indicating netrin is required for branching and synaptic differentiation through DCC signaling.
This document discusses various materials and therapies for peripheral nerve regeneration. It covers guidance therapies using nerve conduits made from natural and synthetic biomaterials. Biomolecular therapies involve delivering growth factors to promote regeneration. Cellular therapies utilize Schwann cells, stem cells, and genetically modified cells. Advanced techniques include nerve conduits fabricated using 3D printing, injection molding and aligned polymer fibers. Future areas of focus are multi-chamber conduits and stem cell therapies to further enhance regeneration.
A Neurovascular Niche for Neurogenesis after Strokejohnohab
Stroke causes cell death but also birth and migration of new neurons within sites of ischemic damage. The cellular environment that induces neuronal regeneration and migration after stroke has not been defined. We have used a model of long-distance migration of newly born neurons from the subventricular zone to cortex after stroke to define the cellular cues that induce neuronal regeneration after CNS injury. Mitotic, genetic, and viral labeling and chemokine/growth factor gain- and loss-of-function studies show that stroke induces neurogenesis from a GFAP-expressing progenitor cell in the subventricular zone and migration of newly born neurons into a unique
neurovascular niche in peri-infarct cortex. Within this neurovascular niche, newly born, immature neurons closely associate with the remodeling vasculature. Neurogenesis and angiogenesis are causally linked through vascular production of stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1). Furthermore, SDF1 and Ang1 promote post-stroke neuroblast migration and behavioral recovery. These experiments define a novel brain environment for neuronal regeneration after stroke and identify molecular mechanisms that are shared between angiogenesis and neurogenesis during functional recovery from brain injury.
Morphological alterations to neurons of the amygdalashiraknafo
This study examined the effects of amyloid-beta (Aβ) accumulation in the amygdala of an Alzheimer's disease mouse model. The mice showed impaired fear conditioning compared to controls. While there was no neuronal loss in the lateral nucleus of the amygdala (LA), the dendritic trees and spines of LA projection neurons were morphologically altered. Specifically, plaque-free neurons in the transgenic mice had decreased large dendritic spines compared to controls. This suggests that Aβ deposition leads to structural changes in the amygdala that may underlie impaired emotional memory seen in Alzheimer's disease.
- The study analyzed Alzheimer's disease pathology and expression of the nuclear receptor Nurr1 in 5XFAD mice, a model of severe amyloidosis and neuronal death.
- In the subiculum region of the hippocampus, amyloid plaques and microgliosis increased with age in 5XFAD mice. Significant neuronal loss occurred by 4 months of age.
- Nurr1 expression, which plays a neuroprotective role, decreased in the hippocampus of 5XFAD mice compared to controls by 4 months. Nurr1 was mainly expressed in neurons.
Passive avoidance training decreases synapse density in the hippocampus of domestic chicks. The study found that 6 hours after training chicks to avoid pecking at a bead coated in a bitter substance, the density of synapses in the dorsal and ventral hippocampus was lower compared to untrained control chicks. By 24 hours post-training, this difference was no longer present. A hemispheric asymmetry was also observed, with some regions showing enhanced synapse density in the left hemisphere for water-trained chicks but in the right hemisphere for methyl anthranilate-trained chicks. The results suggest that passive avoidance learning and stress can prune synapses in the chick hippocampus.
This study used MRI scans to examine brain development between adolescence and adulthood. The key findings were:
1) Brain maturation between adolescence and adulthood was distinct from earlier development and was localized primarily to frontal and striatal regions, with little change elsewhere.
2) Specifically, the study found significant reductions in gray matter in dorsal, medial, and lateral frontal regions as well as in striatal regions between adolescence and adulthood.
3) These regional patterns of brain maturation between adolescence and adulthood align with findings from post-mortem studies and cognitive development, as frontal and striatal regions continue developing functionally during this period.
The study analyzed Purkinje cell responses in the cerebellar flocculus of mice during visually and vestibularly driven eye movements. Recordings were made from Purkinje cells in awake, head-fixed mice undergoing optokinetic and vestibular stimulation. As in other species, the Purkinje cells carried both vestibular and nonvestibular signals related to eye and head movement. However, the mouse Purkinje cells showed a higher sensitivity to eye velocity compared to other species, likely reflecting the smaller range of eye movements in mice.
The document summarizes recent research on the use of stem cells as a potential treatment for Alzheimer's disease. It discusses how neural stem cells, bone marrow stem cells, and embryonic stem cells could be used to replace damaged or dead nerve cells in the brain. However, many challenges remain for stem cells to become an effective Alzheimer's treatment, such as ensuring the cells survive, integrate properly, and target the specific brain regions affected by the disease. While promising, more research is still needed to address these issues before stem cell therapy can be applied successfully for Alzheimer's patients.
This presentation focuses briefly on neural stem cells, the road map of neurogenesis, the markers as well the controversy involved in neurogenesis - that arose in the year 2018.
Poster - determining the effects of tau on synaptic density in a mouse model ...Shaun Croft, MScR
1. The document proposes that tau exacerbates amyloid-beta oligomer (AβO) toxicity at synapses, resulting in synapse loss and cognitive impairment in Alzheimer's disease.
