Effect of plasma ammonia on β-amyloid of CSF and cognitive function in mild Alzheimer's disease / 临床神经病学杂志

Objective To investigate effect of plasma ammonia on β-amyloid(Aβ)of CSF and cognitive function in mild Alzheimer's disease(AD).Methods A total of 108 mild AD patients admitted to our hospital and 47 volunteers(HC group)were studied,the cognitive function were measured and plasma ammonia were detected.The mild AD patients were divided into normal ammonia group(ADA-group)and hyperammonemia group(ADA + group)by the plasma ammonia level.The level of Aβ42,Aβ40,total tau and phosphorylated tau protein in CSF of AD patients were detected,and the results were compared.Results Compared with HC group,the MMSE and Montreal Cognitive Assessment(MoCA)in the ADA-group and ADA + group were significantly lower(all P＜0.001).The MoCA of ADA + group was significantly lower than that of ADA-group(P＜0.001).The plasma ammonia of ADA + group were significantly higher than those of ADA-group and HC group(all P＜0.001).The levels of Aβ42 and Aβ40 in ADA + group were significantly lower than those of ADA-group(t =2.29,P =0.024;t =2.72,P =0.008).In ADA + group,the plasma ammonia level was negatively correlated with the MoCA score(r =-0.47,P＜0.001)and level of Aβ42 in CSF(r =-0.63,P＜0.001).The level of Aβ42 played a partial mediating role between the plasma ammonia level and cognitive function,and mediating effect accounted for 45.94%of the total effect.Conclusion The plasma ammonia level is elevated in some AD patients,high plasma ammonia level may reduce the Aβ42 level in CSF,contributes to Aβ42 deposition which forms the amyloid plaques,ultimately aggravates cognitive impairment.

Optogenetic study of glutamatergic neuron in parasubiculum in visuospatial memory / 中华行为医学与脑科学杂志

Objective:To investigate the function of glutamatergic neuron of the parasubiculum in spatial memory.Methods:Sixteen adult male C57BL/6 mice aged 6-8 weeks were divided into two groups randomly, 0.4 μl AAV5-CaMKⅡα-eNpHR3.0-eYFP was injected into the bilateral parasubiculum respectively in experimental group, equal dose AAV5-CaMKⅡα-eYFP for control group.The optic fiber was implanted 6 weeks after virus injection.The novel object place recognition test was performed one week after optic fiber implantation, continuous yellow light was delivered during the behavioral test to inhibit the function of glutamatergic neuron in the parasubiculum.The standard memory index (D2) was used to evaluate the spatial memory function.SPSS 20.0 software was used to process the data, and the independent-samples t-test and paired-samples t-test were used for data analysis. Results:In the novel object place recognition experiment, the mice showed no preference for either object in both control group(new object: 0.51±0.06, familiar object: 0.49±0.04, t=1.21, P>0.05) and experimental group(new object: 0.49±0.05, familiar object: 0.50±0.04, t=-0.78, P>0.05). Compared with the control group (0.55±0.06), the D2 score of the experimental group (0.26±0.07) was significantly lower ( t=-2.96, P<0.05), and the number of c-fos positive neuron in experimental group (96.33±7.13) was also significantly less than that in control group (127.67±5.24, t=-3.54, P<0.05). Conclusion:Inhibiting glutamatergic neuronal activity in the parasubiculum impairs spatial memory in mice, suggesting that glutamatergic neurons of the parasubiculum play an important role in spatial memory.

Impaired Parahippocampal Gyrus-Orbitofrontal Cortex Circuit Associated with Visuospatial Memory Deficit as a Potential Biomarker and Interventional Approach for Alzheimer Disease / 神经科学通报·英文版

The parahippocampal gyrus-orbitofrontal cortex (PHG-OFC) circuit in humans is homologous to the postrhinal cortex (POR)-ventral lateral orbitofrontal cortex (vlOFC) circuit in rodents. Both are associated with visuospatial malfunctions in Alzheimer's disease (AD). However, the underlying mechanisms remain to be elucidated. In this study, we explored the relationship between an impaired POR-vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice, and investigated alterations of the PHG-OFC circuit by multi-domain magnetic resonance imaging (MRI) in patients on the AD spectrum. We demonstrated that an impaired glutamatergic POR-vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice. Moreover, MRI measurements of the PHG-OFC circuit had an accuracy of 77.33% for the classification of amnestic mild cognitive impairment converters versus non-converters. Thus, the PHG-OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD, thereby providing a potential predictor for AD progression and a promising interventional approach for AD.

