Gait Ignition Failure in JNPL3 Human Tau-mutant Mice

Cognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome.

Differential regulation of Purkinje cell dendritic spines in rolling mouse Nagoya (tg(rol)/tg(rol)), P/Q type calcium channel (alpha1(A)/Ca(v)2.1) mutant / 대한해부학회지

Voltage dependent calcium channels (VDCC) participate in regulation of neuronal Ca2+. The Rolling mouse Nagoya (Cacna1a(tg-rol) ) is a spontaneous P/Q type VDCC mutant, which has been suggested as an animal model for some human neurological diseases such as autosomal dominant cerebellar ataxia (SCA6), familial hemiplegic migraine and episodic ataxia type-2. Morphology of Purkinje cell (PC) dendritic spine is suggested to be regulated by signal molecules such as Ca2+ and by interactions with afferent inputs. The amplitude of excitatory postsynaptic current was decreased in parallel fiber (PF) to PC synapses, whereas apparently increased in climbing fiber (CF) to PC synapses in rolling mice Nagoya. We have studied synaptic morphology changes in cerebella of this mutant strain. We previously found altered synapses between PF varicosity and PC dendritic spines. To study dendritic spine plasticity of PC in the condition of insufficient P/Q type VDCC function, we used high voltage electron microscopy (HVEM). We measured the density and length of PC dendritic spines at tertiary braches. We observed statistically a significant decrease in spine density as well as shorter spine length in rolling mice compared to wild type mice at tertiary dendritic braches. In proximal PC dendrites, however, there were more numerous dendritic spines in rolling mice Nagoya. The differential regulation of rolling PC spines at tertiary and proximal dendrites in rolling mice Nagoya suggests that two major excitatory afferent systems may be regulated reciprocally in the cerebellum of rolling mouse Nagoya.

Effects of Exercise on Structural and Functional Changes in the Aging Brain

Arapid increase in the elderly population has raised social awareness for maintaining the health of the elderly and initiated intense research in neurodegenerative diseases. Exercise can improve not only cardiovascular and musculoskeletal fitness, but also suppresses the symptoms of depression and anxiety, suggesting a possible role of exercise in the regulation of brain function. Based on a substantial body of literature, here we introduce the effects of exercise on the structural and functional changes in the aging brain, and also discuss the molecular and cellular effects of exercise and motor learning. Studies show that regular exercise in the elderly promotes neurocognitive function, prevents loss of brain tissue, and reduces the risk for neurodegenerative diseases and brain injury. Although the molecular mechanisms, by which exercise regulates brain function, has not been fully understood, recent cell biological and biochemical studies reveal that exercise increases neurogenesis in the hippocampus, elevates the levels of neurotrophins such as BDNF and IGF-1 to promote the survival of newly generated neurons. Exercise also induces angiogenesis in the motor cortex and cerebellum to enhance delivery of glucose and oxygen to neurons. Furthermore, complex motor skill learning increases the number of synapses to improve cognitive and motor function. Taken together, these findings clearly demonstrate that exercise serves as a behavioral intervention to prevent cognitive decline as well as neurodegenerative diseases. Thus long-term regular exercise in parallel with various learning experiences will be required to prepare successful aging. This study will provide fundamental insights into research in neurodegenerative diseases and a better understanding of the exercise effects in brain function.

Evaluation of Morphological Plasticity in the Cerebella of Basketball Players with MRI

Cerebellum is a key structure involved in motor learning and coordination. In animal models, motor skill learning increased the volume of molecular layer and the number of synapses on Purkinje cells in the cerebellar cortex. The aim of this study is to investigate whether the analogous change of cerebellar volume occurs in human population who learn specialized motor skills and practice them intensively for a long time. Magnetic resonance image (MRI)-based cerebellar volumetry was performed in basketball players and matched controls with V-works image software. Total brain volume, absolute and relative cerebellar volumes were compared between two groups. There was no significant group difference in the total brain volume, the absolute and the relative cerebellar volume. Thus we could not detect structural change in the cerebellum of this athlete group in the macroscopic level.