Baicalein (BE) has both antioxidant and anti-inflammatory effects. It has also been reported able to improve cerebral blood circulation in brain ischemic injury. However, its chronic efficacy and ...metabolomics in Alzheimer's disease (AD) remain unknown. In this study, BE at 80 mg/kg was administrated through the oral route in J20 AD transgenic mice aged from aged 4 months to aged 10 months. Metabolic- and neurobehavioural phenotyping was done before and after 6 months' treatment to evaluate the drug efficacy and the relevant mechanisms. Meanwhile, molecular docking was used to study the binding affinity of BE and poly (ADP-ribose) polymerase-1 (PARP-1) which is related to neuronal injury. The open field test showed that BE could suppress hyperactivity in J20 mice and increase the frequency of the target quadrant crossing in the Morris Water Maze test. More importantly, BE restored cerebral blood flow back to the normal level after the chronic treatment. A 1H NMR-based metabolomics study showed that BE treatment could restore the tricarboxylic acid cycle in plasma. And such a treatment could suppress oxidative stress, inhibit neuroinflammation, alleviate mitochondrial dysfunction, improve neurotransmission, and restore amino homeostasis via starch and sucrose metabolism and glycolipid metabolism in the cortex and hippocampus, which could affect the behavioural and cerebral blood flow. These findings showed that BE is a potential therapeutic agent for AD.
•Chronic baicalein treatment reverts cognitive impairments and restores cerebral blood flow in Alzheimer disease (AD) mice.•Metabolomics in plasma and in brain of AD mice before/after treatment reveal mechanisms of action of baicalein.•Molecular docking indicates binding of baicalein to PARP-1 protein as one of its mechanisms of action.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the motor and cognitive ...functions, respectively. Multiple common genetic loci such as fused in sarcoma (FUS) have been identified to play a role in ALS and FTD etiology. Current studies indicate that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS affect cognition remains elusive. Using a mouse model expressing an ALS-linked human FUS mutation (R514G-FUS) that mimics endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation of FUS proteins despite the downregulation of mouse FUS mRNA by the R514G-FUS protein during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis revealed a deregulation of genes that cluster in pathways involved in nonsense-mediated decay, protein homeostasis, and mitochondrial functions. Furthermore, the use of in vivo functional imaging demonstrated widespread reduction in cortical volumes but enhanced functional connectivity between hippocampus, basal ganglia and neocortex in R514G-FUS mice. Hence, our findings suggest that disease-linked mutation in FUS may lead to changes in proteostasis and mitochondrial dysfunction that in turn affect brain structure and connectivity resulting in cognitive deficits.
Early life radiation exposure causes abnormal brain development, leading to adult depression. However, few studies have been conducted to explore pre- or post-natal irradiation-induced ...depression-related neuropathological changes. Relevant molecular mechanisms are also poorly understood. We induced adult depression by irradiation of mice at postnatal day 3 (P3) to reveal hippocampal neuropathological changes and investigate their molecular mechanism, focusing on MicroRNA (miR) and its target mRNA and protein. P3 mice were irradiated by γ-rays with 5Gy, and euthanized at 1, 7 and 120 days after irradiation. A behavioral test was conducted before the animals were euthanized at 120 days after irradiation. The animal brains were used for different studies including immunohistochemistry, CAP-miRSeq, Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) and western blotting. The interaction of miR-34a-5p and its target T-cell intracytoplasmic antigen-1 (Tia1) was confirmed by luciferase reporter assay. Overexpression of Tia1 in a neural stem cell (NSC) model was used to further validate findings from the mouse model. Irradiation with 5 Gy at P3 induced depression in adult mice. Animal hippocampal pathological changes included hypoplasia of the infrapyramidal blade of the stratum granulosum, aberrant and impaired cell division, and neurogenesis in the dentate gyrus. At the molecular level, upregulation of miR-34a-5p and downregulation of Tia1 mRNA were observed in both animal and neural stem cell models. The luciferase reporter assay and gene transfection studies further confirmed a direct interaction between miR-43a-5p and Tia1. Our results indicate that the early life γ-radiation-activated miR-43a-5p/Tia1 pathway is involved in the pathogenesis of adult depression. This novel finding may provide a new therapeutic target by inhibiting the miR-43a-5p/Tia1 pathway to prevent radiation-induced pathogenesis of depression.
