scholarly journals Pattern separation and tuning shift in human sensory cortex underlie fear memory

2021 ◽  
Author(s):  
Yuqi You ◽  
Lucas R. Novak ◽  
Kevin Clancy ◽  
Wen Li
Keyword(s):  
Late Onset ◽  
Piriform Cortex ◽  
Fear Memory ◽  
Pattern Separation ◽  
Sensory Cortex ◽  
Evolutionarily Conserved ◽  
Sensory Encoding ◽  
Underlying Mechanisms ◽  
Cortical System

ABSTRACTAnimal research has recognized the role of the sensory cortex in fear memory and two key underlying mechanisms—pattern separation and tuning shift. We interrogated these mechanisms in the human sensory cortex in an olfactory differential conditioning study with a delayed (9-day) retention test. Combining affective appraisal and olfactory psychophysics with functional magnetic resonance imaging (fMRI) multivoxel pattern analysis and voxel-based tuning analysis over a linear odor-morphing continuum, we confirmed affective and perceptual learning and memory and demonstrated associative plasticity in the human olfactory (piriform) cortex. Specifically, the piriform cortex exhibited immediate and lasting enhancement in pattern separation (between the conditioned stimuli/CS and neighboring non-CS) and late-onset yet lasting tuning shift towards the CS, especially in anxious individuals. These findings highlight an evolutionarily conserved sensory cortical system of fear memory, which can underpin sensory encoding of fear/threat and confer a sensory mechanism to the neuropathophysiology of anxiety.

scholarly journals Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease

2021 ◽  
Author(s):  
Roland Friedel ◽  
Yong Huang ◽  
Minghui Wang ◽  
Shalaka Wahane ◽  
Mitzy Ríos de Anda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Plaque ◽  
Reactive Astrocytes ◽  
Glial Activation ◽  
Plaque Burden ◽  
Aβ Amyloid ◽  
Underlying Mechanisms

Abstract Communication between glial cells has a profound effect on the pathophysiology of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Here, we reveal a role of reactive astrocytes in enforcing cell distancing in the glial nets surrounding amyloid plaques, which restricts microglial coverage of Aβ, a prerequisite to detect and engulf amyloid deposits. This process is mediated through guidance receptor Plexin-B1, which we identified as a key network regulator of late-onset AD. We show that Plexin-B1 is robustly upregulated in plaque-associated astrocytes in a corona-like pattern, and its expression levels correlate with plaque burden and disease severity in AD patients. In APP/PS1 mice, an amyloidogenic model of AD, removing Plexin-B1 led to smaller peri-plaque glial nets with relaxed cell distancing and enhanced glial coverage of Aβ plaques, as well as transcriptional changes in both reactive astrocytes and disease-associated microglia that are linked to glial activation and amyloid clearance. Furthermore, amyloid plaque burden was lowered, together with a shift towards dense-core plaques and reduced neuritic dystrophy. Our data thus support a role of Plexin-B1 in controlling glial net structure by imposing cell distancing, leading to poor glial coverage of Aβ, reduced amyloid clearance and compaction. Relaxing cell distancing by targeting guidance receptors may present an alternative strategy to alleviate neuroinflammation in AD by improving glial coverage of Aβ amyloid and plaque compaction.

scholarly journals The Role of Macrophage Migration Inhibitory Factor in Alzheimer′s Disease: Conventionally Pathogenetic or Unconventionally Protective?

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 291 ◽  
Author(s):  
Maria Cristina Petralia ◽  
Giuseppe Battaglia ◽  
Valeria Bruno ◽  
Manuela Pennisi ◽  
Katia Mangano ◽  
...  
Keyword(s):  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Late Onset ◽  
Adaptive Immune System ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Adaptive Immune ◽  
Clinical Observations ◽  
Underlying Mechanisms

Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer′s disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.

scholarly journals Habenula kisspeptin retrieves morphine impaired fear memory in zebrafish

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mageswary Sivalingam ◽  
Satoshi Ogawa ◽  
Ishwar S. Parhar
Keyword(s):  
Fear Memory ◽  
Treated Group ◽  
Mrna Levels ◽  
Morphine Treatment ◽  
Conditioned Place Avoidance ◽  
Serotonin System ◽  
Total Brain ◽  
Evolutionarily Conserved ◽  
Place Avoidance