2. To test this, the authors will use array tomography to analyze synaptic density in mouse models with and without human tau genes near amyloid plaques and determine if tau and AβOs colocalize at degenerating synapses.
3. Preliminary results show synapse loss around plaques and some colocalization of synapses and AβOs, supporting the hypothesis. Completing the data could further understanding of Alzheimer's pathology and identify new treatment targets.
The Brain as a Whole: Executive Neurons and Sustaining Homeostatic GliaInsideScientific
Carl Petersen and Alexei Verkhratsky share their research on homeostatic neuroglia and imaging of neuronal network function. This webinar is brought to you by APS’ new journal, Function, and part of their Physiology in Focus learning series.
During this exclusive live webinar, Carl Petersen and Alexei Verkhratsky discuss astrocyte-mediated homeostatic control of the central nervous system, and how optical and 2-photon microscopy can be used for functional neuroimaging.
Imaging Neuronal Function
Carl Petersen, PhD
Highly dynamic and spatially distributed neuronal circuits in the brain control mammalian behavior. Through technological advances, optical measurements of neuronal function can now be carried out in behaving mice at multiple scales. Wide-field imaging allows the dynamic interactions between different brain areas to be studied as sensory information is processed and transformed into behavioral output. Within a brain region, two-photon microscopy can be used to image the neuronal network activity with cellular resolution allowing different types of projection neurons to be distinguished. Together optical methods provide versatile tools for causal mechanistic understanding of neuronal network function in mice.
Astrocytes: indispensable neuronal supporters in sickness and in health
Alexei Verkhratsky, MD, PhD, DSc
The nervous system is composed of two arms: the executive neurons and the homeostatic neuroglia. The neurons require energy, support, and protection, all of which is provided by the neuroglia. Astrocytes, the principal homeostatic cells of the brain and spinal cord, are tightly integrated into the neural networks and act within the context of the neural tissue. As astrocytes control the homeostasis of the central nervous system at all levels of organization, from the molecular to the whole organ level, we can begin to define and understand brain vulnerabilities to aging and diseases.
Edgardo J. Arroyo is an Associate Research Scientist at Yale University School of Medicine who has extensive experience researching various aspects of myelin formation, degradation, and regeneration in the central and peripheral nervous systems. His research has focused on elucidating the cellular mechanisms and microanatomy of neuron-glial interactions using techniques such as immunohistochemistry, confocal microscopy, and biochemistry. He has studied topics such as the effects of spinal cord injury, stem cell transplantation, sodium channel expression after nerve damage, and how demyelination affects the molecular organization of nodes of Ranvier.
Cerebral Asymmetry: A Quantitative, Multifactorial and Plastic Brain PhenotypeMiguel E. Rentería, PhD
Cerebral asymmetry is a complex, multifactorial phenotype influenced by both genetic and environmental factors. The document reviews evidence of normal and atypical cerebral asymmetry at the macrostructural level from neuroimaging studies. It describes prominent asymmetries such as the Yakovlevian torque and petalia that separate the hemispheres. Asymmetries in regions like the perisylvian area have been linked to lateralization of language and the central sulcus to handedness. Additional asymmetries in areas like Heschl's gyrus correlate with auditory abilities. Factors like age, gender, brain region and disease state can influence the degree of asymmetry observed.
Axon Injury and regeneration in the adult DrosophilaLorena Soares
This document describes an in vivo model for studying axon regeneration in the adult fruit fly Drosophila. The researchers developed a method to precisely sever the axonal tract of peripheral nerves along the wing margin using a laser ablation technique. This allows the response to injury to be characterized over time while leaving the neuronal cell bodies intact. Following ablation, the response progresses through stages including local axon loss near the injury site, scar formation, and in some cases (~50% of flies) axon regrowth and regeneration of the tract by 7 days post-injury. This model provides a way to investigate the genetic and molecular pathways that modulate regeneration capacity in the adult nervous system.
A monkey model of auditory scene analysisPradeepD32
My work impacts half the world who develop age-related hearing loss with difficulty understanding speech in noise. To understand how the brain solves the cocktail party problem, I need to record from neurons suitable only in animals. Monkeys are best suited for this given our similar auditory brains. I use sounds without semantics and employ fMRI to show that monkeys use similar brain regions as humans to separate overlapping sounds. This study is the first to show such evidence in any animal. Now, I can record from monkey neurons and generalize the results to humans!
This document discusses research into growing neurons on silicone as a way to repair damaged neurons and restore cognitive functions. Neurons can grow on silicone due to its similar properties to carbon and ability to transmit electrical signals. Researchers have shown neurons on silicone can control current flow. The hippocampus is an area often damaged in neurological diseases. It plays a key role in memory and spatial awareness. Damage there can cause cognitive deficits treatable by a computer chip that interfaces with brain tissue to perform damaged functions. The goal is to develop this technology to treat conditions like Alzheimer's and epilepsy.
