File Name: stress cognitive impairment and cell adhesion molecules file.zip
- Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline
- Cell Adhesion Molecules and Protein Synthesis Regulation in Neurons
- Th17 and Cognitive Impairment: Possible Mechanisms of Action
Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline
Evidence suggests that the neural cell adhesion molecule NCAM is an important molecular constituent of adaptive and maladaptive circuit re- organization in the central nervous system. Here, we further investigate its putative involvement in amygdala and hippocampus functions during context fear memory formation.
Using laser capture microdissection and quantitative RT—PCR, we show high NCAM mRNA expression levels in the lateral and basolateral subnuclei of the amygdala, as well as their training intensity- and context-dependent regulation during fear memory consolidation. Together, these results suggest an involvement of NCAM-mediated cell recognition processes in information processing of the amygdalo-hippocampal system and in the amygdala-mediated modulation of context fear memory according to stimulus salience.
Appropriate determination of stimulus salience during memory formation is critical for an individual's adaptive responding to the environment, and disturbances of this function are evident in psychopathological states such as mood and anxiety disorders.
Yet the cellular and molecular mechanisms that underlie salience determination remain elusive. NCAM is a glycoprotein of the immunoglobulin superfamily, which mediates homophilic and heterophilic cell—cell and cell—matrix interactions in the developing and adult CNS.
Gene expression analysis, genetic ablation and acute intervention studies using antibodies, peptide fragments or the enzyme endoneuroaminidase N have firmly established the importance of NCAM and the NCAM-associated polysialic acid PSA for hippocampal plasticity and hippocampus-dependent learning tasks Sandi, Further evidence suggests an involvement of NCAM in emotional processes such as impulsive aggression, anxiety and stress responding Stork et al.
In addition to the hippocampus those changes involve brain areas such as the amygdala, which is critical for the modulation of emotional state and emotional memory formation Markram et al.
The aim of this study was to further define the putative role of the amygdala in NCAM-mediated and hippocampus-dependent memory formation. Subsequent exposure to the CS or training context will elicit defensive reactions such as, in rodents, freezing and risk-assessment behaviours, which are displayed in accordance with stimulus salience and stress intensity experienced during training Blanchard et al.
Involvement of hippocampal function occurs whenever a more complex level of information analysis e. Such reciprocal information flow between amygdala and hippocampus becomes evident in vivo in changes of network activity such as increased theta frequency synchronization during fear memory consolidation Narayanan et al.
In this study we first utilized laser capture microdissection and quantitative polymerase chain reaction qPCR to locate fear conditioning-induced NCAM expression changes in subregions of the mouse amygdala and hippocampus.
Considering the dual role of the BLA as entry site for context information to the amygdala and as a modulator of hippocampal function, we systematically varied context salience through contextual pre-exposure, different training intensities, and the use of background and foreground contextual fear-learning tasks, i.
Our data provide additional evidence for a salience-dependent role of NCAM in hippocampus-dependent memory formation and demonstrate the critical importance of the amygdala therein. All studies were conducted in accordance with the European and German regulations for animal experiments and were approved by the Landesverwaltungsamt Sachsonia-Anhalt AZ and Animals were randomly assigned to one of four training groups naive control, cued standard conditioning, cued overtraining and contextual standard conditioning.
Naive control, cued standard conditioning and cued overtraining groups were pre-exposed to the conditioning apparatus over 2 d with two daily sessions of 5 min each.
The presentation of a neutral test stimulus during these pre-exposures as done in the differential mutant conditioning paradigms, see below was omitted for the sake of best possible distinction between cue and context effects. The contextual standard training group was exposed to a novel standard cage serving as neutral context. S1 a , available online. Six hours after training, animals were killed by cervical dislocation.
Pre-experiments confirmed that Pgk expression was independent of treatment groups and referred only to the starting amount of DNA in each sample. Mice were separated 1 wk before the experiments and housed individually throughout the behavioural assessment. Training and testing of animals were always done during the dark cycle between and hours. Therein, stimulus salience was systematically varied through different conditioning paradigms.
Additional naive and unpaired control groups were analysed to test for the specificity of conditioned fear behaviour. In the second step we employed a contextual pre-exposure protocol to minimize differences in the novelty-induced salience modulation of context fear memory Huff et al. To address salience modulation in these groups, mice were also trained with increased stimulus intensity Laxmi et al. Finally, the effect of NCAM mutation on foreground context conditioning was investigated with different training intensities.
Supplementary Fig. S1 b online provides a graphical overview and a detailed description of the different training protocols engaged. Fear memory was tested in a single 6-min retrieval session, 24 h after training. For the analysis of foreground context memory, conditioned animals were re-exposed for 2 min to the training context without subsequent cue presentation.