Abstract The habenula is an evolutionarily conserved brain structure, which has recently been implicated in fear memory. In the zebrafish, kisspeptin (Kiss1) is predominantly expressed in the habenula, which has been implicated as a modulator of fear response. Hence, in the present study, we questioned whether Kiss1 has a role in fear memory and morphine-induced fear memory impairment using an odorant cue (alarm substances, AS)-induced fear avoidance paradigm in adult zebrafish, whereby the fear-conditioned memory can be assessed by a change of basal place preference (= avoidance) of fish due to AS-induced fear experience. Subsequently, to examine the possible role of Kiss1 neurons-serotonergic pathway, kiss1 mRNA and serotonin levels were measured. AS exposure triggered fear episodes and fear-conditioned place avoidance. Morphine treatment followed by AS exposure, significantly impaired fear memory with increased time-spent in AS-paired compartment. However, fish administered with Kiss1 (10–21 mol/fish) after morphine treatment had significantly lower kiss1 mRNA levels but retained fear memory. In addition, the total brain serotonin levels were significantly increased in AS- and Kiss1-treated groups as compared to control and morphine treated group. These results suggest that habenular Kiss1 might be involved in consolidation or retrieval of fear memory through the serotonin system.

scholarly journals hrT is required for cardiovascular development in zebrafish

Development ◽  
2002 ◽  
Vol 129 (21) ◽  
pp. 5093-5101 ◽  
Author(s):  
Daniel P. Szeto ◽  
Kevin J. P. Griffin ◽  
David Kimelman
Keyword(s):  
Late Onset ◽  
Cardiovascular Development ◽  
Lateral Plate ◽  
T Box ◽  
Vascular Morphogenesis ◽  
Developing Heart ◽  
Evolutionarily Conserved ◽  
Heart Formation ◽  
Cardiovascular Cells

The recently identified zebrafish T-box gene hrT is expressed in the developing heart and in the endothelial cells forming the dorsal aorta. Orthologs of hrT are expressed in cardiovascular cells fromDrosophila to mouse, suggesting that the function of hrT is evolutionarily conserved. The role of hrT in cardiovascular development, however, has not thus far been determined in any animal model. Using morpholino antisense oligonucleotides, we show that zebrafish embryos lacking hrT function have dysmorphic hearts and an absence of blood circulation. Although the early events in heart formation were normal inhrT morphant embryos, subsequently the hearts failed to undergo looping, and late onset defects in chamber morphology and gene expression were observed. In particular, we found that the loss of hrT function led to a dramatic upregulation of tbx5, a gene required for normal heart morphogenesis. Conversely, we show that overexpression of hrT causes a significant downregulation of tbx5, indicating that one key role ofhrT is to regulate the levels of tbx5. Secondly, we found that HrT is required to inhibit the expression of the blood lineage markersgata1 and gata2 in the most posterior lateral plate mesoderm. Finally, we show that HrT is required for vasculogenesis in the trunk, leading to similar vascular defects to those observed in midline mutants such as floating head. hrT expression in the vascular progenitors depends upon midline mesoderm, indicating that this expression is one important component of the response to a midline-derived signal during vascular morphogenesis.

scholarly journals IFT88 transports Gucy2d, a guanylyl cyclase, to maintain sensory cilia function in Drosophila

2020 ◽  
Author(s):  
Sascha Werner ◽  
Sihem Zitouni ◽  
Pilar Okenve-Ramos ◽  
Susana Mendonca ◽  
Anje Sporbert ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Guanylyl Cyclase ◽  
Potential Role ◽  
Late Onset ◽  
Intraflagellar Transport ◽  
Human Diseases ◽  
Evolutionarily Conserved ◽  
Sensory Cilia ◽  
Ciliated Neurons

