Zika virus (ZIKV) can cause microcephaly in the fetus. However, its effects on body growth and the development of children with postnatal ZIKV infection are largely unknown. To examine this, we ...intraperitoneally challenged mouse pups with ZIKV. Infection causes an irreversible growth delay and deficits in spatial learning and memory, with growth-relevant hormones significantly reduced during infection. These effects are associated with ZIKV RNA expression in the hypothalamus, blood, and brain but not in the pituitary and thyroid. Infection is also associated with hypothalamic inflammation, and ZIKV antigen is detectable in neuroendocrine cells producing thyrotropin-releasing hormone. Moreover, early administration of growth hormone could significantly improve growth delay. Our results demonstrate that ZIKV can infect the hypothalamus, causing multi-hormone deficiencies and delayed growth and development in a mouse model. Therefore, prospective multidisciplinary follow-up of ZIKV-infected children may be necessary to understand potential effects of this virus on childhood development.
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•ZIKV infection in mouse pups causes irreversible growth delay and memory impairment•Hormones from hypothalamus, pituitary, and thyroid are reduced during ZIKV infection•Hypothalamic cells producing thyrotropin-releasing hormone can be infected by ZIKV•Early administration of growth hormone improves growth delay caused by ZIKV infection
Wu et al. find that ZIKV infection in mouse pups causes hypothalamic damage and dysfunction of the hypothalamic-pituitary axis, featuring multi-hormone deficiencies and resulting in irreversible growth delay and memory impairment during adulthood. Early administration of the relevant hormones could partially improve the long-term sequelae in the neuroendocrine system.
Currently, there is no cure for Alzheimer’s disease (AD) in humans; treatment is symptomatic only. Aging of the population, together with an unhealthy diet and lifestyle, contribute to the steady, ...global increase of AD patients. This increase creates significant health, societal and economical challenges even for the most developed countries. AD progresses from an asymptomatic stage to a progressively worsening cognitive impairment. The AD cognitive impairment is underpinned by progressive memory impairment, an increasing inability to recall recent events, to execute recently planned actions, and to learn. These changes prevent the AD patient from leading an independent and fulfilling life. Nanotechnology (NT) enables a new, alternative pathway for development of AD treatment interventions. At present, the NT treatments for attenuation of AD memory impairment are at the animal model stage. Over the past four years, there has been a steady increase in publications of AD animal models with a wide variety of original NT treatment interventions, able to attenuate memory impairment. NT therapy development, in animal models of AD, is faced with the twin challenges of the nature of AD, a chronic impairment, unique to human, of the tau protein and A β peptides that regulate several key physiological brain processes, and the incomplete understanding of AD′s aetiology. This paper reviews the state-of-the-art in NT based treatments for AD memory impairment in animal models and discusses the future work for translation to the successful treatment of AD cognitive impairment in human.
Aegle marmelos (L.) Correa (A. marmelos) has been used in Ayurvedic medicine as a brain tonic however its neuroprotective effect against streptozotocin (STZ) induced cognitive impairment and ...oxidative stress has not been reported yet in vivo. Therefore, the present study was attempted to investigate the neuroprotective potential of ethanolic extract of A. marmelos leaves (AME) on STZ induced memory impairment in male rats.
Albino Wistar rats were pre-treated orally with AME at the doses 200 and 400 mg/kg for two weeks, followed by intracerebroventricular (i.c.v.) injection of STZ (3 mg/kg) on day 1 and 3. Two weeks after STZ administration, behavioural parameters were monitored using Morris water maze task. Biochemical and histopathological studies were carried out after three weeks of STZ administration. The levels of oxidative stress markers (malondialdehyde (MDA), glutathione, nitrite, catalase) neuroinflammatory mediators; tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and acetylcholinesterase (AChE) activity were estimated in hippocampus of rat brain. Donepezil (5 mg/kg) was taken as a standard drug.
The levels of MDA, nitrite, TNF-α and IL-6 were significantly increased while glutathione levels were significantly decreased in hippocampus of STZ-treated rats. Further, a significant decrease in the activity of catalase and increase in AChE activity was observed indicating cholinergic hypofunction and neuronal damage in STZ-treated animals. All these alterations were significantly ameliorated by AME in a dose dependent manner.
