Neuroscience
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K369I tau mice demonstrate a shift towards striatal neuron burst firing and goal-directed behaviour.
Pathological forms of the microtubule-associated protein tau are involved in a large group of neurodegenerative diseases named tauopathies, including frontotemporal lobar degeneration (FTLD-tau). K369I mutant tau transgenic mice (K3 mice) recapitulate neural and behavioural symptoms of FTLD, including tau aggregates in the cortex, alterations to nigrostriatum, memory deficits and parkinsonism. The aim of this study was to further characterise the K3 mouse model by examining functional alterations to the striatum. ⋯ The observed pattern of behaviour in K3 mice is suggestive of deficits in dorsal lateral striatal function and this was supported by our electrophysiological findings. Thus, both the electrophysiological and behavioural alterations indicate that K3 mice have early deficits in striatal function. This finding adds to the growing literature which indicate that the striatum is impacted in tau-related neuropathies such as FTLD, and further suggests that the K3 model is a unique mouse model for investigating FTLD especially with striatal involvement.
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The incidence of mild cognitive impairment in Parkinson's disease (PDMCI) is as high as 18-55%. However, the pathological mechanism of PDMCI is not yet clear. Our previous research showed that microvascular pathology and chronic cerebral hypoperfusion participated in the occurrence and development of PDMCI. ⋯ When Nogo-A expression was downregulated, the cognitive and microvascular impairments were alleviated, and the expression of sphingosine-1-phosphate receptor 2 (S1PR2) and the RhoA/ROCK signaling pathway were inhibited. These findings suggested that Nogo-A could bind to S1PR2, activate related signaling pathways, and lead to the inhibition of vascular remodeling in PDMCI mice. This study indicated that Nogo-A downregulation could mediate microvascular remodeling and provide further insights into the pathogenesis of PDMCI.
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Dopamine loss in Parkinson's disease (PD) is associated with abnormal oscillatory activity in the cortico-basal ganglia network. However, the oscillatory pattern of striatal neurons in PD remains poorly defined. Here, we analyzed the local field potentials in one untreated and five MPTP-treated non-human primates (NHP) with chronic, advanced parkinsonism. ⋯ Both alpha and low-beta frequency band oscillations of the striatum were highly coherent with the cortical and pallidal oscillations, confirming the presence of abnormal 8-20 Hz oscillatory activity in the cortico-basal ganglia network in parkinsonian NHPs. The reversal of parkinsonism induced by acute levodopa administration was associated with reduced 8-20 Hz oscillations in the striatum. These findings indicate that pathological oscillations at alpha and low-beta bands are also present in the striatum concordant with basal ganglia network changes in the primate model of PD.
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Alterations in the functional organization of motor cortex and interictal motor deficits are observed in people with epilepsy. While seizures in the rat lead to more cortical area devoted to simple cortical forelimb movement representations (motor maps) assessed using short-duration intracortical microstimulation (ICMS), the effect of seizures on complex movements derived with long-duration ICMS is unknown. Further, the relationship between motor map expression and motor impairment is not well understood. ⋯ Bicuculline also significantly expanded forelimb motor maps (108%) but without increasing representational overlap. Moreover, expanded map areas in bicuculline rats evoked qualitatively distinct forelimb movements to long-duration, but not short-duration (n = 5), ICMS that were truncated. Our evidence indicates that motor map expansion following repeated experimental seizures is associated with reduced segregation between cortical movement representations that is not entirely due to reduced cortical inhibition but may contribute to interictal motor deficits in some individuals with epilepsy.
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Chylomicron Retention Disease (CMRD) is a rare inherited lipid malabsorption syndrome that exhibits a recessive hypocholesterolemia in infants. CMRD has been associated with genetic mutations of SAR1B-a member of the Arf GTPase family involved in the secretory pathway from the endoplasmic reticulum to the Golgi. CMRD patients suffer from multiple neurological deficits, the etiologies of which remain unclear. ⋯ At postnatal day 3, the neurons stalled in the white matter fail to develop axons across the midline of the corpus callosum, resulting in the loss of the neurons later on. hSAR1B(D137N), a CMRD-associated mutant of SAR1B, also impairs the positioning of the cortical neurons in the mouse brain, suggesting a dominant-negative effect by the human heterozygous mutant. The results indicate that SAR1B is crucial to radial migration and axon morphogenesis of the cortical neurons. Our study reveals a cell-autonomous action of Sar1b, which is unrelated to lipid absorption from the gut, on the development of the cerebral cortex.