Planned comparisons were conducted to specify genotype effects as well as different training effects within either genotype. Reference and ground electrodes were implanted close to midline over the nasal and cerebellar region, respectively.
The electrode ensemble was fed through a rubber socket and fixed to the skull with dental cement. Animals were allowed to recover for 3—4 d before behavioural experiments commenced.
On retrieval day, a plug was connected to the implanted socket under a low dose of an inhalable anaesthetic Isofluran, Baxter, Germany. Using a swivel commutator, field potentials of the amygdala and hippocampus were recorded in the freely behaving animal undergoing a standard retrieval session. Amplified signals, band-pass filtered between 0. Phase shifts in cross-correlograms were calculated with respect to the deviation of the first peak from zero.
Freezing behaviour and peak synchronization levels were compared between genotypes with Student's t test. Values are indicated as dCT [difference of cycle times, compared to the housekeeping gene phosphoglycerate kinase Pgk ], with more negative values indicating higher NCAM expression. Values given are dCT. The values listed below the graphs show the relative expression towards Pgk RQ , relative expression compared to the naive controls is given in Table 1.
Subsequently, training effects were investigated. The cued standard conditioning group displayed intermediate levels in the BLA with 0. Relative expression compared to the naive control group demonstrates the increase in NCAM mRNA expression in the LA after contextual standard conditioning and the decrease in the BLA after both contextual standard conditioning and cued overtraining.
No significant expression changes could be detected in any of the other areas. In agreement with our previous observations Laxmi et al. In contrast, risk assessment behaviour was predominant during retrieval of background context fear memory i. Using these parameters, we were able to show that NCAM-deficient mice displayed deficits in both foreground and background context memory under conditions of increased context salience.
Being almost undetectable i. In fact, freezing behaviour was increased in both, paired 7. While deficits were apparent in contextual freezing, no difference between genotypes was observed in risk assessment behaviour.
Even after overtraining, levels of contextual freezing were generally low. Unpaired standard training elicited high background context freezing in mice of both genotypes. Accordingly, the previously described increase in background context fear behaviour due to overtraining Laxmi et al. At the same time risk assessment was not significantly affected by genotype or training intensity Fig.
In order to control for the specificity of contextual learning deficits in NCAM mutant mice, we further tested stimulus-specific auditory-cued fear memory. As cues were presented in the fear memory context, we dissected cue-specific responses by subtracting the animals' background context freezing and risk assessment values. S2 a, c for details. Cue-specific freezing and risk assessment values were normalized to context-specific freezing a, b and risk assessment c, d components, in an attempt to reflect that all tests were performed in the training context.
S2 b, d for details. In both genotypes, we observed a correlation of network activities at the theta frequency range during fear memory retrieval peak correlation between 5. NCAM is thought to play a key role in adaptive and maladaptive cellular changes in the CNS that underlie memory formation, stress response and changes in emotional state Sandi, In this study we provide evidence for an involvement of NCAM in amygdalo-hippocampal interactions during consolidation of fear memory by demonstrating 1 expression changes of NCAM mRNA in the amygdala of fear-conditioned mice, 2 disturbance of amygdala-mediated modulation of hippocampus-dependent fear memory and 3 reduced amygdalo-hippocampal theta synchronization during fear memory retrieval of NCAM null mutant mice.
Our data suggest that NCAM-mediated processes in the amygdala are involved in the determination or coding of salience information during contextual fear memory formation. Memory-related changes in NCAM expression have been shown to be time-, stress- and region-dependent Sandi, ; Sandi et al.
While several previous studies focused on hippocampal NCAM expression changes at the protein level Lopez-Fernandez et al. This time-point of fear memory consolidation is characterized by a strong induction of mRNA expression Bergado-Acosta et al.
A prominent reduction of NCAM mRNA expression was evident in the BLA after foreground contextual conditioning and after cued overtraining, known to produce generalization of fear memory to the contextual background Laxmi et al. Previously, an increased expression of the polysialylated form of NCAM has been observed in the BLA following intensive auditory-cued fear conditioning Markram et al.
As both reduced expression of the core protein and increased polysialylation may reduce NCAM-mediated adhesion, these effects might serve similar cellular functions.
However, acute pre- and post-training removal of PSA and genetically induced deficiency in polysialylation in ST8SiaIV mutant mice both failed to disturb auditory-cued fear conditioning Markram et al.
On the other hand, both NCAM null mutant mice and mice that overexpress a soluble extracellular fragment of the NCAM molecule display deficits in fear memory to a cue and context Pillai-Nair et al. These findings suggest that NCAM function in the amygdala may be strongly determined by changes in its core protein expression. Here, we focused on the most robust changes in NCAM gene expression. However, it can be expected that increased sample size, microdissection of smaller subregions and additional time-points will help to reveal more subtle changes and to more precisely dissect pathways that undergo NCAM-dependent changes in fear memory formation.