The neuroprotective potential of A. marmelos against STZ induced oxidative stress and cognitive deficit in rats indicates its therapeutic value in Alzheimer's disease (AD).
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Loss of brain glutathione has been associated with cognitive decline and neuronal death during aging and neurodegenerative diseases. However, whether decreased glutathione precedes or follows ...neuronal dysfunction has not been unambiguously elucidated. Previous attempts to address this issue were approached by fully eliminating glutathione, a strategy causing abrupt lethality or premature neuronal death that led to multiple interpretations. To overcome this drawback, here we aimed to moderately decrease glutathione content by genetically knocking down the rate-limiting enzyme of glutathione biosynthesis in mouse neurons in vivo. Biochemical and morphological analyses of the brain revealed a modest glutathione decrease and redox stress throughout the hippocampus, although neuronal dendrite disruption and glial activation was confined to the hippocampal CA1 layer. Furthermore, the behavioral characterization exhibited signs consistent with cognitive impairment. These results indicate that the hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function.
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•Whether glutathione fall precedes or follows neuronal dysfunction is unknown.•A genetic approach to downregulate glutathione in neurons in vivo was generated.•Systematic characterization reveals redox stress throughout the hippocampus.•Neuronal dendrite disruption was confined to neurons of the CA1 layer.•Behavioral characterization exhibits cognitive impairment.
Objective: Our study explored the retrieval deficit and the associative deficit hypotheses of memory impairments in Parkinson's disease (PD). The former supports a memory deficit mediated by ...attention/executive dysfunctions, whereas the latter hypothesizes a hippocampal memory impairment in PD. Method: We studied 31 controls and 34 PD patients classified as PD with normal cognition (PD-NC; n = 18) and PD with mild cognitive impairment (PD-MCI; n= 16). To test the retrieval deficit hypothesis, we measured the performance in encoding, retention, and recognition in verbal and visual domains; to test the associative deficit hypothesis, we used a specific associative binding measure. Using resting-state functional-MRI, we compared the functional connectivity of different hippocampal subfields between PD patients and controls, and we related it to memory performance. Results: Consistently with the retrieval deficit hypothesis, PD-MCI, and PD-NC, were impaired in free recall encoding and retention in comparison to controls, especially in the visual domain. However, as predicted by the associative deficit hypothesis, PD-MCI and, to a lesser extent, PD-NC, showed also significant associative and binding deficits in cued recall. Notably, PD patients compared to controls did not show structural differences, although they had lower connectivity between the anterior hippocampi and the precuneus/superior parietal cortex. Worse performance in memory was associated with a more severe disruption of the hippocampal connectivity. Conclusions: The pervasive pattern of memory impairment in PD supports both hypotheses. The interplay between the hippocampus, related to associative memory deficits, and the precuneus, related to attentional control, provides a neural signature that reconciles them.
General Scientific Summary
Our study contributes significant new findings of memory disorder in patients that suffer from both Parkinson's disease and mild cognitive impairment. We tried to coherently reconcile the basic hypotheses for the interpretation of memory impairment in Parkinson's disease: the retrieval deficit and associative deficit hypotheses. Using resting-state functional-MRI, our study reveals the brain mechanisms that enable the development of memory retrieval deficit and associative memory deficit in Parkinson's disease and mild cognitive impairment.
Retrograde amnesia has been largely documented in patients with amnestic mild cognitive impairment (a-MCI) and Alzheimer’s disease (AD). However, it is still not clear whether ineffectiveness in ...recalling past acquired information reflects loss of individual memory traces or failure to access specific stored traces. We aimed to disentangle the differential contribution of storage and retrieval processes to the pattern of retrograde amnesia in these patients. This issue was investigated in 18 a-MCI and 19 AD patients who were compared to 20 healthy controls. A novel questionnaire about public events was used; it consisted of two procedures (i.e., a free recall test and a true/false recognition test). Crucial differences emerged in the way the two groups of patients performed the experimental tasks. In fact, although both a-MCI and AD patients showed a similar pattern of impairment on the free recall test, a-MCI patients were able to normalise their performance on the recognition test, thus overcoming their deficits at the time of recall. Conversely, AD patients showed both reduced free recall ability and diminished sensitivity to benefit from recognition in recalling public events. Our findings suggest that the memory processes underlying RA were different for a-MCI and AD. Deficits in remote memory are prevalently explained by impaired retrieval abilities in a-MCI and by impaired storage in AD. This distinction between retrograde amnesia due to defective trace utilisation in a-MCI and trace storage in AD is consistent with the temporal unfolding of declining anterograde memory over the course of disease progression to AD.
