Amyloid<i>β</i>Enhances Typical Rodent Behavior While It Impairs Contextual Memory Consolidation

Salgado-Puga, Karla; Prado-Alcalá, Roberto A.; Peña‐Ortega, Fernando

doi:10.1155/2015/526912

Cited by 16 publications

(9 citation statements)

References 85 publications

(129 reference statements)

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“…The effect of glutamate on this well-established indicator of animal fear and anxiety was validated further by the recorded glutamate-mediated initiation of fear and anxiety-like behavior, which was revealed by increased rearing frequency in glutamate-treated rats compared to controls. In correlation with the anxiogenic effects of glutamate that we found, bilateral intracerebroventricular injections of Aβ caused deficits in spatial learning and anxiety-like behavior in rats (Wong et al 2016), while intrahippocampal application of Aβ may underlie mild anxiety state in rats (Salgado-Puga et al 2015).…”

Section: Discussionsupporting

confidence: 76%

Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity

et al. 2021

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The hallmarks of Alzheimer's disease (AD) pathology include senile plaques accumulation and neurofibrillary tangles, which is thought to underlie synaptic failure. Recent evidence however supports that synaptic failure in AD may instead be instigated by enhanced N-methyl-D-aspartate (NMDA) activity, via a reciprocal relationship between soluble amyloid-β (Aβ) accumulation and increased glutamate agonist. While previous studies have shown Aβ-mediated alterations to the glutamatergic system during AD, the underlying etiology of excitotoxic glutamate-induced changes has not been explored. Here, we investigated the acute effects of stereotaxic dentate gyrus (DG) glutamate injection on behavior and molecular expression of specific proteins and neurochemicals modulating hippocampal functions. Dependence of glutamate-mediated effects on NMDA receptor (NMDAR) hyperactivation was tested using NMDARs antagonist memantine. DG of Wistar rats (12-weeks-old) were bilaterally microinjected with glutamate (500 mM) with or without daily intraperitoneal (i.p.) memantine injection (20 mg/kg) for 14 days, while controls received either intrahippocampal/i.p. PBS or i.p. memantine. Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine. In glutamate-treated rats, increased NO expression was accompanied by marked reduction in profiles of glutathione-s-transferase and glutathione peroxidase. Similarly, glutamatemediated increase in acetylcholinesterase expression corroborated downregulation of synaptophysin and PSD-95, coupled with initiation of reactive astrogliosis (GFAP). While neurofilament immunolocalization/immunoexpression was unperturbed, we found glutamate-mediated reduction in neurogenic markers Ki67 and PCNA immunoexpression, with a decrease in NR2B protein expression, whereas mGluR1 remains unchanged. In addition, increased expression of apoptotic regulatory proteins p53 and Bax was seen in glutamate infused rats, corroborating chromatolytic degeneration of granule neurons in the DG. Interestingly, memantine abrogated most of the degenerative changes associated with glutamate excitotoxicity in this study. Taken together, our findings causally link acute glutamate dyshomeostasis in the DG with development of AD-related behavioral impairment and molecular neurodegeneration.

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Section: Discussionsupporting

confidence: 76%

Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity

et al. 2021

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“…Wister rats with oligomeric Aβ injected into the CA1 region of the hippocampus showed increased anxiety and memory impairment compared to vehicle injected rats without affecting hippocampal integrity (Salgado-Puga et al, 2015). This suggests, that Aβ oligomers trigger anxious behavior and memory impairment via cellular processes.…”

Section: Preclinical Research On Npd Related Behaviormentioning

confidence: 94%

Steps Towards Developing Effective Treatments for Neuropsychiatric Disturbances in Alzheimer’s Disease: Insights From Preclinical Models, Clinical Data, and Future Directions

Clement

Wiborg

Asuni

2020

Front. Aging Neurosci.

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Alzheimer's disease (AD) is the most common form of dementia worldwide. It is mostly known for its devastating effect on memory and learning but behavioral alterations commonly known as neuropsychiatric disturbances (NPDs) are also characteristics of the disease. These include apathy, depression-like behavior, and sleep disturbances, and they all contribute to an increased caregiver burden and earlier institutionalization. The interaction between NPDs and AD pathology is not well understood, but the consensus is that they contribute to disease progression and faster decline. Consequently, recognizing and treating NPDs might improve AD pathology and increase the quality of life for both patients and caregivers. In this review article, we examine previous and current literature on apathy, depressive symptoms, and sleep disturbances in AD patients and preclinical AD mechanistic models. We hypothesize that tau accumulation, beta-amyloid (Aβ) aggregation, neuroinflammation, mitochondrial damage, and loss of the locus coeruleus (LC)-norepinephrine (NE) system all collectively impact the development of NPDs and contribute synergistically to AD pathology. Targeting more than one of these processes might provide the most optimal strategy for treating NPDs and AD. The development of such clinical approaches would be preceded by preclinical studies, for which robust and reliable mechanistic models of NPD-like behavior are needed. Thus, developing effective preclinical research models represents an important step towards a better understanding of NPDs in AD.

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“…Assessment of burrowing activity was performed following previously published protocols (Deacon, 2006; Deacon, 2012; Salgado‐Puga et al, 2015). Briefly, burrows were built from 20 cm long and 7.6 cm wide segments of plastic cylinders with one end closed with plastic plug, leaving the other end open and elevated ~3 cm from the surface.…”

Section: Methodsmentioning

confidence: 99%

Abnormal innate and learned behavior induced by neuron–microglia miscommunication is related to CA3 reconfiguration

Méndez-Salcido

Torres-Flores

Ordaz

et al. 2022

Glia

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Neuron-microglia communication through the Cx3cr1-Cx3cl1 axis is essential for the development and refinement of neural circuits, which determine their function into adulthood. In the present work we set out to extend the behavioral characterization of Cx3cr1 À/À mice evaluating innate behaviors and spatial navigation, both dependent on hippocampal function. Our results show that Cx3cr1-deficient mice, which show some changes in microglial and synaptic terminals morphology and density, exhibit alterations in activities of daily living and in the rapid encoding of novel spatial information that, nonetheless, improves with training. A neural substrate for these cognitive deficiencies was found in the form of synaptic dysfunction in the CA3 region of the hippocampus, with a marked impact on the mossy fiber (MF) pathway. A network analysis of the CA3 microcircuit reveals the effect of these synaptic alterations on the functional connectivity among CA3 neurons with diminished strength and topological reorganization in Cx3cr1-deficient mice. Neonatal population activity of the CA3 region in Cx3cr1-deficient mice shows a marked reorganization around the giant depolarizing potentials, the first form of network-driven activity of the hippocampus, suggesting that alterations found in adult subjects arise early on in postnatal development, a critical period of microglia-dependent neural circuit refinement. Our results show that interruption of the Cx3cr1-Cx3cl1/neuronmicroglia axis leads to changes in CA3 configuration that affect innate and learned behaviors.

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AmyloidβEnhances Typical Rodent Behavior While It Impairs Contextual Memory Consolidation

Cited by 16 publications

References 85 publications

Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity

Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity

Steps Towards Developing Effective Treatments for Neuropsychiatric Disturbances in Alzheimer’s Disease: Insights From Preclinical Models, Clinical Data, and Future Directions

Abnormal innate and learned behavior induced by neuron–microglia miscommunication is related to CA3 reconfiguration

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