scholarly journals TGFβRI antagonist inhibits HIV-1 Nef-induced CC chemokine family ligand 2 (CCL2) in the brain and prevents spatial learning impairment

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Gladys Chompre ◽  
Neysha Martinez-Orengo ◽  
Myrella Cruz ◽  
James T. Porter ◽  
Richard J. Noel
Keyword(s):  
Spatial Learning ◽  
Recognition Task ◽  
Cytokine Gene Expression ◽  
Spatial Learning And Memory ◽  
Dependent Manner ◽  
The Novel ◽  
Tgfβ Signaling ◽  
Location Recognition ◽  
The Brain ◽  
Hiv 1

Abstract Background HIV-1–associated neurocognitive disorders (HAND) progression is related to continued inflammation despite undetectable viral loads and may be caused by early viral proteins expressed by latently infected cells. Astrocytes represent an HIV reservoir in the brain where the early viral neurotoxin negative factor (Nef) is produced. We previously demonstrated that astrocytic expression of Nef in the hippocampus of rats causes inflammation, macrophage infiltration, and memory impairment. Since these processes are affected by TGFβ signaling pathways, and TGFβ-1 is found at higher levels in the central nervous system of HIV-1+ individuals and is released by astrocytes, we hypothesized a role for TGFβ-1 in our model of Nef neurotoxicity. Methods To test this hypothesis, we compared cytokine gene expression by cultured astrocytes expressing Nef or green fluorescent protein. To determine the role of Nef and a TGFβRI inhibitor on memory and learning, we infused astrocytes expressing Nef into the hippocampus of rats and then treated them daily with an oral dose of SD208 (10 mg/kg) or placebo for 7 days. During this time, locomotor activity was recorded in an open field and spatial learning tested in the novel location recognition paradigm. Postmortem tissue analyses of inflammatory and signaling molecules were conducted using immunohistochemistry and immunofluorescence. Results TGFβ-1 was induced in cultures expressing Nef at 24 h followed by CCL2 induction which was prevented by blocking TGFβRI with SD208 (competitive inhibitor). Interestingly, Nef seems to change the TGFβRI localization as suggested by the distribution of the immunoreactivity. Nef caused a deficit in spatial learning that was recovered upon co-administration of SD208. Brain tissue from Nef-treated rats given SD208 showed reduced CCL2, phospho-SMAD2, cluster of differentiation 163 (CD163), and GFAP immunoreactivity compared to the placebo group. Conclusions Consistent with our previous findings, rats treated with Nef showed deficits in spatial learning and memory in the novel location recognition task. In contrast, rats treated with Nef + SD208 showed better spatial learning suggesting that Nef disrupts memory formation in a TGFβ-1-dependent manner. The TGFβRI inhibitor further reduced the induction of inflammation by Nef which was concomitant with decreased TGFβ signaling. Our findings suggest that TGFβ-1 signaling is an intriguing target to reduce neuroHIV.

scholarly journals Reappearance of Hippocampal CA1 Neurons after Ischemia is Associated with Recovery of Learning and Memory

2005 ◽  
Vol 25 (12) ◽  
pp. 1586-1595 ◽  
Author(s):  
Olof Bendel ◽  
Tjerk Bueters ◽  
Mia von Euler ◽  
Sven Ove Ögren ◽  
Johan Sandin ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Cognitive Functions ◽  
Spatial Learning And Memory ◽  
Neuronal Marker ◽  
Ca1 Neurons ◽  
Ca1 Region ◽  
Hippocampal Ca1 ◽  
The Brain

The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2'-deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.

Prandial increase of leptin in the brain activates spatial learning and memory

2010 ◽  
Vol 17 (2) ◽  
pp. 119-127 ◽  
Author(s):  
Yutaka Oomura ◽  
Shuji Aou ◽  
Kouji Fukunaga
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Spatial Learning And Memory ◽  
The Brain

scholarly journals Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior

2019 ◽  
Vol 116 (13) ◽  
pp. 6379-6384 ◽  
Author(s):  
Marion Soto ◽  
Weikang Cai ◽  
Masahiro Konishi ◽  
C. Ronald Kahn
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Insulin Receptors ◽  
Synaptic Function ◽  
Spatial Learning And Memory ◽  
Central Amygdala ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose ◽  
The Brain ◽  
Behavior And Cognition