This document contains three annotated bibliographies summarizing research articles:
The first summarizes a study finding that intracellular gold nanoparticles increase neuronal excitability and seizure activity in mice brains. The second describes research using an automated maze to assess hippocampus-sensitive memory in mice. The third summarizes a study using magnetic resonance imaging to find age-dependent axonal transport deficits in a mouse model of frontotemporal dementia.
Aminah Sheikh's research focuses on understanding the neural mechanisms underlying abnormal brain development that result from early brain injuries. Using a neonatal rat model of hypoxia-ischemia, she investigates how these injuries damage subplate neurons in the developing brain and alter the maturation of brain circuits. Her work aims to identify targets for therapies to prevent long-term cognitive impairment resulting from neonatal brain damage.
Adult Neurogenesis and it's Role in Alzheimer'sAbhishek Das
This document summarizes adult neurogenesis and its role in brain disorders such as Alzheimer's disease. It describes how new neurons are generated from neural stem cells in the subventricular zone and hippocampus of the adult brain. Alterations in neurogenesis are linked to neurological conditions like Alzheimer's, where neurofibrillary tangles and amyloid plaques accumulate and neurons die, affecting areas like the hippocampus early on. Efforts are underway to understand how neurogenesis contributes to disease and potentially harness neural stem cells to help repair symptoms.
Abhishek Das_20131056_BIO334_Adult Neurogenesis_RevisedAbhishek Das
This document summarizes adult neurogenesis and its role in brain disorders such as Alzheimer's disease. It describes how new neurons are generated from neural stem cells in the subventricular zone and hippocampus of the adult brain. Alterations in neurogenesis are linked to neurological conditions - decreased neurogenesis is associated with Alzheimer's disease, where neurofibrillary tangles and amyloid plaques accumulate and cause neuronal death. Efforts are being made to understand how neurogenesis contributes to disease and potentially harness neural stem cells to help repair symptoms.
This document reports on a study that tested the effects of isoxazole 9 (Isx-9), a small synthetic molecule, on adult hippocampal neurogenesis in rats. The study found that administering Isx-9 for 14 days potentiated cell proliferation and increased the number of immature neurons in the hippocampal dentate gyrus. Isx-9 treatment also completely reversed the reduction in cell proliferation and neuronal commitment observed in vehicle-treated animals that were subjected to repeated handling and injections. These findings demonstrate that Isx-9 has promising pro-neurogenic properties and could help mitigate stress-induced deficits in adult hippocampal neurogenesis.
This chapter discusses the amygdala in Alzheimer's disease (AD). It notes that the amygdala is severely affected by AD pathology and is involved in emotional processing. Damage to the amygdala in AD leads to neuropsychiatric symptoms like anxiety and personality changes in patients. Studies also show impaired emotional memory in AD patients that correlates with amygdala atrophy. Autopsies reveal neurofibrillary tangles, amyloid plaques and neuronal loss in the amygdala of AD patients. Imaging studies further demonstrate amygdala volume reductions in AD patients, even in early stages, associated with cognitive impairment.
1. The study found that NMDA receptor activation triggers an association between the tumor suppressor protein PTEN and the synaptic scaffolding protein PSD-95.
2. This association requires a PDZ-binding motif on PTEN and leads to PTEN being recruited to and anchored at dendritic spines.
3. Enhancing PTEN's lipid phosphatase activity was found to specifically drive depression of AMPA receptor-mediated synaptic responses, and this activity was required for NMDA receptor-dependent long-term depression (LTD) but not other forms of plasticity.
This document summarizes a study that found phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) is continuously required to maintain AMPA receptor clustering at the postsynaptic membrane, which is necessary for sustaining synaptic function. The study manipulated PIP3 levels in hippocampal neurons and found that reducing PIP3 impaired the accumulation of PSD-95 in spines and caused AMPA receptors to become more mobile and migrate away from the postsynaptic density, leading to synaptic depression over time. Therefore, constant low-level turnover of PIP3 at synapses is required to maintain AMPA receptor clustering and synaptic strength under normal conditions.
WIP is a negative regulator of neuronal maturation and synaptic activity. Mice lacking WIP (WIP-/-) have enlarged neuronal somas and overgrown neuritic and dendritic branches, especially during early development. WIP-/- neurons also have increased amplitude and frequency of miniature excitatory postsynaptic currents, indicating more mature synapses than in wild-type neurons. This reveals WIP as a previously unknown regulator of neuronal maturation and synaptic activity.
1) A peptide called FGL enhances learning and memory in rodents by stimulating the delivery of glutamate receptors to synapses, strengthening synaptic transmission. This effect is mediated through the activation of protein kinase C.
2) FGL treatment heightens the induction of long-term potentiation in response to synaptic activity, improving the encoding of information.
3) FGL is poised to begin clinical trials this year for Alzheimer's disease, as prior studies show it improves memory and reduces neuropathology in rodent models of AD.
This document summarizes research investigating the cellular and molecular mechanisms underlying cognitive enhancement induced by a peptide called FGL. The key findings are:
1. FGL activates fibroblast growth factor receptor (FGFR) signaling pathways in vivo and in vitro.
2. FGL enhances long-term potentiation (LTP) in hippocampal slices by facilitating delivery of AMPA receptors to synapses through activation of NMDA receptors.