Cilia are involved in a plethora of motility and sensory-related functions. Ciliary defects cause several ciliopathies, some of which with late-onset, suggesting cilia are actively maintained. While much is known about cilia assembly, little is understood about the mechanisms of their maintenance. Given that intraflagellar transport (IFT) is essential for cilium assembly, we investigated the role of one of its main players, IFT88, in ciliary maintenance. We show that DmIFT88, the Drosophila melanogaster orthologue of IFT88, continues to move along fully formed sensory cilia, and that its acute knockdown in the ciliated neurons of the adult affects sensory behaviour. We further identify DmGucy2d, the Drosophila guanylyl cyclase 2d, as a DmIFT88 cargo, whose loss also leads to defects in sensory behaviour maintenance. DmIFT88 binds to the intracellular part of DmGucy2d, a highly, evolutionarily conserved and mutated in several degenerative retina diseases, taking the cyclase into the cilia. Our results offer a novel mechanism for the maintenance of sensory cilia function and its potential role in human diseases.

scholarly journals The role of piriform associative connections in odor categorization

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xiaojun Bao ◽  
Louise LG Raguet ◽  
Sydni M Cole ◽  
James D Howard ◽  
Jay A Gottfried
Keyword(s):  
Activity Patterns ◽  
Piriform Cortex ◽  
Discrimination Performance ◽  
Object Identification ◽  
Pattern Separation ◽  
Odor Perception ◽  
Drug Induced ◽  
Multivariate Pattern ◽  
The Brain

Distributed neural activity patterns are widely proposed to underlie object identification and categorization in the brain. In the olfactory domain, pattern-based representations of odor objects are encoded in piriform cortex. This region receives both afferent and associative inputs, though their relative contributions to odor perception are poorly understood. Here, we combined a placebo-controlled pharmacological fMRI paradigm with multivariate pattern analyses to test the role of associative connections in sustaining olfactory categorical representations. Administration of baclofen, a GABA(B) agonist known to attenuate piriform associative inputs, interfered with within-category pattern separation in piriform cortex, and the magnitude of this drug-induced change predicted perceptual alterations in fine-odor discrimination performance. Comparatively, baclofen reduced pattern separation between odor categories in orbitofrontal cortex, and impeded within-category generalization in hippocampus. Our findings suggest that odor categorization is a dynamic process concurrently engaging stimulus discrimination and generalization at different stages of olfactory information processing, and highlight the importance of associative networks in maintaining categorical boundaries.

scholarly journals ABCA7—A Member of the ABC Transporter Family in Healthy and Ailing Brain

2020 ◽  
Vol 10 (2) ◽  
pp. 121
Author(s):  
Alexei A. Surguchev ◽  
Andrei Surguchov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Transporter Family ◽  
New Findings ◽  
A Cell ◽  
Underlying Mechanisms ◽  
Meta Analyses

Identification of genetic markers of a human disease, which is generally sporadic, may become an essential tool for the investigation of its molecular mechanisms. The role of ABCA7 in Alzheimer’s disease (AD) was discovered less than ten years ago when meta-analyses provided evidence that rs3764650 is a new AD susceptibility locus. Recent research advances in this locus and new evidence regarding ABCA7 contribution to the AD pathogenesis brought a new understanding of the underlying mechanisms of this disorder. An interesting, up-to-date review article "ABCA7 and Pathogenic Pathways of Alzheimer’s Disease" by Aikawa et al. (2018), outlines the ABCA7 role in AD and summarizes new findings in this exciting area. ABC transporters or ATP-binding cassette transporters are a superfamily of proteins belonging to a cell transport system. Currently, members of the family are the focus of attention because of their central role in drug pharmacokinetics. Two recent findings are the reason why much attention is drawn to the ABCA7 family. First, is the biochemical data showing a role of ABCA7 in amyloid pathology. Second, genetic data identifying ABCA7 gene variants as loci responsible for the late-onset AD. These results point to the ABCA7 as a significant new contributor to the pathogenesis of AD.

scholarly journals Reduction of WDR81 impairs autophagic clearance of aggregated proteins and cell viability in neurodegenerative phenotypes