Short-tailed opossums (Monodelphis domestica) belong to the branch of marsupial mammals that diverged from eutherian mammals approximately 180 million years ago. They are small in size, lack a ...marsupial pouch, and may have retained more morphological characteristics of early marsupial neocortex than most other marsupials. In the present study, we used several different histochemical and immunochemical procedures to reveal the architectonic characteristics of cortical areas in short-tailed opossums. Subdivisions of cortex were identified in brain sections cut in the coronal, sagittal, horizontal or tangential planes and processed for a calcium-binding protein, parvalbumin (PV), neurofilament protein epitopes recognized by SMI-32, the vesicle glutamate transporter 2 (VGluT2), myelin, cytochrome oxidase (CO), and Nissl substance. These different procedures revealed similar boundaries among areas, suggesting that functionally relevant borders were detected. The results allowed a fuller description and more precise demarcation of previously identified sensory areas, and the delineation of additional subdivisions of cortex. Area 17 (V1) was especially prominent, with a densely populated layer 4, high myelination levels, and dark staining of PV and VGluT2 immunopositive terminations. These architectonic features were present, albeit less pronounced, in somatosensory and auditory cortex. The major findings support the conclusion that short-tailed opossums have fewer cortical areas and their neocortex is less distinctly laminated than most other mammals.
The ANP32 family of proteins have been implicated in neuronal function through biochemical and cellular biology studies in neurons, as well as by recent behavioural studies of a gene-trapped ...loss-of-function mutation of Anp32e in mice, particularly with respect to fine motor function. A second targeted allele of the Anp32e, however, did not appear to demonstrate neurological phenotypes.
Using a stringently controlled cohort of ten-generation backcrossed, co-caged, sex-matched, littermate pairs, we assayed for potential motor defects in the targeted ANP32E-deficient mice. We found no phenotypic difference in any assays.
Since it is unlikely that the gene-trap is a more complete loss-of-function, our results suggest that ANP32E has no appreciable effect on motor functions and that genetic background differences most likely account for the gene-trap phenomena.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Allometric studies in primates have shown that the cerebral cortex, cerebellum, and remaining brain structures increase in size as a linear function of their numbers of neurons and nonneuronal cells ...across primates. Whether such scaling rules also apply to functionally related structures such as those of the auditory system is unknown. Here, we investigate the scaling of brain structures in the auditory pathway of six primate species and the closely related tree shrew. Using the isotropic fractionator method to estimate the numbers of neurons and nonneuronal cells in the inferior colliculus, medial geniculate nucleus, and auditory cortex (Ac), we assessed how they scaled across species and examined the relative scaling relationships among them. As expected, each auditory structure scales in mass as a linear function of its number of neurons, with no significant changes in neuronal density across species. The Ac scales proportionately with the cerebral cortex as a whole, maintaining a relative mass of approximately 1% and a relative number of neurons of 0.7%. However, the Ac gains neurons faster than both subcortical structures examined. As a result, larger primate brains have increased ratios of cortical to subcortical neurons involved in processing auditory information.
Behavioral phenotyping has been gaining prominence due to the increased use of transgenic animal models of neurological disorders. Repeated testing in the same cohort of animals can reduce the ...overall number of animals used and is desired especially when animal numbers are difficult to obtain as well as for studies involving within-subject design such as drug treatments or aging. This review aims to provide researchers with a comprehensive overview of the carryover effects when subjecting the same set of animals to the same behavioral test. We have focused on three behavioral domains of testing: anxiety, cognition and depression. Based on a review of the literature and our own experiences as a neurobehavioral core facility, we have found that manipulating inter-test interval, environmental contextual cues and stimuli can mitigate the carryover effects to a large extent, although there are certain tests that still show strong residual effects. In addition, the effects of strain on carryover effects from repeated testing are also discussed in this review.