3. Both the LTP enhancement and cognitive improvement produced by FGL are mediated by initial protein kinase C (PKC) activation followed by sustained calcium/calmodulin-dependent protein kinase II (CaMKII) activation.
4. These results link facilitation
1) The document discusses common intracellular signaling pathways that are involved in both growth/differentiation processes early in development and synaptic plasticity in mature neurons.
2) Two examples are described in detail: the Ras-PI3K pathway and signaling elicited by neural cell adhesion molecules (NCAMs) interacting with growth factor receptors.
3) For the Ras-PI3K pathway, calcium entry via NMDA receptors can activate Ras, which then activates PI3K to produce PIP3 and drive LTP. Alternatively, NMDA receptors can activate Rap proteins to induce PTEN, reduce PIP3, and drive LTD.
1. The study used high-resolution fluorescence recovery after photobleaching (FRAP) to examine the dynamics and organization of AMPA receptors (AMPARs) within the postsynaptic density (PSD) of single dendritic spines in cultured hippocampal neurons.
2. They found that under basal conditions, AMPARs showed limited lateral diffusion within the PSD, but clustered together in a matrix that continuously reshaped in an actin-dependent manner.
3. Application of glutamate increased the intrasynaptic mobility of AMPARs, suggesting activated synapses promote exchange of receptors among subdomains. This supports the idea that the PSD regulates subsynaptic receptor distribution.
1. Cerebral Cortex March 2009;19:586--592
doi:10.1093/cercor/bhn111
Advance Access publication July 16, 2008
Widespread Changes in Dendritic Spines S. Knafo1, L. Alonso-Nanclares1, J. Gonzalez-Soriano2, P. Merino-
Serrais1, I. Fernaud-Espinosa1, I. Ferrer3 and J. DeFelipe1
in a Model of Alzheimer’s Disease
1
Instituto Cajal (CSIC), 28002 Madrid, Spain, 2Department of
Anatomy, Faculty of Veterinary Medicine, Complutense
University, 28040 Madrid, Spain and 3Institut Neuropatologı´ a,
IDIBELL-Hospital Universitari de Bellvitge, Universitat de
Barcelona, Hospitalet de LLobregat, 08907 Barcelona, Spain
The mechanism by which dementia occurs in patients with of the axo-spinous synapse (Zuo et al. 2005). Importantly,
Alzheimer’s disease (AD) is not known. We assessed changes in recent evidence indicates that spine heads are targets of
Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010
hippocampal dendritic spines of APP/PS1 transgenic mice that oligomeric Ab (Lacor et al. 2007). Therefore, spine head
accumulate amyloid beta throughout the brain. Three-dimensional morphology may link Ab pathology and synaptic dysfunction.
analysis of 21 507 dendritic spines in the dentate gyrus, a region We individually injected granular neurons in the dentate
crucial for learning and memory, revealed a substantial decrease in gyrus with a fluorescent dye and counterstained Ab plaques
the frequency of large spines in plaque-free regions of APP/PS1 with thiflavin-s. We measured the head volume and neck length
mice. Plaque-related dendrites also show striking alterations in in 3 dimensions of thousands of individual dendritic spines that
spine density and morphology. However, plaques occupy only 3.9% have been scanned by confocal microscopy. Our results show
of the molecular layer volume. Because large spines are considered that plaques substantially affect dendrites and spines. Impor-
to be the physical traces of long-term memory, widespread tantly, we also determined that plaque-free regions of APP/PS1
decrease in the frequency of large spines likely contributes to the mice are affected. These regions are very deficient in large
cognitive impairments observed in this AD model. spines, although spine density is conserved. We suggest that
widespread decreased frequency of large spines contributes to
Keywords: Alzheimer’s disease, confocal microscopy, dementia, dentate the cognitive deficits found in this AD model.
gyrus, transgenic mice
Materials and Methods
Introduction Mice
The mouse line used in this study (N = 9, age 12--14 months) expressed
One of the primary pathological characteristics of Alzheimer’s a Mo/Hu APP695swe construct in conjunction with the exon-9--deleted
disease (AD) is the presence of amyloid plaques, formed by variant of human presenilin 1 (PS1-dE9) (Scheuner et al. 1996). Age-
aggregated b-amyloid (Ab) peptides. In mice, the expression of matched littermates served as controls (N = 9). The experiments were
chimeric mouse/human amyloid precursor protein (Mo/ approved by the ethical institutional committee according to National
HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), Institutes of Health guidelines.
proteins that are both involved in familial forms of AD, lead to
an early amyloid pathology. These double transgenic mice Intracellular Injections
(APP/PS1) are often used as an animal model of AD, although The preparation of brains for intracellular injections is detailed in the
they do not develop the extensive neuronal loss or neurofi- supplemental methods. A total of 235 granular neurons from Tg– mice
and 462 neurons from APP/PS1 mice were microinjected individually
brillary changes typical in AD (Irizarry et al. 1997). Neverthe-
with Alexa594 (Invitrogen, Eugene, OR, Fig. 1a,b). After injection,
less, this mouse model is used to investigate the effect of Ab plaques were counterstained with thioflavin-s. Image acquisition and
overproduction and deposition on brain circuitry. processing are described in the supplemental information. All
Although Ab plaques have been associated with changes in morphological measurements were performed on stacks that did not
neurite morphology and dendritic spine density (Tsai et al. contain images of plaques (see supplemental information).
