Az agy öregedése és a neurodegeneráció: A neuroendokrin szabályozás szerepe = The role of neuroendocrine regulation in brain aging and neurodegeneration

A kutatás célja a hypophysis-mellékvesekéreg (HPA) hormonok és az ösztrogének szerepének vizsgálata volt az agy öregedésére és a neurodegenerációra patkányokban. Vizsgálták az öregkorban adott kortikoszteron (CORT) hatását a szerotoninerg és a kolinerg rostok degenerációjára az öregedés alatt. Vizsgálták továbbá az újszülöttkorban adott ACTH 4-9 analóg peptid hatását a HPA rendszer működésére és az adaptációs magatartásra felnőtt- és öregkorban. Tanulmányozták az agy öregedésével együtt járó szerotoninerg neurodegenerációt félmajmokon (Tupaia belangeri). Az öregkori CORT túladagolás krónikus körülmények között fokozta a szerotoninerg idegrostok degenerációját és csökkentette a tanulási teljesítményt. Immuncitokémiai módszerrel részletes leírást adtak az alfa és a béta típusú ösztrogén receptorok jellegzetességeiről öreg nőstény patkányok hippocampusában. Kimutatták, hogy az újszülöttkori ACTH peptid kezelés mellett az öregkorra jellemző napi kortikoszteron szint-ingadozás beszűkülése jelentős mértékben elmarad. Közölték, hogy az öregedés során a szerotoninerg rostok sűrűsége a hippocampus egyes régióiban szignifikánsan csökken félmajmokon. Végül jelentős előrelépés történt az in vivo állatkísérletes demencia modellek kidolgozásában patkányokon. Az eredmények azt mutatják, hogy az öregedés alatt jelentkező HPA és gonád hormon változások szerepet játszhatnak az öregedésre jellemző neuronális involúcióban és különösen a neurodegeneráció mechanizmusában. | The role of pituitary-adrenocortical hormones (HPA hormones) and that of estrogens on brain aging and neurodegeneration has been studied in rats. During aging the spontaneous degeneration of serotonergic and cholinergic fibers were studied after prolonged corticosterone (CORT) exposure. The immediate and long-term effects of neonatal administration of ACTH4-9 peptide analogue were investigated on the development and age-related functioning of HPA axis and adaptive behaviour. Furthermore, the age-dependent degeneration of serotonergic fibers was also followed in the hippocampus of tree shrews (Tupaia belangeri). Chronic CORT exposure in aged rats resulted in enhanced serotonergic fiber degeneration and inhibited learning performance. A detailed description of qualitative and quantitative aspects of alpha and beta estrogen receptors has been provided in the hippocampus of aging female rats. Neonatal treatment with ACTH4-9 peptide analogue prevented the age-specific attenuation of amplitude of diurnal CORT rhythm in the circulation. Aging has been coupled with a decrement of serotonergic fiber density in some subregions of hippocampus in old tree shrews. A considerable progress has also been achieved in the improvement of in vivo animal models studying brain neurodegeneration. The results show that the disturbed HPA and gonadal functions during aging might be contributing factors to neuronal decline in the advanced age and especially during neurodegeneration

Object-Place Recognition Learning Triggers Rapid Induction of Plasticity-Related Immediate Early Genes and Synaptic Proteins in the Rat Dentate Gyrus

Long-term recognition memory requires protein synthesis, but little is known about the coordinate regulation of specific genes. Here, we examined expression of the plasticity-associated immediate early genes (Arc, Zif268, and Narp) in the dentate gyrus following long-term object-place recognition learning in rats. RT-PCR analysis from dentate gyrus tissue collected shortly after training did not reveal learning-specific changes in Arc mRNA expression. In situ hybridization and immunohistochemistry were therefore used to assess possible sparse effects on gene expression. Learning about objects increased the density of granule cells expressing Arc, and to a lesser extent Narp, specifically in the dorsal blade of the dentate gyrus, while Zif268 expression was elevated across both blades. Thus, object-place recognition triggers rapid, blade-specific upregulation of plasticity-associated immediate early genes. Furthermore, Western blot analysis of dentate gyrus homogenates demonstrated concomitant upregulation of three postsynaptic density proteins (Arc, PSD-95, and α-CaMKII) with key roles in long-term synaptic plasticity and long-term memory

Dihydropyridine derivatives modulate heat shock responses and have a neuroprotective effect in a transgenic mouse model of Alzheimer’s disease

Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells and by maintaining proteins in an active state. Alzheimer’s disease (AD) is thought to be caused by β- amyloid peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD

Stress néonatal et régulation à long terme de la prise alimentaire chez le rat : explorations neuroendocriniennes, morphofonctionnelles et comportementales

