Age-related deterioration in conditional avoidance task in the SAM-P/10 mouse, an animal model of spontaneous brain atrophy

A novel inbred strain of mouse ‘SAM-P/10’ (Senescence Accelerated Mouse) is a model of age-related brain atrophy characterized by age-related loss and shrinkage of neurons in the cerebral neocortex. Age-related changes in learning and memory skills of SAM-P/10 mice were investigated usinng a newly developed conditional avoidance task in a T-maze. Comparisons were made with findings in the SAM-R/1 strain which shows a little loss and no shrinkage of neocortical neurons. Four-month-old SAM-R/1 and SAM-P/10 performed well during a 10-day training schedule of the conditional avoidance task. SAM-R/1 mice over 17 months of age were slower learners than younger SAM-R/1 mice but reached nearly the same high percentage avoidance as seen in the 4-month-old mice during the last 4 days of the schedule. Performance of the SAM-P/10 mice gradually worsened with aging and 10- to 12-month-old SAM-P/10 mice could not reach the percentage avoidance seen with the 4-month-old mice, even after the 10-day training. When the mean percentage of succesful avoidance or escape behavior on every training day was plotted, the curves were much the same for both SAM-R/1 and SAM-P/10 mice, of any age. These results show that aged SAM-P/10 mice retained the left-right turning discrimination in the T-maze and lost the ability to predict the forthcoming aversive shock by associating conditioned stimulus and unconditioned stimulus.     

The frissonnant mutant mouse, a model of dopamino-sensitive, inherited motor syndrome.

The frissonnant (fri) mutation is an autosomic recessive mutation which spontaneously appeared in the stock of C3H mice. fri mutant mice have locomotor instability and rapid tremor. Since tremor ceases when mutant mice have sleep or are anaesthetized, and because of their obvious stereotyped motor behavior, these mice could represent an inherited Parkinsonian syndrome. We show here that the fri/fri mouse fulfills two out of the three criteria required to validate an experimental model of human disease, that is isomorphism, homology and predictivity. Indeed, fri/fri mice present an important motor deficit accompanying visible tremor and stereotypies. They display some memory deficits as in human Parkinson's desease. l-Dopa and apomorphine (dopaminergic agonists), ropinirole (selective D2 agonist), and selegiline (an monoamino-oxidase B [MAO-B] inhibitor) improve their clinical status. However, neither anatomopathological evidence of nigrostriatal lesion, nor decrease in tyrosine hydroxylase production could be seen.     

Non-Alzheimer-type pattern of brain cholineacetyltransferase reduction in dominantly inherited olivopontocerebellar atrophy

We recently reported reduced activity of the cholinergic marker enzyme cholineacetyltransferase (ChAT) in several brain regions of patients with dominantly inherited olivopontocerebellar atrophy (OPCA). To document the regional extent of these changes we performed a comprehensive examination of the behavior of ChAT throughout both cerebral cortical and subcortical brain areas in 5 patients from one large OPCA pedigree. As compared with the controls, mean ChAT activities in OPCA were reduced by 39 to 72% in all (n = 27) cerebral cortical areas examined and in several thalamic subdivisions, caudate head, globus pallidus, red nucleus, and medial olfactory area. In contradistinction to findings in Alzheimer's disease (AD), mean ChAT levels in OPCA amygdala and hippocampal subdivisions were either normal or only mildly reduced. The lack of severe disabling dementia in our OPCA patients compared with AD patients having a similar cortical cholinergic reduction could be explained by an absence of either a marked cholinergic loss in amygdala or hippocampus or significant loss of noncholinergic cerebral cortical and limbic neurons as occurs in AD brain. We suggest that this and other OPCA pedigrees having a cortical cholinergic reduction represent a unique model for the study of behavioral consequences of a more selective cerebral cortical cholinergic lesion rather than a limbic cholinergic lesion.     

Multiple sclerosis as a model to investigate SARS-CoV-2 effect on brain atrophy

Introduction

Data on structural brain changes after infection with SARS-CoV-2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS-CoV-2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates.

Methods

Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre-SARS-CoV-2 images with age as an explanatory variable. The residuals were used to determine whether the post-SARS-CoV-2 volumes differed significantly from the baseline.

Results

Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS-CoV-2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection.

Conclusions

Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS-CoV-2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.     