2004; Spires et al. 2005), there is a poor correlation between
plaque load and cognitive functions (Terry et al. 1991), raising Spine Morphology
doubts as to whether the accumulation of Ab plaques in the Imaris 5.0 (Bitplane AG, Zurich, Switzerland) was used to measure
brain induces AD. Nevertheless, morphological studies on AD spine head volume and neck length. A solid surface that exactly
models and patients have so far focused on the structural matched the contours of the head was constructed for each spine
(Isosurface module, Fig. 1j--m, Supplemental Fig. 1b,c). For details, see
changes occurring within or proximal to plaques (Tsai et al.
supplemental methods.
2004; Spires et al. 2005).
Dendritic spines represent the major postsynaptic elements
of excitatory synapses in the cerebral cortex (Gray 1959) and Unbiased Stereology
The number of labeled plaques was estimated by optical fractionator.
are fundamental to memory, learning and cognition (Lamp- The volume of plaques was estimated with the Nucleator probe (Moller
recht and LeDoux 2004). Dendritic spines undergo remarkable et al. 1990), as described in the supplemental methods.
activity-dependent structural changes (Lang et al. 2004; Tsai
et al. 2004). The spine head size influences spine motility and
Statistics
stability. Spine head size determines the probability that a spine For all measured morphological parameters, values were averaged to
bears a synapse (Arellano et al. 2007). Furthermore, there is give a cell mean. Neurons from each animal were averaged for an
a strong correlation between spine head size and the strength animal mean. Normality was tested using the Kolmogorov--Smirnov test.
Ó The Author 2008. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: journals.permissions@oxfordjournals.org
2. Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010
Figure 1. Intracellular injections and methodology. Panoramic confocal composite (103) views of the dentate gyrus, showing Alexa594 injected neurons and thioflavin-s positive
plaques in a TgÀ mouse (a) and an APP/PS1 mouse (b). Representative projection images of granular neurons from a TgÀ mouse (c) and from an APP/PS1 mouse (d). (e) An
example of a dendrite passing within a plaque. (f) An example of a dendrite in contact with a plaque. (g--i) The method used to distinguish dendrites and spines within plaques. (g)
A plaque suspected to contain a dendrite due to the rotation of its 3D image. (h) The plaque surface is marked with the aid of the IsoSurface tool of Imaris software. (i) The voxels
outside the surface are set to zero, leaving only the dendritic segment within the plaque. This process was performed after measurements of the spine head and neck that were
done blindly. (j, k) The method used for spine head volume measurements. (j) A solid surface that exactly matched the contours of the head was constructed for each spine (k). (l,
m) Amplified image of a short dendritic segment with (l) and without (m) the marked spine heads. Stacks used for images (e--m) were taken with a 633 glycerol objective, NA
1.3, electronic zoom 3.2). Scale bar, (a, b) 150 lm, (c, d) 40 lm, (e) 6 lm, (f, j, k) 4 lm, (g--i) 10 lm, (l, m) 2.5 lm.
Because our values had Gaussian distributions, a 2-tailed unpaired t-test We examined 1,589 amyloid plaques and 462 APP/PS1
was used to test for overall effect. When more than 2 groups were injected granular neurons by confocal microscopy (633,
compared, a one-way ANOVA was used, followed by the Newman-- glycerol, zoom 3.2, Fig. 1a--d). We encountered 52 dendrites
Keuls multiple comparison post hoc test. Data are presented as the
mean ± SE.
that passed within plaques and 32 dendrites that contacted
a plaque but did not pass within it (Fig. 1e,f). Typical plaques,
positive for thiflavin-s, consisted of a core, surrounded by
Results a diffuse ring of decreasing density (Cruz et al. 1997). The
dendrites passing within plaques were always located in the
Altered Spine Density in Plaque-Related Dendrites diffuse peripheral ring (Fig. 1e,g--i).
We used APP/PS1 mice at the age of 12--14 months. Because Dendrites were categorized according to their location with
transgenic mice of this age range show cognitive decline (Malm respect to Ab plaques (Fig. 2a). Categories included: 1)
et al. 2007) and deficits in cortical plasticity (Battaglia et al. dendrites from transgene-negative (control) mice (Tg–), 2)
2007), our working hypothesis was that these mice would dendrites located in a plaque-free area throughout their length
exhibit substantial changes in their dendritic spines. Although (Plaque-free), 3) dendrites that passed within a plaque (Pla-
the toxic effects of Ab plaques on dendritic spines have been que), and 4) dendrites in contact with a plaque edge (part of
documented before in the neocortex (Tsai et al. 2004; Spires the dendrite located within 0.2 lm from the plaque edge, as
et al. 2005), we hypothesized that in the dentate gyrus, Ab measured 3D) but did not pass through it (In contact, see
plaques would also have a tropic effect, given the extensive Supplemental Fig. 1a,b).
sprouting in the hippocampal molecular layer seen in an AD Spine density was significantly different among the 4
model (Masliah et al. 1991). categories of dendrites (P = 0.019, one-way ANOVA, Fig. 2b).