Previous studies have shown that insulin and IGF-1 signaling in the brain, especially the hypothalamus, is important for regulation of systemic metabolism. Here, we develop mice in which we have specifically inactivated both insulin receptors (IRs) and IGF-1 receptors (IGF1Rs) in the hippocampus (Hippo-DKO) or central amygdala (CeA-DKO) by stereotaxic delivery of AAV-Cre into IRlox/lox/IGF1Rlox/loxmice. Consequently, both Hippo-DKO and CeA-DKO mice have decreased levels of the GluA1 subunit of glutamate AMPA receptor and display increased anxiety-like behavior, impaired cognition, and metabolic abnormalities, including glucose intolerance. Hippo-DKO mice also display abnormal spatial learning and memory whereas CeA-DKO mice have impaired cold-induced thermogenesis. Thus, insulin/IGF-1 signaling has common roles in the hippocampus and central amygdala, affecting synaptic function, systemic glucose homeostasis, behavior, and cognition. In addition, in the hippocampus, insulin/IGF-1 signaling is important for spatial learning and memory whereas insulin/IGF-1 signaling in the central amygdala controls thermogenesis via regulation of neural circuits innervating interscapular brown adipose tissue.

scholarly journals Microglia control glutamatergic synapses in the adult mouse hippocampus

2021 ◽  
Author(s):  
Bernadette Basilico ◽  
Laura Ferrucci ◽  
Patrizia Ratano ◽  
Maria T. Golia ◽  
Alfonso Grimaldi ◽  
...  
Keyword(s):  
Recognition Task ◽  
Adult Brain ◽  
The Novel ◽  
Spine Density ◽  
Synaptic Organization ◽  
Glutamatergic Synapses ◽  
Hippocampal Synapses ◽  
Hippocampal Ca3 ◽  
Novel Object Recognition Task ◽  
The Brain

ABSTRACTMicroglial cells are active players in regulating synaptic development and plasticity in the brain. However, how these cells influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological depletion of microglia, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features accompanied by higher levels of plasticity. In addition, microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. Remarkably, microglial repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in synaptic organization and activity of glutamatergic synapses.

scholarly journals Tumor Necrosis Factor (TNF) Is Required for Spatial Learning and Memory in Male Mice under Physiological, but Not Immune-Challenged Conditions

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 608
Author(s):  
Leda Mygind ◽  
Marianne Skov-Skov Bergh ◽  
Vivien Tejsi ◽  
Ramanan Vaitheeswaran ◽  
Kate L. Lambertsen ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Tumor Necrosis ◽  
Spatial Learning And Memory ◽  
Male Mice ◽  
Inflammatory Conditions ◽  
Baseline Conditions ◽  
The Brain ◽  
Necrosis Factor

Increasing evidence demonstrates that inflammatory cytokines—such as tumor necrosis factor (TNF)—are produced at low levels in the brain under physiological conditions and may be crucial for synaptic plasticity, neurogenesis, learning and memory. Here, we examined the effects of developmental TNF deletion on spatial learning and memory using 11–13-month-old TNF knockout (KO) and C57BL6/J wild-type (WT) mice. The animals were tested in the Barnes maze (BM) arena under baseline conditions and 48 h following an injection of the endotoxin lipopolysaccharide (LPS), which was administered at a dose of 0.5 mg/kg. Vehicle-treated KO mice were impaired compared to WT mice during the acquisition and memory-probing phases of the BM test. No behavioral differences were observed between WT and TNF-KO mice after LPS treatment. Moreover, there were no differences in the hippocampal content of glutamate and noradrenaline between groups. The effects of TNF deletion on spatial learning and memory were observed in male, but not female mice, which were not different compared to WT mice under baseline conditions. These results indicate that TNF is required for spatial learning and memory in male mice under physiological, non-inflammatory conditions, however not following the administration of LPS. Inflammatory signalling can thereby modulate spatial cognition in male subjects, highlighting the importance of sex- and probably age-stratified analysis when examining the role of TNF in the brain.

