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

A tápanyagfelvétel és az energia-háztartás neuroendokrin szabályozása = Neuroendocrine regulation of nutrition and energy homeostasis

Az elhízás epidemiológiai súlya egyre nyomasztóbb a társadalomban. Eredmények: 1) Vizsgálták az obezitogén és antiobezitogén környezeti hatásokat a magzati egyedfejlődés során. A többszörösen telítetlen zsírsavak (PUFA-k) metabolikus programozó hatását igazolták. Döntően az n-3 PUFA hiány a fejlődés során olyan kórélettani hatásokat produkált, ami a gyermekkori elhízás modelljének is megfelel: inzulin rezisztencia, csökkent glukóz tolerancia, csökkent leptin érzékenység, fokozott zsírlerakódás. A PUFA többlet, ezzel ellentétesen, csökkentette a vér inzulin és leptin szinteket, csökkent a vér triglicerid és nőtt a HDL koleszterin mennyiség, javult a glukóz tolerancia. Néhány metabolikus hatás és a javuló kognitív teljesítmény még öregkorban is kimutatható volt. 2) A táplálék felvétel és az energia háztartás hypothalamikus szabályozásának vizsgálata során kimutatták, hogy kolinerg neuronok találhatók a n. arcuatusban, melyek orexigén támogató hatásukat az M3-as receptoron fejtik ki. M3 receptor antagonistával a neurogén elhízás kivéghető. Továbbá valószínű, hogy a hypothalamikus kolinerg rendszer szerepet játszik a vízfelvétel szabályozásában is. 3) Magatartási szelekcióval előidézett, epigenetikailag rögzült fokozott fizikai aktivitás egerekben olyan anyagcsere változásokat hozott létre, melyek megakadályozták a zsírdús diéta által kiváltott elhízást. Konklúzió: az elhízás prevenciója mind genetikai, mind környezeti hatások szempontjából megvalósíthatónak számít. | The epidemiologic burden of obesity extensively risks the health of society. Aims and results: 1) The obesitogenic and antiobesitogenic environmental factors during fetal development were investigated. The programming action of poly-unsaturated fatty acids (PUFAs) has been proven. PUFA deficient diet produced symptoms characteristic to childhood obesity: insulin resistance, decreased glucose tolerance, decreased leptin sensitivity, increase fat deposition. Contrary, PUFA supplementation decreased blood insulin, leptin and triglycerides levels, increased HDL cholesterol and glucose tolerance. Some metabolic effects and the improved cognitive performance lasted up to old ages. 2) Interaction between peptidergic and classical (cholinerg) neurotransmitter systems was also studied in the regulation of food intake and energy metabolism. Cholinerg neurons have been found in the n. arcuatus, which exert orexigen support on MCH neurons through M3 receptors and markedly influence water intake as well. M3 antagonist 4-DAMP prevented neurogen obesity induced by SHU9119. 3) Interaction between nutrition and physical activity studies showed that mice selected for high running wheel activity showed profound antiobesitogenic metabolic changes and consequent resistance against diet induced obesity. Summary: the results showed that obesity prevention can be supported by both genetic and environmental interventions in the course of development

Temporal and spatial dynamics of corticosteroid receptor down-regulation in rat brain following social defeat

The experiments explored the nature and time course of changes in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) binding in homogenates of various brain regions and pituitary of male Wistar rats following social defeat stress. One week after defeat, the binding capacity of GRs was decreased in the hippocampus and the hypothalamus while no changes were observed in the parietal cortex and the pituitary. The number of MRs remained at the same level as in undefeated rats. Three weeks postdefeat, the initially down-regulated GR returned to baseline level in the hippocampus and the hypothalamus. However, GR binding was now decreased in the parietal cortex. Severe down-regulation of MRs was detected in the hippocampal and septal tissue. The results show that brief but intense stress like social defeat induces a long-lasting down-regulation of corticosteroid receptors and that the temporal dynamics of these changes are not only differential for GRs and MRs but also for brain sites.

Eating habits modulate short term memory and epigenetical regulation of brain derived neurotrophic factor in hippocampus of low- and high running capacity rats

Exercise capacity and dietary restriction (DR) are linked to improved quality of life, including enhanced brain function and neuro-protection. Brain derived neurotrophic factor (BDNF) is one of the key proteins involved in the beneficial effects of exercise on brain. Low capacity runner (LCR) and high capacity runner (HCR) rats were subjected to DR in order to investigate the regulation of BDNF. HCR-DR rats out-performed other groups in a passive avoidance test. BDNF content increased significantly in the hippocampus of HCR-DR groups compared to control groups (p<0.05). The acetylation of H3 increased significantly only in the LCR-DR group. However, chip-assay revealed that the specific binding between acetylated histone H3 and BNDF promoter was increased in both LCR-DR and HCR-DR groups. In spite of these increases in binding, at the transcriptional level only, the LCR-DR group showed an increase in BDNF mRNA content. Additionally, DR also induced the activity of cAMP response element-binding protein (CREB), while the content of SIRT1 was not altered. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was elevated in HCR-DR groups. But, based on the levels of nuclear respiratory factor-1 and cytocrome c oxidase, it appears that DR did not cause mitochondrial biogenesis. The data suggest that DR-mediated induction of BDNF levels includes chromatin remodeling. Moreover, DR does not induce mitochondrial biogenesis in the hippocampus of LCR/HCR rats. DR results in different responses to a passive avoidance test, and BDNF regulation in LCR and HCR rats

Molekuláris mechanizmusok vizsgálata a vestibularis rendszer fejlődése, regenerációja és plaszticitása során = Investigation of molecular mechanisms in the development, regeneration and plasticity of vestibular system