Cerebral Cortex March 2009, V 19 N 3 587
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Figure 2. Pronounced changes in dendritic spine density in plaque-related dendrites. (a) Representative projection images of dendrites from TgÀ and APP/PS1 mice (633,
glycerol). Note the variation in spine density among dendrites. TgÀ, dendrite from a control mouse; PF, dendrite located in plaque-free region of APP/PS1 mouse; IC, dendrite of
which a part is in contact with a plaque; P, dendrite that passes within a plaque, with and without the green channel that contains the plaque image. (b) Spine density was
significantly decreased in Plaque dendrites and increased for In contact dendrites. Note that spine density is similar in TgÀ mice and plaque-free areas. (c) Cumulative frequency
curves show shifts in spine density of plaque-related dendrites. (d) Spine density as a function of distance from soma is similar in TgÀ mice and APP/PS1 mice in plaque-free
regions. (e) For each plaque-related dendritic segment, the distance of the plaque from the soma was measured, and the ratio between spine density for the segment and the
average spine density for the same distance in TgÀ mice was calculated. Scale bar, 3 lm. *P 0.05, **P 0.01, ***P 0.001.
In Plaque dendrites, spine density was significantly lower than (P = 0.0016, one-way ANOVA, Fig. 3b). Average head volume
in other categories of dendrites (0.950 ± 0.075 spines/lm, N = was significantly lower (P < 0.05, Newman--Keuls multiple
9, P < 0.001, Newman--Keuls multiple comparison test). Spine comparison post hoc test) in Plaque-free spines (0.080 ± 0.004
density for In contact dendrites was significantly higher than in lm3; 9913 spines) and for In contact spines (0.076 ± 0.006; 443
other categories of dendrites (2.05 ± 0.13, N = 9, P < 0.001). spines), when compared with Plaque spines (0.107 ± 0.008;
Spine density for Plaque-free dendrites (1.521 ± 0.047, N = 9) 474 spines), and control (0.103 ± 0.006; 10 677 spines).
was not significantly different than control (Tg–) dendrites Although the average head volumes for control spines and
(1.410 ± 0.052, N = 9). Plaque spines were similar, frequency analysis revealed that the
Spine density normally changes as a function of distance within-groups distribution was substantially different between
from the soma. Sholl analysis can be used to examine spine the 2 groups (Fig. 3c). Within plaques, there was a 36%
density at different distances from the soma. Sholl analysis decrease in the prevalence of small-headed spines (head
revealed that spine density for Plaque-free dendrites was volume < 0.05 lm3) and a 40% increase in the prevalence of
similar to control (Tg–) dendrites over their entire length spines with a medium-size head (head volume 0.05--0.1 lm3),
(Fig. 2d). Spine density for each segment located within or in compared with control spines (Fig. 3c). The prevalence of
contact with a plaque was compared with the average spine large-headed spines (large spines, head volume > 0.1 lm3) was
density at same distance from soma in Tg– mice. We found similar for both dendritic types (Fig. 3c). Our measurements
a decrease of 37.21 ± 6.03% in spine density within plaques show that large spines represent 23% of Tg– dentate gyrus
(P < 0.0001, t-test) and a 37.77 ± 15.77% increase in spine spines but only 14.4% of the plaque-free APP/PS1 spines. This
density of In contact dendrites (P = 0.01, Fig. 2e). Thus, we implies a decrease of 38% in the prevalence of large spines in
found considerable sprouting of spines in dendrites contacting the plaque-free regions of APP/PS1 mice. When compared with
Ab plaques, whereas there was a loss of spines in dendrites control mice, there was a 52% decrease in the prevalence of
passing through Ab plaques. large spines in dendrites contacting plaques (Fig. 3d). We also
divided the granular neurons into neurons that have come into
Decreased Frequency of Large Spines in Plaque-Free contact with or passed within plaques at some point along their
Areas length and those that never contacted a plaque. An analysis of
Spine head volume and neck length were measured in 3 the spine head volume revealed that spines located in plaque-
dimensions in confocal image stacks. Head volume was free regions had a similar head volume although they arise from
significantly different among the 4 categories of dendrites different neuronal types (Supplemental Fig. 2).
588 Widespread Changes in Dendritic Spines in a Model of AD d
Knafo et al.
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Figure 3. Changes in spine morphology occur both within and outside Ab plaques. (a) Maximum projection confocal images (633, glycerol) of representative dendrites. Note
the great variation in spine morphology among groups. Scale bar, 1.5 lm. (b) Decreased average head volume for spines located outside plaques. (c) Cumulative frequency plots
showing the distribution of spine head volumes. (d) The frequency of large spines is substantially reduced outside plaques. (e) Bar graphs showing that spines located within
plaques have longer necks. (f) Cumulative frequency curves showing the distribution of neck lengths. (g) On the left, density of plaques in the molecular layer of the dentate gyrus.