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009415
Author(s):  
Xuezhao Liu ◽  
Limin Yin ◽  
Tianyou Li ◽  
Lingxi Lin ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Cell Viability ◽  
Protein Quality ◽  
Protein Aggregates ◽  
Neuron Loss ◽  
Pathological Conditions ◽  
Evolutionarily Conserved ◽  
Underlying Mechanisms ◽  
Autophagic Proteins ◽  
Wd40 Repeats

Neurodegenerative diseases are characterized by neuron loss and accumulation of undegraded protein aggregates. These phenotypes are partially due to defective protein degradation in neuronal cells. Autophagic clearance of aggregated proteins is critical to protein quality control, but the underlying mechanisms are still poorly understood. Here we report the essential role of WDR81 in autophagic clearance of protein aggregates in models of Huntington’s disease (HD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In hippocampus and cortex of patients with HD, PD and AD, protein level of endogenous WDR81 is decreased but autophagic receptor p62 accumulates significantly. WDR81 facilitates the recruitment of autophagic proteins onto Htt polyQ aggregates and promotes autophagic clearance of Htt polyQ subsequently. The BEACH and MFS domains of WDR81 are sufficient for its recruitment onto Htt polyQ aggregates, and its WD40 repeats are essential for WDR81 interaction with covalent bound ATG5-ATG12. Reduction of WDR81 impairs the viability of mouse primary neurons, while overexpression of WDR81 restores the viability of fibroblasts from HD patients. Notably, in Caenorhabditis elegans, deletion of the WDR81 homolog (SORF-2) causes accumulation of p62 bodies and exacerbates neuron loss induced by overexpressed α-synuclein. As expected, overexpression of SORF-2 or human WDR81 restores neuron viability in worms. These results demonstrate that WDR81 has crucial evolutionarily conserved roles in autophagic clearance of protein aggregates and maintenance of cell viability under pathological conditions, and its reduction provides mechanistic insights into the pathogenesis of HD, PD, AD and brain disorders related to WDR81 mutations.

Response Interference as a Mechanism Underlying Implicit Measures

2008 ◽  
Vol 24 (4) ◽  
pp. 218-225 ◽  
Author(s):  
Bertram Gawronski ◽  
Roland Deutsch ◽  
Etienne P. LeBel ◽  
Kurt R. Peters
Keyword(s):  
Task Performance ◽  
Psychological Research ◽  
Implicit Measures ◽  
Mediation Model ◽  
Response Interference ◽  
Relevant Evidence ◽  
Moderated Mediation Model ◽  
Stimulus Features ◽  
Underlying Mechanisms

Over the last decade, implicit measures of mental associations (e.g., Implicit Association Test, sequential priming) have become increasingly popular in many areas of psychological research. Even though successful applications provide preliminary support for the validity of these measures, their underlying mechanisms are still controversial. The present article addresses the role of a particular mechanism that is hypothesized to mediate the influence of activated associations on task performance in many implicit measures: response interference (RI). Based on a review of relevant evidence, we argue that RI effects in implicit measures depend on participants’ attention to association-relevant stimulus features, which in turn can influence the reliability and the construct validity of these measures. Drawing on a moderated-mediation model (MMM) of task performance in RI paradigms, we provide several suggestions on how to address these problems in research using implicit measures.

The More You Say, the Less They Hear

2015 ◽  
Vol 27 (4) ◽  
pp. 159-169 ◽  
Author(s):  
Elsbeth D. Asbeek Brusse ◽  
Marieke L. Fransen ◽  
Edith G. Smit
Keyword(s):  
Hearing Protection ◽  
Entertainment Education ◽  
Mediating Role ◽  
Attitude Measures ◽  
Underlying Mechanisms

Abstract. This study examined the effects of disclosure messages in entertainment-education (E-E) on attitudes toward hearing protection and attitude toward the source. In addition, the (mediating) role of the underlying mechanisms (i.e., transportation, identification, and counterarguing) was studied. In an experiment (N = 336), three different disclosure messages were compared with a no-disclosure condition. The results show that more explicit disclosure messages negatively affect transportation and identification and stimulate the generation of counterarguments. In addition, the more explicit disclosure messages affect both attitude measures via two of these processes (i.e., transportation and counterarguing). Less explicit disclosure messages do not have this effect. Implications of the findings are discussed.

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