scholarly journals Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

2004 ◽  
Vol 78 (12) ◽  
pp. 6567-6584 ◽  
Author(s):  
Michael D. Bobardt ◽  
Patrick Salmon ◽  
Lianchun Wang ◽  
Jeffrey D. Esko ◽  
Dana Gabuzda ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Endothelial Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Dependent Manner ◽  
Brain Invasion ◽  
Immunodeficiency Virus ◽  
The Brain ◽  
Hiv 1

ABSTRACT As a neurotropic virus, human immunodeficiency virus type 1 (HIV-1) invades the brain and causes severe neuronal, astrocyte, and myelin damage in AIDS patients. To gain access to the brain, HIV-1 must migrate through brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB). Given that BMECs lack the entry receptor CD4, HIV-1 must use receptors distinct from CD4 to enter these cells. We previously reported that cell surface proteoglycans serve as major HIV-1 receptors on primary human endothelial cells. In this study, we examined whether proteoglycans also impact cell-free HIV-1 invasion of the brain. Using an artificial BBB transmigration assay, we found that both heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) are abundantly expressed on primary BMECs and promote HIV-1 attachment and entry. In contrast, the classical entry receptors, CXCR4 and CCR5, only moderately enhanced these processes. HSPGs and CSPGs captured HIV-1 in a gp120-dependent manner. However, no correlation between coreceptor usage and transmigration was identified. Furthermore, brain-derived viruses did not transmigrate more efficiently than lymphoid-derived viruses, suggesting that the ability of HIV-1 to replicate in the brain does not correlate with its capacity to migrate through the BBB as cell-free virus. Given that HIV-1-proteoglycan interactions are based on electrostatic contacts between basic residues in gp120 and sulfate groups in proteoglycans, HIV-1 may exploit these interactions to rapidly enter and migrate through the BBB to invade the brain.

scholarly journals HIC1 controls cellular- and HIV-1- gene transcription via interactions with CTIP2 and HMGA1

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Valentin Le Douce ◽  
Faezeh Forouzanfar ◽  
Sebastian Eilebrecht ◽  
Benoit Van Driessche ◽  
Amina Ait-Ammar ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Transcription ◽  
Transcriptional Regulators ◽  
Viral Reservoir ◽  
Dependent Manner ◽  
Viral Promoter ◽  
Acetylation Status ◽  
Cellular Genes ◽  
The Brain ◽  
Hiv 1

Abstract Among many cellular transcriptional regulators, Bcl11b/CTIP2 and HGMA1 have been described to control the establishment and the persistence of HIV-1 latency in microglial cells, the main viral reservoir in the brain. In this present work, we identify and characterize a transcription factor i.e. HIC1, which physically interacts with both Bcl11b/CTIP2 and HMGA1 to co-regulate specific subsets of cellular genes and the viral HIV-1 gene. Our results suggest that HIC1 represses Tat dependent HIV-1 transcription. Interestingly, this repression of Tat function is linked to HIC1 K314 acetylation status and to SIRT1 deacetylase activity. Finally, we show that HIC1 interacts and cooperates with HGMA1 to regulate Tat dependent HIV-1 transcription. Our results also suggest that HIC1 repression of Tat function happens in a TAR dependent manner and that this TAR element may serve as HIC1 reservoir at the viral promoter to facilitate HIC1/TAT interaction.

scholarly journals Effect of Dehydroepiandrosterone Sulfate on the Modulation of Memory and Learning in Sprague-Dawley Rat Hippocampus

2019 ◽  
Vol 2 ◽  
pp. 291-295
Author(s):  
Asma Ulhusna Shaimi ◽  
Hasmah Abdullah ◽  
Zalina Ismail ◽  
Wan Amir Nizam Wan Ahmad
Keyword(s):  
Learning And Memory ◽  
Morris Water Maze ◽  
Spatial Learning ◽  
Water Maze ◽  
Rat Hippocampus ◽  
Control Group ◽  
Spatial Learning And Memory ◽  
Sprague Dawley ◽  
Swimming Pattern ◽  
The Brain