On the right, the fraction of the molecular layer volume occupied by plaques. *P 0.05, **P 0.01, ***P 0.001.
Significant differences in average spine neck length, as was then determined, using unbiased stereology, the total number
measured manually in 3 dimensions, were found among of plaques and their volume in the molecular layer. From this,
dendritic categories (P < 0.0001, one-way ANOVA, Fig. 3e,f). we calculated the total volume occupied by plaques.
Plaque spines had a longer neck (0.634 ± 0.028 lm, P < 0.001, The estimated total number of molecular layer plaques per
Newman--Keuls Multiple Comparison Test) than control spines mouse in one hemisphere was 609.9 ± 37.14 (range 555--756
(0.443 ± 0.012) and Plaque-free spines (0.455 ± 0.035). Necks plaques/mouse, N = 5 mice). The density of plaques in the
of In contact spines showed intermediate length (0.540 ± inner molecular layer (IML) was 3.00 ± 0.25 plaques/100 lm3,
0.026) and were significantly different from other dendritic whereas the density of plaques in the middle/outer molecular
categories (P < 0.05). layer (M/OML) was 5.99 ± 0.39 plaques/100 lm3 (Fig. 3g). This
observation supports the finding that plaques in the dentate
Amyloid Plaques Occupy a Small Fraction of the gyrus of AD brains have a strong tendency to line up in the
Molecular Layer Volume molecular layer, approximately two-thirds of the way from
We have described remarkable changes within and near the top of the hippocampal fissure (Crain and Burger 1989).
plaques that can affect local synaptic circuits. To quantitatively The average plaque volume was 5657 ± 1488 lm3 in the IML
determine the impact of plaques on the dentate gyrus and 8719 ± 1109 lm3 in the M/OML (P > 0.05). The estimated
connectivity, we immunocytochemically stained Ab plaques volume occupied by Ab plaques was 1.59 ± 0.39% in IML and
in sections of APP/PS1 brains, taken from the same mice. We 5.15 ± 0.60% in the M/OML (Fig. 3g). The volume occupied by
Cerebral Cortex March 2009, V 19 N 3 589
5. Ab plaques in the entire molecular layer was 3.9 ± 0.4%. These explained by alterations to the ratio of spine formation to
results suggest that under our experimental conditions, Ab elimination, leading a higher proportion of aspiny dendrites as
plaques occupy a relatively small fraction of the total molecular observed in the cortex of Tg2576 mice (Spires-Jones et al. 2007).
layer volume. In contrast to our observations, a recent study reported
a reduction in spine density in the hippocampus of APP mice
before and after the appearance of plaques (Jacobsen et al.
Discussion
2006). This discrepancy could be related to the fact that
The current study shows that plaque-free regions of the a different mouse model was used in this study (APP vs. APP/
dentate gyrus in APP/PS1 mice are deficient in large spines and PS1), as well as a different staining method (Golgi staining vs.
that dendritic spines are also affected locally by Ab plaques. intracellular injections), and a different method for quantifica-
However, under our experimental conditions, plaques occupy tion (quantification of short dendritic segments vs. full
a volume below 4% of the dentate gyrus molecular layer. dendritic lengths). A decrease in spine density in the
hippocampus of aged APP/PS1 mice described previously
Decreased Frequency of Large Spines may Imply Loss of (Moolman et al. 2004) could be explained by including the
Downloaded from cercor.oxfordjournals.org at Universidad Autonoma de Madrid on December 3, 2010
Memory dendrites located within plaques in the analysis, because spine
Dendritic spine heads bear the vast majority (90%) of density is significantly lower at these sites (see Tsai et al. 2004
excitatory synapses in the central nervous system (Gray and Fig. 1b). Other studies reported a decrease in synaptic
1959). They undergo remarkable activity-dependent structural density in AD models (Dong et al. 2007; Priller et al. 2007).
changes (Lang et al. 2004; Knafo et al. 2005) and are targets of However, although we quantified dendritic spines, these earlier
oligomeric Ab (Lacor et al. 2007). Although morphological studies quantified synapses regardless of their location (spine
changes within Ab plaques can affect local synaptic circuits, or dendritic shaft). Thus, the possibility that the decrease in
because plaques occupy a minor fraction of the dentate gyrus synaptic density arises from the loss of shaft synapses cannot be
volume, widespread changes outside plaques are more likely to excluded.
contribute to the synaptic and cognitive impairments found in The increased spine density in the vicinity of the plaques can
APP/PS1 mice (Battaglia et al. 2007; Malm et al. 2007). be explained by the release of neurotrophic factors, such as
Large spines contain polyribosomes that locally regulate brain-derived neurotrophic factor by astrocytes that typically
protein synthesis and are surrounded by perisynaptic astroglial surround Ab plaques (Mandybur 1989; Saha et al. 2006). It is
processes that regulate local glutamate and Ca2+ levels (Ostroff tempting to speculate that the growth of new spines in the
et al. 2002; Haber et al. 2006; Witcher et al. 2007). Large spines vicinity of the plaques is an attempt by the diseased brain to
persist for months in the mouse cerebral cortex (Grutzendler compensate for the loss of spines within them.