Spontaneous spongy degeneration of the brain stem in SAM-P/8 mice, a newly developed memory-deficient strain

A spontaneous spongy degeneration of the brain stem and spinal cord was discovered in a murine model of accelerated senescence (SAM), cared for under both conventional (SAM-P/8) and specific pathogen-free (SAM-P/8/Ta) conditions. SAM-P/8 and SAM-P/8/Ta showed no clinical neurological abnormalities, yet there was a deterioration in learning and memory abilities. Light microscopic examination revealed a spongy degeneration in the brain stem and spinal cord, in the reticular formation, and proliferation of hypertrophic astrocytes in the spongy area. The spongiform degeneration progressed with advancing age from four to eight months, after which the entire brain was involved. Astrocytosis increased with advancing degeneration. Ultrastructurally, mild dendritic swelling occurred at one month of age. At two months of age, moderate postsynaptic swelling and a widening of intracellular membrane structure were observed, and at age five months there were large vacuoles circumscribed by membranous lamellae, identifiable as myelin. Vacuoles in SAM-P/8 proved to be swollen neuronal processes and oligodendroglial processes. These SAM-P/8 and SAM-P/8/Ta strains of mice are new memory-deficient strains with spontaneous spongy degeneration associated with aging.     

Motor performance and regional brain metabolism of spontaneous murine mutations with cerebellar atrophy.

Three spontaneous mutations with cerebellar atrophy were evaluated for motor coordination and regional brain metabolism, as assessed by cytochrome oxidase (CO) activity. Despite similar neuropathological characteristics, the behavioral phenotype of Lurcher is less severe than that of staggerer, possibly caused by the slower onset of their neuronal degeneration. Although fewer cerebellar cells degenerate in hot-foot than in Lurcher, their motor deficits are more severe, indicating the presence of dysfunctional cells. CO activity in the deep cerebellar nuclei was increased in Lurcher and staggerer but unchanged in hot-foot, probably due to the severe loss of GABAergic input from Purkinje cells in the first two mutants but not the third. Altered CO activity in cerebellar-related pathways was linearly correlated with motor performance, indicating that the activity of this enzyme is associated not only with neuronal activity but also with motor performance.     

Bladder dysfunction in a transgenic mouse model of multiple system atrophy

Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α‐synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)–human α‐synuclein (hαSyn) transgenic and control wild‐type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age‐related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP‐hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn‐related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA. © 2013 Movement Disorder Society     

Riluzole attenuates spinal muscular atrophy disease progression in a mouse model

Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations of the survival motor neuron 1 gene (SMN1). No curative treatment is available. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display a degenerative process of motor neurons similar to that found in human SMA. To test whether riluzole, which exhibits neurotrophic properties, might have a protective role in SMA, mutant mice were treated with it after the onset of the degenerative process. Riluzole improved median survival and exerted a protective effect against aberrant cytoskeletal organization of motor synaptic terminals but not against loss of proximal axons. These results demonstrate that the disease course of SMA can be attenuated after the onset of neuromuscular defects and may warrant further investigation in a therapeutic trial in SMA.     

Cholinergic deficits in the septal-hippocampal pathway of the SAM-P/8 senescence accelerated mouse

Senescence accelerated prone mouse strains (SAM-P) and resistant strains (SAM-R) have proven useful in elucidating aspects of the aging process. The senescence accelerated mouse SAM-P/8 strain exhibits severe age-related learning and memory impairments well before the median age of survival. Disruption of the brain cholinergic system produces learning and memory impairments as severe as those seen in aging SAM-P/8 mice. Therefore, we compared the effects of aging on cholinergic parameters in the septal-hippocampal pathway, a region known to play a role in learning and memory, in SAM-P/8 mice and mice of the senescence resistant SAM-R/1 strain. Between 4 and 12 months of age we observed a 40-50% decrease in choline acetyltransferase (ChAT) activity in two of three subregions of the hippocampus in the SAM-P/8, but not the SAM-R/1 strain. Between 4 and 12 months, SAM-P/8 mice also showed a 40-50% decrease in ChAT activity in the septal region that was maximal by 8 months of age. By contrast, these age-related changes were not observed in the control SAM-R/1 mouse strain. The changes in ChAT in the SAMP/8 mouse strain were limited to the septal-hippocampal cholinergic pathway. There were no differences in ChAT activity in the nucleus basalis of Meynert, nor any of several neocortical areas to which it projects. To determine the neurochemical specificity of these alterations, the activity of glutamic acid decarboxylase (GAD), was also measured in the septum and hippocampus of SAM-P/8 mice. There were no age-related alterations in the hippocampus, but a significant 50% increase in GAD activity in the septal nucleus at 12 months of age. There were no age-related alterations in either nicotinic (3H-cytisine) or muscarinic (3H-QNB) cholinergic receptor binding in the cortex or hippocampus of SAM-P/8 mice. However, there were significant strain differences. At 2 months of age, 3H-QNB binding was higher in hippocampus of the SAM-R/1 than in SAM-P/8 mice. Similarly, 3H-cytisine binding in cortex of SAM-R/1 mice was higher at both 2 and 13 months than in SAM-P/8 mice. The results suggest that a compromised septal-hippocampal cholinergic pathway may contribute to the previously reported early onset of impaired learning and memory in the SAM-P/8 mouse strain.     

Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings

A form of dominantly inherited olivopontocerebellar atrophy (OPCA) occurs commonly in persons of Spanish ancestry in northeastern Cuba. Its prevalence in the Province of Holguin is 41 per 100,000, a figure much higher than that found in western Cuba or in other parts of the world. The high prevalence is probably the result of a founder effect, but might be due to an interaction between a mutant gene and an unidentified environmental neurotoxin. We describe the clinical features of this disorder, and the neuropathological abnormalities in 7 autopsied patients. In addition, we report biochemical findings in plasma, cerebrospinal fluid (CSF) and urine obtained from 10 living OPCA patients. Quantitation of amino acids in fasting plasma showed a number of differences between the Cuban patients and healthy Canadian controls, but these are likely to have been caused by dietary differences. Amino acid concentrations in the CSF of the Cuban OPCA patients were similar to those of healthy Cuban controls, except for a decreased concentration of ethanolamine. Mean concentrations of dopamine metabolites were significantly low in the CSF of the OPCA patients, corresponding to neuronal depletion observed in the substantia nigra of autopsied cases. Examination of the patients' urines provided no evidence that either cyanide or 3-acetylpyridine is involved in causing this form of OPCA.     

Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE

Purpose: Temporal hypometabolism on fluorodeoxyglucose positron emission tomography (FDG‐PET) is a common finding in patients with drug‐resistant temporal lobe epilepsy (TLE). The pathophysiology underlying the hypometabolism, including whether it reflects a primary epileptogenic process, or whether it occurs later as result of limbic atrophy or as a result of chronic seizures, remains unknown. This study aimed to investigate the ontologic relationship among limbic atrophy, histological changes, and hypometabolism in rats. Methods: Serial in vivo imaging with FDG‐PET and volumetric magnetic resonance imaging (MRI) was acquired before and during the process of limbic epileptogenesis resulting from kainic acid–induced status epilepticus in the rat. The imaging data were correlated with histologic measures of cell loss, and markers of astrogliosis (glial fibrillary acid protein [GFAP]), synaptogenesis (synaptophysin), glucose transporter 1 (Glut1) and energy metabolism (cytochrome oxidase C), on brains of the animals following the final imaging point. Key Findings: Hippocampal hypometabolism on FDG‐PET was found to be present 24 h following status epilepticus, tending to lessen by 1 week and then become more marked again following the onset of spontaneous seizures. Atrophy of limbic structures was evident from 7 days post‐SE, becoming progressively more marked on serial MRI over subsequent weeks. No relationship was observed between the severity of MRI‐detected atrophy or CA1 pyramidal cell loss and the degree of the hypometabolism on FDG‐PET. However, an inverse relationship was observed between hypometabolism and increased expression of the Glut1 and synaptophysin in the hippocampus. Significance: These findings demonstrate that hypometabolism occurs early in the processes of limbic epileptogenesis and is not merely a consequence of pyramidal cell loss or the progressive atrophy of limbic brain structures that follow. The hypometabolism may reflect cellular mechanisms occurring early during epileptogenesis in addition to any effects of the subsequent recurrent spontaneous seizures.     

