scholarly journals Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein–induced Inflammation through a Vagomimetic Action in Mice

2018 ◽  
Vol 128 (5) ◽  
pp. 921-931 ◽  
Author(s):  
Jun Hu ◽  
Susana Vacas ◽  
Xiaomei Feng ◽  
David Lutrin ◽  
Yosuke Uchida ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Fear Conditioning ◽  
Nicotinic Acetylcholine Receptors ◽  
Surgical Trauma ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Trace Fear Conditioning ◽  
Molecular Pattern ◽  
Molecular Group ◽  
Trace Fear

Abstract Background Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-associated molecular pattern–induced cognitive decline. Methods Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines. Results Damage-associated molecular pattern–induced cognitive decline and inflammation (mean ± SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 ± 8.69% vs. 41.45 ± 7.64%, P < 0.0001; plasma interleukin [IL]-1β: 7.0 ± 2.2 pg/ml vs. 49.8 ± 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 ± 1.6 pg/ml vs. 19.5 ± 1.7 pg/ml, P < 0.0001; hippocampal IL-1β: 4.1 ± 3.0 pg/mg vs. 41.6 ± 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 ± 1.3 pg/mg vs. 16.2 ± 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation–resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 ± 0.1 vs. 0.7 ± 0.1, P < 0.0001; spleen: 1.5 ± 0.2 vs. 0.6 ± 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 ± 0.2 vs. 0.9 ± 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 ± 0.2 vs. 3.0 ± 0.3, P < 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade. Conclusions Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern–mediated cognitive decline.

Trace Fear Conditioning Detects Hypoxic-Ischemic Brain Injury in Neonatal Mice

2011 ◽  
Vol 33 (3-4) ◽  
pp. 222-230 ◽  
Author(s):  
Katarina Järlestedt ◽  
Alison L. Atkins ◽  
Henrik Hagberg ◽  
Marcela Pekna ◽  
Carina Mallard
Keyword(s):  
Brain Injury ◽  
Fear Conditioning ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Neonatal Mice ◽  
Trace Fear Conditioning ◽  
Hypoxic Ischemic Brain Injury ◽  
Trace Fear

scholarly journals A Genome-Wide Arrayed cDNA Screen to Identify Functional Modulators of α7 Nicotinic Acetylcholine Receptors

2016 ◽  
Vol 22 (2) ◽  
pp. 155-165 ◽  
Author(s):  
Elizabeth B. Rex ◽  
Nikhil Shukla ◽  
Shenyan Gu ◽  
David Bredt ◽  
Daniel DiSepio
Keyword(s):  
Cdna Library ◽  
High Throughput ◽  
Protein Interactions ◽  
Nicotinic Acetylcholine Receptors ◽  
Calcium Flux ◽  
Functional Assay ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Genome Wide ◽  
A Genome

Cellular signaling is in part regulated by the composition and subcellular localization of a series of protein interactions that collectively form a signaling complex. Using the α7 nicotinic acetylcholine receptor (α7nAChR) as a proof-of-concept target, we developed a platform to identify functional modulators (or auxiliary proteins) of α7nAChR signaling. The Broad cDNA library was transiently cotransfected with α7nAChR cDNA in HEK293T cells in a high-throughput fashion. Using this approach in combination with a functional assay, we identified positive modulators of α7nAChR activity. We identified known positive modulators/auxiliary proteins present in the cDNA library that regulate α7nAChR signaling, in addition to identifying novel modulators of α7nAChR signaling. These included NACHO, SPDYE11, TCF4, and ZC3H12A, all of which increased PNU-120596-mediated nicotine-dependent calcium flux. Importantly, these auxiliary proteins did not modulate GluR1(o)-mediated Ca flux. To elucidate a possible mechanism of action, we employed an α7nAChR-HA surface staining assay. NACHO enhanced α7nAChR surface expression; however, the mechanism responsible for the SPDYE11-, TCF4-, and ZC3H12A-dependent modulation of α7nAChR has yet to be defined. This report describes the development and validation of a high-throughput, genome-wide cDNA screening platform coupled to FLIPR functional assays in order to identify functional modulators of α7nAChR signaling.

Dissociable effects of hippocampus lesions on expression of fear and trace fear conditioning memories in rats

Hippocampus ◽  
2006 ◽  
Vol 16 (2) ◽  
pp. 103-113 ◽  
Author(s):  
Michael A. Burman ◽  
Mark J. Starr ◽  
Jonathan C. Gewirtz
Keyword(s):  
Fear Conditioning ◽  
Trace Fear Conditioning ◽  
Trace Fear

scholarly journals The role of GFAP and vimentin in learning and memory

2019 ◽  
Vol 400 (9) ◽  
pp. 1147-1156 ◽  
Author(s):  
Ulrika Wilhelmsson ◽  
Andrea Pozo-Rodrigalvarez ◽  
Marie Kalm ◽  
Yolanda de Pablo ◽  
Åsa Widestrand ◽  
...  
Keyword(s):  
Object Recognition ◽  
Fear Conditioning ◽  
Morris Water Maze ◽  
Exploratory Behavior ◽  
Water Maze ◽  
Trace Fear Conditioning ◽  
Memory Extinction ◽  
Post Traumatic ◽  
Trace Fear

Abstract Intermediate filaments (also termed nanofilaments) are involved in many cellular functions and play important roles in cellular responses to stress. The upregulation of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins of astrocytes, is the hallmark of astrocyte activation and reactive gliosis in response to injury, ischemia or neurodegeneration. Reactive gliosis is essential for the protective role of astrocytes at acute stages of neurotrauma or ischemic stroke. However, GFAP and Vim were also linked to neural plasticity and regenerative responses in healthy and injured brain. Mice deficient for GFAP and vimentin (GFAP−/−Vim−/−) exhibit increased post-traumatic synaptic plasticity and increased basal and post-traumatic hippocampal neurogenesis. Here we assessed the locomotor and exploratory behavior of GFAP−/−Vim−/− mice, their learning, memory and memory extinction, by using the open field, object recognition and Morris water maze tests, trace fear conditioning, and by recording reversal learning in IntelliCages. While the locomotion, exploratory behavior and learning of GFAP−/−Vim−/− mice, as assessed by object recognition, the Morris water maze, and trace fear conditioning tests, were comparable to wildtype mice, GFAP−/−Vim−/− mice showed more pronounced memory extinction when tested in IntelliCages, a finding compatible with the scenario of an increased rate of reorganization of the hippocampal circuitry.

scholarly journals Time course of dorsal and ventral hippocampal involvement in the expression of trace fear conditioning

2013 ◽  
Vol 106 ◽  
pp. 316-323 ◽  
Author(s):  
David Cox ◽  
Jennifer Czerniawski ◽  
Fredrick Ree ◽  
Tim Otto
Keyword(s):  
Fear Conditioning ◽  
Time Course ◽  
Trace Fear Conditioning ◽  
Trace Fear
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