The aim of this work was to study immediate and persistent effects of a neonatal stress (maternal deprivation) on the hypothalamo-pituitary-adrenal (HPA) axis and on the food intake in the rat. Experimental rat pups were placed in an incubator either on the 5th or the 14th postnatal day (DEP5 or DEP14 treatment); control rats were not separated from the mother. Maternal deprivation induced no HPA response on the 5th postnatal day, but it activated the HPA axis on the 14th postnatal day. In adults, a diminution of the corticosterone feedback appeared in DEP5 rats in a stressful situation, whereas a transitory increase of the ACTH response was observed in DEP14 rats. We show for the first time that the perturbation of neonatal maturation modifies persistently feeding behaviour, and this modification depends on the age at which deprivation is experienced. Both DEP groups had a diminished basal food intake and an increased anorexic response to dexnorfenfluramine. DEP5 rats had also a decreased preference for carbohydrates, an increased hedonic response, and a decreased anorexic response to dexfenfluramine. The anorexic response of DEP14 rats to restraint stress was increased. Our results, showing a connection between maternal deprivation and disturbed feeding behaviour as well as anxiety, support the hypothesis according to which early stress increases vulnerability to many psychiatric diseases, such as anorexia nervosa and depression. In the future, maternal deprivation can become a useful model for the research into human eating disorders.Le but de ce travail était d'étudier les effets immédiats et persistants d'un stress néonatal (séparation maternelle) sur l'axe corticotrope et la prise alimentaire chez le rat. Les ratons expérimentaux sont placés 24 heures dans une couveuse, le JPN 5 (rats SEP5), ou le JPN 14 (rats SEP14), les ratons témoins ne sont pas séparés de la mère. La séparation maternelle n'induit aucune réaction corticotrope le JPN 5, mais elle active cet axe le JPN 14. A l'âge adulte, une diminution du rétrocontrôle par la corticostérone apparaît chez les rats SEP5 en situation de stress, alors qu'une augmentation transitoire de la réponse ACTH est observée chez les rats SEP14. Nous montrons pour la première fois que la perturbation de la maturation néonatale modifie de façon persistante le comportement alimentaire, et ce de façon dépendant de l'âge où elle est subie. Les deux groupes SEP ont une prise alimentaire basale diminuée et une réponse anorexique à la dexnorfenfluramine augmentée. Les rats SEP5 ont aussi une préférence diminuée pour les glucides, une réponse hédonique accrue et une réponse anorexique diminuée à la dexfenfluramine. Les rats SEP14 répondent plus fortement au stimulus de contention. Nos résultats, qui établissent une connexion entre la séparation maternelle et la perturbation du comportement alimentaire et de l'anxiété, supportent l'hypothèse que le stress précoce augmente la vulnérabilité à plusieurs maladies psychiques, comme l'anorexie mentale et la dépression. Dans l'avenir, la séparation maternelle peut devenir un modèle utile des troubles du comportement alimentaire humain

Stress néonatal et régulation à long terme de la prise alimentaire chez le rat (explorations neuroendocriniennes, morphofonctionnelles et comportementales)

Le but de ce travail était d'étudier les effets immédiats et persistants d'un stress néonatal (séparation maternelle) sur l'axe corticotrope et la prise alimentaire chez le rat. Les ratons expérimentaux sont placés 24 heures dans une couveuse, le JPN 5 (rats SEP5), ou le JPN 14 (rats SEP14), les ratons témoins ne sont pas séparés de la mère. La séparation maternelle n'induit aucune réaction corticotrope le JPN 5, mais elle active cet axe le JPN 14. A l'âge adulte, une diminution du rétrocontrôle par la corticostérone apparaît chez les rats SEP5 en situation de stress, alors qu'une augmentation transitoire de la réponse ACTH est observée chez les rats SEP14. Nous montrons pour la première fois que la perturbation de la maturation néonatale modifie de façon persistante le comportement alimentaire, et ce de façon dépendant de l'âge où elle est subie. Les deux groupes SEP ont une prise alimentaire basale diminuée et une réponse anorexique à la dexnorfenfluramine augmentée. Les rats SEP5 ont aussi une préférence diminuée pour les glucides, une réponse hédonique accrue et une réponse anorexique diminuée à la dexfenfluramine. Les rats SEP14 répondent plus fortement au stimulus de contention. Nos résultats, qui établissent une connexion entre la séparation maternelle et la perturbation du comportement alimentaire et de l'anxiété, supportent l'hypothèse que le stress précoce augmente la vulnérabilité à plusieurs maladies psychiques, comme l'anorexie mentale et la dépression. Dans l'avenir, la séparation maternelle peut devenir un modèle utile des troubles du comportement alimentaire humain.The aim of this work was to study immediate and persistent effects of a neonatal stress (maternal deprivation) on the hypothalamo-pituitary-adrenal (HPA) axis and on the food intake in the rat. Experimental rat pups were placed in an incubator either on the 5th or the 14th postnatal day (DEP5 or DEP14 treatment); control rats were not separated from the mother. Maternal deprivation induced no HPA response on the 5th postnatal day, but it activated the HPA axis on the 14th postnatal day. In adults, a diminution of the corticosterone feedback appeared in DEP5 rats in a stressful situation, whereas a transitory increase of the ACTH response was observed in DEP14 rats. We show for the first time that the perturbation of neonatal maturation modifies persistently feeding behaviour, and this modification depends on the age at which deprivation is experienced. Both DEP groups had a diminished basal food intake and an increased anorexic response to dexnorfenfluramine. DEP5 rats had also a decreased preference for carbohydrates, an increased hedonic response, and a decreased anorexic response to dexfenfluramine. The anorexic response of DEP14 rats to restraint stress was increased. Our results, showing a connection between maternal deprivation and disturbed feeding behaviour as well as anxiety, support the hypothesis according to which early stress increases vulnerability to many psychiatric diseases, such as anorexia nervosa and depression. In the future, maternal deprivation can become a useful model for the research into human eating disorders.NANCY1-SCD Sciences & Techniques (545782101) / SudocSudocFranceF