The Glutamatergic Postrhinal Cortex-Ventrolateral Orbitofrontal Cortex Pathway Regulates Spatial Memory Retrieval / 神经科学通报·英文版

A deficit in spatial memory has been taken as an early predictor of Alzheimer's disease (AD) or mild cognitive impairment (MCI). The uncinate fasciculus (UF) is a long-range white-matter tract that connects the anterior temporal lobe with the orbitofrontal cortex (OFC) in primates. Previous studies have shown that the UF impairment associated with spatial memory deficits may be an important pathological change in aging and AD, but its exact role in spatial memory is not well understood. The pathway arising from the postrhinal cortex (POR) and projecting to the ventrolateral orbitofrontal cortex (vlOFC) performs most of the functions of the UF in rodents. Although the literature suggests an association between spatial memory and the regions connected by the POR-vlOFC pathway, the function of the pathway in spatial memory is relatively unknown. To further illuminate the function of the UF in spatial memory, we dissected the POR-vlOFC pathway in mice. We determined that the POR-vlOFC pathway is a glutamatergic structure, and that glutamatergic neurons in the POR regulate spatial memory retrieval. We also demonstrated that the POR-vlOFC pathway specifically transmits spatial information to participate in memory retrieval. These findings provide a deeper understanding of UF function and dysfunction related to disorders of memory, as in MCI and AD.

The improvement effect of TREK-1 potassium channel blockade on the behavior of depression model rats / 中华行为医学与脑科学杂志

Objective To study the effect of TREK-1 potassium channel blocker on the behavior in rats with depression.Methods Forty-eight healthy adult male Sprague Dawley (SD) rats were divided into 6 groups as following:control + saline (CON group),control + fluoxetine (CON + FLU group),control + SID1900 (CON+SID group),CUMS + saline (CUMS group),CUMS + fluoxetine (CUMS+FLU group) and CUMS + SID1900 (CUMS+SID group) with 8 in each group.Isolated living conditions combining chronic unpredicted mild stress (CUMS) were used to establish depression model in rats.Four weeks after modeling,fluoxetine 10 mg· kg-1,SID1900 5.1 mg · kg-1 and 0.9％ sodium chloride were given by intraperitoneal injection respectively.Body weight and behavioral performance of rats in several experiment paradigms were measured after drug administration.The behavioral paradigms included sucrose preference test(SPT),open field test(OFT) and forced swimming test(FST).Results Drug administration had no significant effect on body weight and behavioral performance in non stress rats (P＞0.05),however,after chronic unpredicted mild stress the body weight,percentage of sucrose consumption,movement distances and rearing times in CUMS group were decreased dramatically contrast to CON group,but the immobility duration was increased significantly (all P＜0.001).After treatment with drug for 14 days,the sucrose consumption percentage(62.03± 6.99) ％) and rearing times (18.57 ± 6.37) in CUMS+SID group were increased contrast to C UMS group ((45.46± 15.54) ％,(5.83±3.06)),while the immobility time((123.57±26.73) s) was decreased compared with that in CUMS group((174.33±40.68) s).When drug administration for 28 days,the sucrose consumption percentage((79.64± 11.37) ％),the total distance as well as the rearing times ((13.18 ± 3.17) m,(19.33±3.33)) within OFT in CUMS+FLU group were increased in comparison with CUMS group((48.06± 17.10) ％,(4.45±3.69) m,(5.17± 2.99)),and the immobility duration ((97.83± 18.97) s) in CUMS+FLU group was shorter than that ((194.83±37.97) s) in CUMS group(P＜0.05).Notably,the immobility time in CUMS+SID group ((44.29± 14.30)s) was shortened obviously compared with that in CUMS+FLU group ((97.83± 18.97)s) (P＜0.01).Conclusion Blockade of TREK-1 potassium channel can ameliorate the depression-like behavior rapidly in rats.