Acute episodes of amnestic syndrome can be a challenging diagnostic problem. Except for nonvascular etiology, thalamic strokes or infarction involving several temporal lobe structures has been ...reported in earlier cases. The authors report a patient who suddenly developed memory loss without any other focal neurologic deficits. Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) performed 1 day after onset revealed acute infarction involving the bilateral fornix column and the genu of corpus callosum. Because simple fornix infarcts often have no obvious positive neurological signs, most of the related manifestations were provided by family members, are easy to be diagnosed falsely, and missed in clinical areas, we suggest that bilateral fornix infarction should be considered in the diagnosis of an acute onset amnestic syndrome.
In recent decades, neurogenesis in the adult brain has been well demonstrated in a number of animal species, including humans. Interestingly, work with rodents has shown that adult neurogenesis in ...the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, as increasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adult neurogenesis declines with age and has been suggested to play a role in impaired progressive learning and memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed to boost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor forms of neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampus and entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival, proliferation, and differentiation. Hence, we hypothesized that pro-NGF and its p75 neurotrophin receptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test this hypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1), which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTR signaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) + progenitors express p75NTR both, in healthy humans and control animals, although the percentage of DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in these progenitors is significantly decreased in AD conditions compared to controls. In order to assess the contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, we injected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 mice and animals are subjected to a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increase the percentage of DCX+ progenitors in the DG region of these animals. In summary, our results suggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blocking adult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken into consideration for better understanding of AD pathology. Additionally, we provide a new molecular entry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD.
The Morris water maze, which has been used for more than 30 years, is one of the most famous learning and memory tasks among animals. This method is robust and reliable, and it can be carried out ...anywhere with little effort. Nowadays, there are many companies creating analysis software to easily analyze the Morris water maze results. However, these softwares are costly and may be difficult for researchers in developing countries especially with limited research funds. Only escape latency and time spent in the target quadrant can be manually obtained after video review. To resolve this problem and to extend the ability to detect learning and memory impairment in the Morris water maze, we provide a novel low-cost analysis method using common office tools combined with ImageJ software to analyze learning and memory impairment in rat or mouse models. In this study, we used the 2-vessel occlusion (2VO) rats and sham-operated control rats as learning and memory deficit rats and normal rats, respectively. Taken together, travel distance, swimming speed, and swimming traces can be acquired from this method, which will help researchers to investigate further impairment of learning and memory in animal models.
Status epilepticus (SE) is a medical emergency exemplified by self-sustaining, unceasing seizures or swiftly recurring seizure events with no recovery between seizures. The early phase after SE event ...is associated with neurodegeneration, neuroinflammation, and abnormal neurogenesis in the hippocampus though the extent of these changes depends on the severity and duration of seizures. In many instances, over a period, the initial precipitating injury caused by SE leads to temporal lobe epilepsy (TLE), typified by spontaneous recurrent seizures, cognitive, memory and mood impairments associated with chronic inflammation, reduced neurogenesis, abnormal synaptic reorganization, and multiple molecular changes in the hippocampus. While antiepileptic drugs are efficacious for terminating or greatly reducing seizures in most cases of SE, they have proved ineffective for easing SE-induced epileptogenesis and TLE. Despite considerable advances in elucidating SE-induced multiple cellular, electrophysiological, and molecular changes in the brain, efficient strategies that prevent SE-induced TLE development are yet to be discovered. This review critically confers the efficacy and promise of resveratrol, a phytoalexin found in the skin of red grapes, for easing SE-induced neurodegeneration, neuroinflammation, aberrant neurogenesis, and for restraining the evolution of SE-induced brain injury into a chronic epileptic state typified by spontaneous recurrent seizures, and learning, memory, and mood impairments.
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