•Repeating the same behavioral test on the same animals may cause carryover effects.•Carryover effects differ across different anxiety, cognition and depression tests.•Repeated testing poses a problem when prior experience changes the animal’s behavior.•Changing inter-test intervals and environmental cues can mitigate carryover effects.
Abstract The effect of acute irradiation with 5 Gy or fractionated exposure with 0.5 Gy continuously for 10 days (a total dose of 5 Gy) was evaluated in an immature BALB/c mouse model. ...Radioprotective effect of ursolic acid (at 25 mg/kg/daily administered 1 h after acute or each of fractionated irradiations, and continuously for 30 days) was also investigated. We found that both acute and fractionated irradiation at a total dose of 5 Gy did not induce any mortality within 30 days after exposure to postnatal day 26 (P26) BALB/c mice, but reduced animal weigh gain in the first few weeks. At 90 days after irradiation, the weight of animals with acute irradiation was still significantly lower than the control group; no significant difference though was observed for those fractionatedly exposed mice compared to the control group. Behavioral tests indicated that acute irradiation at 5 Gy induced deficits in learning and memory in the contextual fear conditioning test. The memory for novel object recognition was also impaired. Similar changes were not observed in mice with fractionated irradiation. Immunohistochemical study demonstrated clearly that acute and fractionated irradiations induced impairment of neurogenesis in the subgranular zone (SGZ) of the dentate gyrus although fractionated exposure induced much lesser loss of newly generated neurons. Ursolic acid administered at 25 mg/kg/daily for 30 days after irradiation greatly improved acute irradiation-induced deficits in contextual learning and memory and in novel object recognition memory although it exacerbated radiation-induced reduction of neurogenesis in SGZ.
TDP-43 aggregates are the defining pathological hallmark for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Strikingly, these TDP-43 proteinopathies are also found in other ...neurodegenerative diseases, including Alzheimer's disease and are prevalent in the brains of old-aged humans. Furthermore, disease-causal mutations in TDP-43 have been identified for ALS and FTD. Collectively, the evidence indicates that TDP-43 dysfunctions lead to motor and cognitive deficits. To determine whether the mouse line expressing an ALS-linked mutation in TDP-43 (Q331K) can be used to study ALS-FTD spectrum disorders, we performed a systematic and longitudinal behavioral assessment that covered motor and cognitive functions. Deficits in motor and cognitive abilities were observed as early as 3 months of age and persisted through to 12 months of age. Within the cognitive modalities, the hippocampus-mediated spatial learning and memory, and contextual fear conditioning, were normal; whereas the frontal cortex-mediated working memory and cognitive flexibility were impaired. Biochemically, the human TDP-43 transgene downregulates endogenous mouse TDP-43 mRNA and protein, resulting in human TDP-43 protein that is comparable with the physiological level in cerebral cortex and hippocampus. Furthermore, Q331K TDP-43 is largely retained at the nucleus without apparent aggregates. Taken together, our data suggest that motor and frontal cortex may be more vulnerable to disease-linked mutation in TDP-43 and, this mouse model may be used to assess ALS-FTD–related spectrum diseases and the molecular underpinnings associated with the phenotypes.
•Mice expressing TDP-43 mutation (Q331K) were used to test their motor and cognition functions.•Motor and cognitive deficits were observed at 3-month-old and persisted through to 12 months of age.•Frontal cortex–mediated working memory and cognitive flexibility of Q331K mice were impaired.•Hippocampal-dependent spatial learning and memory and contextual fear conditioning is normal.•Human TDP-43 protein expression downregulates mouse TDP-43 mRNA and protein.•Q331K expresses in the normal physiological level in cortex and hippocampus without aggregation.
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