et al. 2002; Trachtenberg et al. 2002). Large spines bear
synapses exceptionally stable (Bourne and Harris 2007). Large Ab Plaques Protect Large Spines
spines are also enriched with a-amino-3-hydroxy-5-methyl-4- Notably, the prevalence of large spines within plaques and in
isoxazolepropionic acid receptors (Matsuzaki et al. 2001), Tg– control mice was similar. Although we observed a 36%
which make their synapses functionally stronger (Matsuzaki decrease in spine density within plaques, this decrease was
et al. 2001; Nimchinsky et al. 2004; Ashby et al. 2006). mainly due to a decrease in the frequency of spines with small
Moreover, large spines are formed after synaptic potentiation heads (see Fig. 3c). This may imply that plaques serve as
in the dentate gyrus (Bourne and Harris 2007) and in CA1 a protective microenvironment for large spines. The persis-
region (Lang et al. 2004; Matsuzaki et al. 2004). Thus, large tence of large spines within plaques can contribute to the weak
spines were proposed to act as physical traces of long-term correlation between the quantity of amyloid deposition and
memory (Kasai et al. 2003; Bourne and Harris, 2007). dementia (Katzman et al. 1988). The sprouting of spines in
Given that large spines in the dentate gyrus bear stable
dendrites of immediate proximity to plaques is another
synapses that form part of the hippocampal memory storage observation that can explain the same phenomenon. These
system (Bontempi et al. 1999), a decrease in the frequency of dendrites possess predominantly small-headed spines. How-
large spines should lead to the memory loss seen in APP/PS1 ever, it remains to be determined whether spines within and
mice (Malm et al. 2007). Nevertheless, it is possible that the near plaque bear synapses and if these synapses are functional.
decreased frequency of large dendritic spines is secondary to To summarize, we suggest that the substantial alterations in
the cognitive impairments observed in APP/PS1 mice, and dendritic spines within plaques most likely affect local synaptic
those in plasticity (Fiala et al. 2002). Both memory and synaptic connections. However, it is difficult to determine whether
plasticity are disrupted in AD models and patients (Nalbantoglu these changes contribute to the cognitive impairment seen in
et al. 1997), potentially preventing plasticity-related spine these mice. Because the plaque load and cognitive impairment
enlargement (Lang et al. 2004). in AD patients does not appear to be correlated (Terry et al.
1991), it is possible that the contribution of plaques to cognitive
Dendritic Spines are Altered by Ab Plaques impairment is relatively insignificant. Therefore, we propose that
We report here that dendrites that pass through a plaque lose the widespread changes in plaque-free regions, corresponding to
spines, whereas dendrites that contact a plaque gain spines. more than 95% of the neuropil, may have a more important
Dendrites located in plaque-free areas show a spine density influence on the cognitive status of these mice.
similar to those of Tg– mice but have a decreased frequency of
large spines. Decreased spine density within plaques and
sprouting of spines in the vicinity of plaques have been Supplementary Material
documented in the neocortex (Ferrer et al. 1990; Tsai et al. Supplementary material can be found at: http://www.cercor.
2004). The decreased spine density within plaques could be oxfordjournals.org/
590 Widespread Changes in Dendritic Spines in a Model of AD d
Knafo et al.
6. Funding Knafo S, Libersat F, Barkai E. 2005. Olfactory learning-induced
morphological modifications in single dendritic spines of young
CIBERNED grant, Fundacion Caixa (BM05-47-0); The EU 6th rats. Eur J Neurosci. 21:2217--2226.
Framework Program (PROMEMORIA LSHM-CT-2005-512012); Lacor PN, Buniel MC, Furlow PW, Sanz Clemente A, Velasco PT,
the Spanish Ministry of Science and Technology (grant Wood M, Viola KL, Klein WL. 2007. A{beta} Oligomer-induced
BFU2006-13395); and Juan de la Cierva Program of the Ministry aberrations in synapse composition, shape, and density provide
of Science and Technology fellowship to S.K. a molecular basis for loss of connectivity in Alzheimer’s disease.
J Neurosci. 27:796--807.
Lamprecht R, LeDoux J. 2004. Structural plasticity and memory. Nat Rev
Notes Neurosci. 5:45--54.
Lang C, Barco A, Zablow L, Kandel ER, Siegelbaum SA, Zakharenko SS.
We thank Gabriel Santpere, Ana Martinez, and Gerard Muntane for
2004. Transient expansion of synaptically connected dendritic
genotyping the mice. Conflict of Interest : None declared.
spines upon induction of hippocampal long-term potentiation. Proc
Address correspondence to S. Knafo, MD, PhD, Cajal Institute, CSIC, Natl Acad Sci USA. 101:16665--16670.
Av. Dr. Arce 37, 28002, Madrid, Spain. Email: shira.knafo@gmail.com. Malm TM, Iivonen H, Goldsteins G, Keksa-Goldsteine V, Ahtoniemi T,
Kanninen K, Salminen A, Auriola S, Van Groen T, Tanila H, et al.
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2007. Pyrrolidine dithiocarbamate activates Akt and improves
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