Neuroscience
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Parkinson's disease (PD) is the second most common neurodegenerative disease and there are no effective treatments that either slow or reverse the degeneration of the dopamine (DA) pathway. Using a 4-week progressive MPTP (1-methyl-1,2,3,6-tetrahydropyridine) neurotoxin model of PD, which is characterized by neuroinflammation, loss of nigrostriatal DA, and motor dysfunction, as seen in patients with PD, we tested whether post-MPTP treatment with glatiramer acetate (GA), an immunomodulatory drug, could reverse these changes. GA restored the grip dysfunction and gait abnormalities that were evident in the MPTP treated group. ⋯ Alpha synuclein (syn-1) levels within the midbrain and striatum were decreased following MPTP, while GA facilitated recovery to VEH levels in the striatum in the MPTP group. Although DA tissue analysis revealed no significant increase in striatal DA or 3,4-Dihydroxyphenylacetic acid levels (DOPAC) in the MPTP group treated with GA, DA turnover (DOPAC/DA) recovered back to VEH levels following GA treatment. GA treatment effectively reversed clinical (motor dysfunction) and pathology (TH, IBA1, BDNF expression) of PD in a murine model.
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Activation of the M1 muscarinic acetylcholine receptor (M1R) may be an effective therapeutic approach for Alzheimer's disease (AD), dementia with Lewy bodies, and schizophrenia. Previously, the M1R/M4R agonist xanomeline was shown to improve cognitive function and exert antipsychotic effects in patients with AD and schizophrenia. However, its clinical development was discontinued because of its cholinomimetic side effects. ⋯ Other than in the orbital cortex and claustrum, TAK-071 induced similar c-Fos expression patterns. When donepezil was co-administered to increase the levels of acetylcholine, the number of TAK-071-induced c-Fos-positive cells in these brain regions was increased. TAK-071, through induction of similar neural activation as that seen with xanomeline, may produce procognitive and antipsychotic effects with improved cholinergic side effects.
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The cerebrospinal fluid (CSF) movement and its influence on substance distribution and elimination from the CSF system have been thoroughly analyzed and discussed in the light of the new hypothesis of CSF physiology. As a result, CSF movement is not presented as a circulation, but a permanent rhythmic systolic-diastolic pulsation in all directions. Such movement also represents the main force of substance distribution inside the CSF system. ⋯ If a certain transport mechanism is not available at one site, the substance will be distributed by CSF movement along the CSF system and into the CNS region where that transport mechanism is available. Pharmacological manipulation suggests that the residence time and the substance travel distance along the CSF system depend on the capacity of transport mechanisms situated on CNS blood capillaries. Physiological absorption of the CSF into the venous sinuses and/or lymphatics, due to their small surface area, should be of minor importance in comparison with the huge absorptive surface area of the microvessel network.
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Subjective well-being (SWB) is closely related to our physical and mental health. Existing studies show that neural or genetic basis underpins individual difference in SWB. Moreover, researchers have found high enrichment of SWB-related mutations in the central nervous system, but the relationship between the genetic architecture of SWB and brain morphology has not been explored. ⋯ In whole-brain analyses, we found that a higher PGS was significantly associated with increased CT in the right superior temporal gyrus (STG) and GMV in the right insula, both of which are involved in social cognition and emotional processing. More importantly, these findings were repeatable at some different thresholds. The results may suggest that the brain morphology of right STG and insula is partly regulated by SWB-related genetic factors.
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Stress is an additive factor in the development of depressive-like profiles that mainly onsets during adolescence. However, effects of early post-weaning stress on developing brain neurochemical pathways in inducing anxiety- and depressive-like profiles in vulnerable females have not been extensively studied. The Wistar Kyoto (WKY) rat, a putative model of adolescent depression and stress-sensitivity could elucidate the pathophysiology of stress-related depression in vulnerability. ⋯ Medial prefrontal cortex, a still maturing brain area, exhibited increased serotonin (5-HT) metabolite (p < 0.01) and turnover rates (p < 0.01) indicative of altered/maladaptive serotonergic functioning. Nucleus accumbens (p < 0.05) and dorsal striatum (p < 0.01) also depicted increased 5-HT metabolite, with the latter also demonstrating reduced Dopamine turnover (p < 0.01) as a result of homotypic stress. Hence, female WKY rats could constitute a diathesis-stress model to study underlying mechanisms of stress-related depression.