Affiliation between aggressors and third parties following conflicts in long-tailed macaques (Macaca, fascicularis)

Studies on cercopithecine monkeys have shown that soon after an agonistic conflict, victims have increased rates of affiliation with the agressor - reconciliation - but not with other group members. Postconflict affiliation is thought to function to restore disturbed relationships and to reduce social tension. This study on a captive group of long-tailed macaques (Macaca fascicularis,) is focused on postconflict affiliative behavior of the aggressor. Increased rates of contact between female aggressors and kin of the victim occurred, as well as between female aggressors and their own kin. Furthermore, there were increased rates of contact between aggressors-males and females - and other group members. The increase in contacts with the victim's kin was selective, i.e., it could not be ascribed to the increased contact tendency with group members in general, and was not a side effect of the aggressor's proximity to the victim due to reconciliation. The increase in contacts with own kin was not selective. The fact that male aggressors do not have increased postconflict contacts with their kin or with kin of the victim is in agreement with the notion that males are less integrated in the nepotistic matrilineal network than females are. The fact that studies by others that focused on the victim evidence no increase in postconflict contacts with kin of the opponent or with other group members may be explained by the aggressor's larger influence over the postconflict situation: to reduce social tension, it might be more effective to affiliate with the aggressor than with the victim. Our findings emphasize that conflicts influence the behavior of other monkeys besides the direct contestants and, thus, indicate that the disturbance of social homeostasis is a matter of concern for all group members

Postconflict affiliation and stress-related behavior of long-tailed macaque aggressors

Previous studies on macaques and baboons showed that after agonistic conflicts aggressees as well as aggressors show an increase in stress-related behavior such as scratching. Reconciliation reduces stress-related behavior of the aggressee. We investigated the influence of various affiliative postconflict behaviors of the aggressor on the aggressor's scratching rates in captive long-tailed macaques: reconciliation, contacts with the aggressee's kin (or substitute reconciliation), and contact with other group members (or triadic affiliation). After a conflict, the aggressor showed an increase in rates of scratching. Scratching rates were reduced after reconciled conflicts compared to nonreconciled conflicts. Substitute reconciliation did not reduce scratching when we controlled for the influence of reconciliation, i.e., the aggressor might not interpret it as a substitute for reconciliation. Triadic affiliation did not reduce scratching rates, hence, triadic affiliation probably does not console the aggressor. Scratching rates after reconciliation are significantly lower than scratching rates after triadic affiliation. This proves that the stress-reducing effect of reconciliation is not due to the calming effect of general body contact but that the stress reduction is specifically associated with contacts with the former opponent. The contestants are anxious about their relationship, and only reconciliation takes away this anxiety. Reconciliation is thus an important social repair strategy

Comparative study on the effects of kynurenic acid and glucosamine–kynurenic acid

Kynurenic acid (KYNA) is the only known endogenous N-methyl-d-aspartate (NMDA) receptor inhibitor and might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, its use as a neuroprotective compound is practically excluded because KYNA does not readily cross the blood-brain barrier (BBB). We recently synthetized a new compound, glucosamine–kynurenic acid (KYNA-NH-GLUC), which is presumed to cross the BBB more easily. In this study, the effects of KYNA and KYNA-NH-GLUC on behavior and cortical activity were investigated in adult rats. The results show that (1) on intracerebroventricular application, the behavioral changes induced by KYNA and by KYNA-NH-GLUC are quite similar; (2) on intravenous administration, KYNA (25 mg/kg) has no effect on the somatosensory-evoked cortical potentials, whereas KYNA-NH-GLUC (25 mg/kg) causes transient but appreciable reductions in the amplitudes of the evoked responses within 5 min after application; and (3) the results of in vitro studies demonstrated that both KYNA and KYNA-NH-GLUC reduced the amplitudes of the field excitatory postsynaptic potentials (fEPSPs). These observations suggest that the two compounds have similar effects, but that KYNA-NH-GLUC passes the BBB much more readily than does KYNA. These results imply that the conjugated NH-GLUC is of importance in the passage across the BBB

Behaviour changes in a transgenic model of Huntington's disease. Behav.

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