We applied foreground and background context conditioning to address the putative activation of different pathways in the amygdalo-hippocampal system. This differential involvement of amygdala and hippocampus subregions is reflected in region-specific activation patterns of the protein kinase ERK following fear conditioning Trifilieff et al.
Our current data do not show any significant change of NCAM expression in dorsal hippocampal subregions after either foreground context conditioning or background context conditioning of different intensities. The BLA, in contrast, which is critical for both forms of contextual learning Calandreau et al. Based on these expression data, we hypothesized a role of NCAM-mediated cell recognition in the mediation and salience-dependent modulation of hippocampus-dependent background and foreground context fear memory through the BLA.
Huff et al. To analyse their behaviour at a consolidated stage — hence the presumed outcome of altered NCAM function — fear memory retrieval was tested 24 h after training. S2 but did not interfere with cued or contextual fear memory, hence excluding an involvement of latent inhibition Laxmi et al. As pre-exposure is not related to painful events, a context-specific memory deficit rather than potential differences in pain threshold detection in the mutants should be held accountable for the observed behavioural differences.
Facilitation of cue and context memory has been observed with stress pre-treatment and post-training corticosterone administration Cordero et al. Following this line of evidence we further investigated the effect of increased amygdala involvement during salient overtraining on NCAM mutant mice. Risk assessment and freezing are forms of defensive behaviour displayed by mice according to the intensity and proximity of a given threat Blanchard et al.
Thus, our observations strongly support the idea that the NCAM null mutation evokes deficits in the salience-dependent modulation of context fear memory through the amygdala. We cannot rule out that disturbed fasciculation of the mossy fibre tract and laminar growth of CA3 in NCAM-deficient mice Cremer et al. However, this structural abnormality cannot explain the salience dependence of the observed NCAM mutant deficits in context fear memory, nor their deficits in cued fear memory when lacking contextual pre-exposure.
We therefore investigated potential changes in neural activity patterns in the amygdalo-hippocampal pathway of fear-conditioned NCAM mutant mice. We previously observed synchronization of theta activity between amygdala and hippocampus during fear memory retrieval, probably reflecting a memory-specific recruitment of ensemble activity and information processing in the amygdalo-hippocampal system Narayanan et al.
Cell Adhesion Molecules and Protein Synthesis Regulation in Neurons
Evidence suggests that the neural cell adhesion molecule NCAM is an important molecular constituent of adaptive and maladaptive circuit re- organization in the central nervous system. Here, we further investigate its putative involvement in amygdala and hippocampus functions during context fear memory formation. Using laser capture microdissection and quantitative RT—PCR, we show high NCAM mRNA expression levels in the lateral and basolateral subnuclei of the amygdala, as well as their training intensity- and context-dependent regulation during fear memory consolidation. Together, these results suggest an involvement of NCAM-mediated cell recognition processes in information processing of the amygdalo-hippocampal system and in the amygdala-mediated modulation of context fear memory according to stimulus salience. Appropriate determination of stimulus salience during memory formation is critical for an individual's adaptive responding to the environment, and disturbances of this function are evident in psychopathological states such as mood and anxiety disorders.
Disclosures: Dr. Yang reported a patent to US Provisional Application no. No other disclosures were reported. Robison, Xiuli Zhao, Shanti S. Kuentzel, Sridar V.
Cell adhesion molecules have been shown to regulate synaptic function in the the behavioural disorders resulting from stress, deficits in learning and memory.
Th17 and Cognitive Impairment: Possible Mechanisms of Action
Cell adhesion molecules CAMs mediate interactions of neurons with the extracellular environment by forming adhesive bonds with CAMs on adjacent membranes or via binding to proteins of the extracellular matrix. Binding of CAMs to their extracellular ligands results in the activation of intracellular signaling cascades, leading to changes in neuronal structure and the molecular composition and function of neuronal contacts. Ultimately, many of these changes depend on the synthesis of new proteins.
Higher circulating concentrations of cellular adhesion molecules CAMs can be used as markers of endothelial dysfunction.
Address correspondence to Achille E. E-mail: achille. Achille E. Tchalla, Gregory A. Wellenius, Farzaneh A. Travison, Thierry Dantoine, Lewis A. Elevated plasma soluble vascular cell adhesion molecule-1 sVCAM-1 is a presumed marker of endothelial dysfunction, both in the brain and systemic circulation.
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Additionally, all animals were tested on 10 measures of sensory/motor function, emotionality and stress reactivity. We report that the Nr-CAM.
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