Dehydroepiandrosterone sulphate (DHEAS) is a neurosteroid that is found in greater concentration within the brain rather than in any other body organ (Corpechot et al., 1981) and studies have shown that in the brain, DHEAS has a role in enhancing both learning and memory (Markowski et.al., 2001). This present study investigated the relationship between DHEAS and spatial learning and memory in the rat hippocampus. Male Sprague-Dawley rats were divided into two groups and their spatial learning behaviour was evaluated with the Morris Water Maze. The intensity of DHEAS was simultaneously recorded in real time via the Fiber Fluorescence Microscopy (FFM) S-650 probe of the Cellvisio system. There were significant changes in the swimming pattern of the experimental groups obtained via the Morris Water Maze from day 1 until day 5 and day 6 for the probe test. Meanwhile, it was also seen that the intensity of DHEAS fluorescence increased in parallel to the swimming pattern of the experimental rats in comparison to the control group. The findings suggest that the changes in DHEAS fluorescence has a strong link to both spatial learning and memory.

scholarly journals Targeted Reducing of Tauopathy Alleviates Epileptic Seizures and Spatial Memory Impairment in an Optogenetically Inducible Mouse Model of Epilepsy

2021 ◽  
Vol 8 ◽  
Author(s):  
Yang Gao ◽  
Jie Zheng ◽  
Tao Jiang ◽  
Guilin Pi ◽  
Fei Sun ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Epileptic Seizures ◽  
Neuronal Firing ◽  
Spatial Learning And Memory ◽  
Memory Impairments ◽  
Optogenetic Stimulation ◽  
Hippocampal Ca1 ◽  
The Brain

Intracellular deposition of hyperphosphorylated tau has been reported in the brain of epilepsy patients, but its contribution to epileptic seizures and the association with spatial cognitive functions remain unclear. Here, we found that repeated optogenetic stimulation of the excitatory neurons in ventral hippocampal CA1 subset could induce a controllable epileptic seizure in mice. Simultaneously, the mice showed spatial learning and memory deficits with a prominently elevated total tau and phospho-tau levels in the brain. Importantly, selective facilitating tau degradation by using a novel designed proteolysis-targeting chimera named C4 could effectively ameliorate the epileptic seizures with remarkable restoration of neuronal firing activities and improvement of spatial learning and memory functions. These results confirm that abnormal tau accumulation plays a pivotal role in the epileptic seizures and the epilepsy-associated spatial memory impairments, which provides new molecular target for the therapeutics.

scholarly journals Coronin 1A Expression in Human Astroglia, its Function in Physiology and Astrogliosis in HIV-1 Neuropathogenesis

2020 ◽  
Author(s):  
Hriday Shanker Pandey ◽  
Rishabh Kapoor ◽  
Bindu ◽  
Pankaj Seth
Keyword(s):  
Cell Activity ◽  
Neuronal Population ◽  
Dependent Manner ◽  
The Novel ◽  
Reactive Astrogliosis ◽  
Calcium Dependent ◽  
Inflammatory Molecules ◽  
First Time ◽  
Activity Dependent ◽  
Hiv 1

Abstract In most neurodegenerative disorders, including neuroAIDS, reactive astroglia are detrimental to the neuronal population. Calcium and its downstream regulators play a central role in mediating glial activation. Coronin 1A, an acting binding protein, majorly reported in cells of hematopoietic origin, regulates cell activity in a calcium-dependent manner, but its role in astroglial physiology and astrogliosis is largely unknown. Using a well-characterized primary culture of human astroglia and neurons, we explored the roles of Coronin 1A in astroglia physiology and the mechanisms by which it facilitates reactive astrogliosis. In this study, we report for the first time, that human primary astroglia express Coronin 1A, and it plays activity-dependent roles in events such as PLCγ1 phosphorylation followed by Calcium mobilization from the intracellular stores. HIV-1 Tat, a potent neurotoxicant that induces astrogliosis, enhances the expression of Coronin 1A, apart from affecting GFAP and pro-inflammatory molecules. Downregulation of Coronin 1A ameliorated the HIV-1 Tat-induced deleterious effects of reactive astroglia, measured as enhanced GFAP expression and release of IL-6, and Glutamate and thus reduced glia-mediated neurodegeneration. Our findings also suggest that out of a pool of dysregulated miRNAs studied by us, hsa-miR-92b-5p regulates Coronin 1A expression which further facilitates reactive astrogliosis under the effect of HIV-1 Tat. These findings highlight the novel roles of Coronin 1A in regulating the astroglial physiology and astrogliosis observed in HIV-1 neuropathogenesis.

Sign in / Sign up

Export Citation Format

Share Document