Erythropoietin is neuroprotective in a transgenic mouse model of multiple system atrophy

Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease‐modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)‐α‐synuclein transgenic mice exposed to 3‐nitropropionic acid featuring multiple system atrophy‐like pathology including oligodendroglial α‐synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3‐nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate‐regulated phosphoprotein (DARPP‐32) was analyzed stereologically. Animals receiving erythropoietin before and after 3‐nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3‐nitropropionic acid‐treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3‐nitropropionic acid‐induced loss of tyrosine hydroxylase and DARPP‐32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin‐treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)‐α‐synuclein 3‐nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy. © 2011 Movement Disorder Society     

Rifampicin reduces alpha-synuclein in a transgenic mouse model of multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by oligodendrocytic cytoplasmic inclusions containing abnormally aggregated alpha-synuclein. This aggregation has been linked to the neurodegeneration observed in MSA. Current MSA treatments are aimed at controlling symptoms rather than tackling the underlying cause of neurodegeneration. This study investigates the ability of the antibiotic rifampicin to reduce alpha-synuclein aggregation and the associated neurodegeneration in a transgenic mouse model of MSA. We report a reduction in monomeric and oligomeric alpha-synuclein and a reduction in phosphorylated alpha-synuclein (S129) upon rifampicin treatment. This reduction in alpha-synuclein aggregation was accompanied by reduced neurodegeneration. On the basis of its anti-aggregenic properties, we conclude that rifampicin may have therapeutic potential for MSA.     

Coenzyme Q10 as a therapeutic candidate for treating inherited photoreceptor degeneration

<正>Inherited photoreceptor degeneration(IPD):The human retina is a highly specialised tissue that enables the perception of light across a range of intensities and colours.It covers about65%of the inner surface of the eye and contains three layers of cells:the outer nuclear layer(ONL)containing the cell bodies and nuclei of the light-sensitive rod and cone photoreceptors     

Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory

Memory, learning and behavior of senescence accelerated mouse (SAM-P/8) were investigated by using passive avoidance response, T-maze and open field and the findings were compared with those from senescence resistant mouse (SAM-R/1 control). SAM-P/8 mice showed a remarkable age-related deterioration in ability of memory and learning in passive avoidance response. This age-related memory and learning deficit was linked to a deterioration in the ability of acquisition and was not due to impairment in the ability of retention and hyperactivity, as observed in the open field. In the alternation T-maze tests, SAM-P/8 showed as high a rate of alternations as did the SAM-R/1 and in the T-maze avoidance tests, SAM-P/8 also showed as intact a memory ability as seen in the SAM-R/1, despite a memory deficit in the passive avoidance response. Thus, SAM-P/8 may prove to be a pertinent model for researching mechanisms related to the memory deficit seen in senile humans.     

Striatal atrophy and dendritic alterations in a knock-in mouse model of Huntington's disease

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by progressive atrophy of the striatum, cerebral cortex, and white matter tracks. Major pathological hallmarks of HD include neuronal loss, primarily in the striatum, and dendritic anomalies in surviving striatal neurons. Although many mouse models of HD have been generated, their success at reproducing all pathological features of the disease is not fully known. Previously, we demonstrated extensive striatal neuronal loss and striatal atrophy at 20-26 months of age in a knock-in (KI) mouse model of HD. To further investigate this model, which carries a human exon 1 with ～119 CAG repeats inserted into the mouse gene (initially 140 repeats), we have examined whether these mice exhibit the atrophy and neuronal anomalies characteristic of HD. Stereological analyses revealed no changes in the striatal volume of male and female homozygote mice at 4 months, however striatal atrophy was already present at 12 months in both sexes. Analysis of cortical and corpus callosum volume in male homozygotes revealed a loss in corpus callosum volume by 20-26 months. At this later age, the surviving striatal neurons displayed extensive loss of spines in distal branch orders that affected both immature and mature spines. Mirroring late stage HD striatal neuronal morphology, the striatal neurons at this late age also showed reduced dendritic complexity, as revealed by Sholl analysis. Tyrosine hydroxylase immunoreactivity was also decreased in the striatum of 20-26 month old KI mice, suggesting an alteration in striatal inputs. These data further indicate that CAG140 homozygote KI mice exhibit HD-like pathological features and are a useful model to test the effects of early and/or sustained administration of novel neuroprotective treatments.     

Multiple sclerosis as a model to investigate SARS‐CoV‐2 effect on brain atrophy

IntroductionData on structural brain changes after infection with SARS‐CoV‐2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS‐CoV‐2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates.MethodsGlobal and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre‐SARS‐CoV‐2 images with age as an explanatory variable. The residuals were used to determine whether the post‐SARS‐CoV‐2 volumes differed significantly from the baseline.ResultsFourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS‐CoV‐2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection.ConclusionsOur results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS‐CoV‐2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.