Csirkeembriók gerincvelőjében és agytörzsében kimutattuk, hogy a neuronok körüli, extracellularis matrixban (ECM) gazdag perineuronalis háló (PNN) az embrionális életben megjelenik, míg az emlősökben csak postnatalisan alakul ki. Ez arra utal, hogy a fészekhagyó madaraknál a kikeléskor megfigyelhető, koordinált mozgás hátterében álló neuronhálózat már az embrionális korban stabilizálódik. Leírtuk az ECM molekulák heterogén megoszlását a PNN-ben a vestibularis magokban, a kisagyban és a szemmozgató agyidegi magokban. A molekuláris heterogenitás magyarázhatja a neuronok eltérő viselkedését a regenerációs és a plaszticitási folyamataiban. A PNN békában csak hyaluronsavat (HA) tartalmaz, míg patkányban chondroitin szulfát proteoglycant (CSPG) is, ami összefüggésben lehet az alacsonyabbrendű élőlények idegrendszerének jelentős regenerációs képességével. A n. VIII. átvágása után kimutattuk, hogy a béka vestibularis magjaiban a HA, patkányban pedig a HA és a CSPG változása időbeli egyezést mutat kompenzációs folyamatokkal. A vestibularis rendszerhez tartozó neuronhálózatokban kimutattuk a vestibularis afferensek monoszinaptikus kapcsolatait és a neuronhálózatokban résztvevő motoneuronok közötti dendrodendritikus és dendroszomatikus kontaktusokat. Ezek a kapcsolatok képezhetik a morfológiai alapját a vestibularis ingerlést követő válaszok gyors és pontos kivitelezésének. Kvantitatív analízissel a patkány nucleus cochlearis dorsalisában azonosítottuk az óriás és a piramis sejteket. | Distribution pattern of extracellular matrix (ECM) showed that the perineuronal net (PNN), condensation of ECM around the neurons, appears in the spinal cord and brainstem of chicken embryos, contrary to the mammalian species. This finding suggests the early stabilization of neuronal circuit underlying the posture and gaze in the precocial birds. The heterogeneous molecular composition of ECM in the PNN of the vestibular nuclei, cerebellum and eye moving motoneurons may be responsible for the different degree of plasticity and regeneration of various parts of the central nervous system (CNS). The hyaluronan-rich and chondroitin sulfat proteoglycan-free PNN of the frog may be associated with the regeneration and plasticity of the frog CNS. Unilateral lesion of eighth cranial nerve is accompanied by the modification of ECM expression in the vestibular nuclei complex of the frog and rat. It was shown that the vestibular fibers establish monosynaptic contacts with the motoneurons of vestibular neuronal circuit. The dendrodendritic and dendrosomatic contacts between the motoneurons of vestibular neuronal circuits did not show any morphological specialization; the long membrane appositions may provide electrotonic interactions and subserve the morphological substrates of co-activation, synchronization and timing of muscle contraction upon body displacement. Giant and pyramidal cells of the dorsal cochlear nucleus were identified by using quantitative analysis of neurons

Permanent upregulation of hippocampal mineralocorticoid receptors after neonatal administration of ACTH-(4–9) analog ORG 2766 in rats

The development of brain corticosteroid receptors may be permanently modified by perinatal hormone treatments, in particular by hormones of the hypothalamic-pituitary-adrenal axis. Changes in binding characteristics of corticosteroid receptors were investigated in rats treated subcutaneously with 1 µg/g body wt of the ACTH-(4–9) analog peptide ORG 2766 once daily at postnatal days 1, 3 and 5. [3H]Corticosterone (CORT) binding capacity (Bmax) and affinity (Kd) were determined at 1-, 2- and 3-weeks old and adult ages in the hippocampal cytosol by using saturation analysis. Mineralocorticoid type receptor (MR) and glucocorticoid receptor (GR) sites were measured separately with single-point analysis applying a selective glucocorticoid ligand RU 28362 saturating GR. An increase in [3H]CORT binding capacity was found during postnatal development which remained permanently high up to adult age. Separate analysis of MR and GR expression indicated that the increment in the number of corticoid receptor sites was due to an increase in number of MRs in both the young and adult rats. It was concluded that neonatal injections of ACTH-(4–9) peptide resulted in a permanent and selective upregulation of hippocampal MRs, which may underlie the previously observed increased vigilance and novelty-induced behavioral reactivity of the peptide-treated adult rats.

Beneficial effect of chronic nimodipine treatment on behavioral dysfunctions of aged rats exposed to perinatal ethanol treatment

The long-term effects of prenatal and early postnatal ethanol exposure were assessed in adult (5-month), aged (24-month), and senescent (30-month) rats on non-aggressive intermale social behavior, and on black-white discrimination and spatial learning behaviors. Furthermore, the effects of chronic application of the Ca2+ channel blocker nimodipine, which reportedly improves behavioral function in aging, were studied on the ethanol-induced behavioral deficits during aging. The results showed that the perinatal alcohol treatment suppressed social behavior by reducing the frequency and duration of social interactions at all ages. Black-white discrimination behavior and appetitively motivated learning in a hole-board were also markedly disturbed. Several measures of social and spatial learning behaviors of ethanol-exposed rats revealed progressive functional decline with aging. Chronic oral treatment with nimodipine improved the social activity and normalized the cognitive behavioral capabilities of aged and senescent rats exposed to ethanol. We concluded that: (1) the behavioral disabilities caused by perinatal ethanol toxicity are persistent in the rat lifespan and become more pronounced with aging; and (2) administration of nimodipine in the aging period improves, with a long-lasting efficacy, the ethanol-induced behavioral dysfunctions in aged rats.