Luciano Domenici

Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate

Resveratrol, a natural phytoalexin found in grapes and red wine, increases longevity in the short-lived invertebrates Caenorhabditis elegans and Drosophila and exerts a variety of biological effects in vertebrates, including protection from ischemia and neurotoxicity. Its effects on vertebrate lifespan were not yet known. The relatively long lifespan of mice, which live at least 2.5 years, is a hurdle for life-long pharmacological trials. Here, the authors used the short-lived seasonal fish Nothobranchius furzeri with a maximum recorded lifespan of 13 weeks in captivity. Short lifespan in this species is not the result of spontaneous or targeted genetic mutations, but a natural trait correlated with the necessity to breed in an ephemeral habitat and tied with accelerated development and expression of ageing biomarkers at a cellular level. Resveratrol was added to the food starting in early adulthood and caused a dose-dependent increase of median and maximum lifespan. In addition, resveratrol delays the age-dependent decay of locomotor activity and cognitive performances and reduces the expression of neurofibrillary degeneration in the brain. These results demonstrate that food supplementation with resveratrol prolongs lifespan and retards the expression of age-dependent traits in a short-lived vertebrate.

Functional postnatal development of the rat primary visual cortex and the role of visual experience: Dark rearing and monocular deprivation

Postnatal development of rat visual cortical functions was studied by recording extracellularly from the primary visual cortex of 22 animals ranging in age from postnatal day 17 (P17) to P45. We found that in the youngest animals (P17-P19) all visual cortical functions tested were immature. Selectivity for orientation and movement direction of visual stimuli was almost absent, most cells received binocular input and their mean receptive field size was 5-6 times the adult size. Visual acuity was half its adult value. These functional properties developed gradually during the following weeks and by P45 they were all adult-like. This functional development is affected by manipulations of the visual input such as dark rearing (DR) and monocular deprivation (MD). DR prevented the normal postnatal maturation of visual cortical functions: in P60 rats, dark reared from birth, their visual cortical functions resembled those of P19-P21 rats. MD from P15 to P45 resulted in a dramatic shift of the ocular dominance distribution (ODD) in favour of the open eye and in a loss of visual acuity for the deprived eye. To determine the sensitive period of rat visual cortex to MD (critical period) we evaluated the shift in ODD of visual cortical neurones in rats that were subjected to the progressive delay of the onset of fixed MD period (10 days). Our results show that the critical period begins around the end of the third postnatal week, peaks between the fourth and fifth week and starts to decline from the end of the fifth week.

Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-β-Mediated Cortical Synaptic Dysfunction

Soluble amyloid-β (Aβ) peptide is likely to play a key role during early stages of Alzheimers disease (AD) by perturbing synaptic function and cognitive processes. Receptor for advanced glycation end products (RAGE) has been identified as a receptor involved in Aβ-induced neuronal dysfunction. We investigated the role of neuronal RAGE in Aβ-induced synaptic dysfunction in the entorhinal cortex, an area of the brain important in memory processes that is affected early in AD. We found that soluble oligomeric Aβ peptide (Aβ42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, Aβ did not inhibit LTP in slices from RAGE-null mutant mice or in slices from wild-type mice treated with anti-RAGE IgG. Similarly, transgenic mice expressing a dominant-negative form of RAGE targeted to neurons showed normal LTP in the presence of Aβ, suggesting that neuronal RAGE functions as a signal transducer for Aβ-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by Aβ, we used inhibitors of stress activated kinases. We found that inhibiting p38 mitogen-activated protein kinase (p38 MAPK), but not blocking c-Jun N-terminal kinase activation, was capable of maintaining LTP in Aβ-treated slices. Moreover, Aβ-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that Aβ impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK.

Neuronal activity regulates the developmental expression and subcellular localization of cortical BDNF mRNA isoforms in vivo

Activity-dependent changes in BDNF expression have been implicated in developmental plasticity. Although its expression is widespread in visual cortex, developmental regulation of its different transcripts by visual experience has not been investigated. Here, we investigated the cellular expression of different BDNF transcripts in rat visual cortex during postnatal development. We found that transcripts I and II are expressed only in adults but III and IV are expressed from early postnatal stage. Total BDNF mRNA is expressed throughout the age groups. Transcripts III and IV show a differential intracellular localization, while former was detected only in cell bodies, latter is present both in cell bodies and dendritic processes. Inhibition of visual activity decreases the levels of exons, with exon IV transcript almost disappearing from dendrites. In vitro experiments also confirmed the above results, indicating activity-dependent regulation of different BDNF promoters with specific temporal and cellular patterns of expression in developing visual cortex.

The Distribution of Brain-derived Neurotrophic Factor and its Receptor trkB in Parvlbumin-containing Neurons of the Rat Visual Cortex

We analysed the distribution of brain‐derived neurotrophic factor (BDNF) and its receptor trkB in the adult rat visual cortex, paying particular attention to a GABAergic neuronal subpopulation—the parvalburnin‐positive cells. We found expression of trkB in the cell body and apical dendrite of pyramidal neurons and in the cell body of non‐pyramidal neurons. Double labelling experiments revealed extensive colocalization of parvalbumin and trkB immunoreactivity in non‐pyramidal neurons. Interestingly, the trkB‐positive pyramidal neurons appeared surrounded by parvalbumin‐labelled boutons. The use of double immunohistochemistry and in situ hybridization histochemistry showed that parvalbumin‐positive neurons express trkB mRNA. BDNF rnRNA was found in several cells. Coexpression of BDNF mRNA and parvalbumin immunoreactivity was extremely rare. These data strongly suggest that BDNF synthesized by cortical neurons acts as a postsynaptically derived factor for parvalbumin‐positive neurons in the adult rat visual cortex.

Large Differences in Aging Phenotype between Strains of the Short-Lived Annual Fish Nothobranchius furzeri

Background A laboratory inbred strain of the annual fish Nothobranchius furzeri shows exceptionally short life expectancy and accelerated expression of age markers. In this study, we analyze new wild-derived lines of this short-lived species. Methodology/Principal Findings We characterized captive survival and age-related traits in F1 and F2 offspring of wild-caught N. furzeri. Wild-derived N. furzeri lines showed expression of lipofuscin and neurodegeneration at age 21 weeks. Median lifespan in the laboratory varied from to 20 to 23 weeks and maximum lifespan from 25 to 32 weeks. These data demonstrate that rapid age-dependent decline and short lifespan are natural characteristics of this species. The N. furzeri distribution range overlaps with gradients in altitude and aridity. Fish from more arid habitats are expected to experience a shorter survival window in the wild. We tested whether captive lines stemming from semi-arid and sub-humid habitats differ in longevity and expression of age-related traits. We detected a clear difference in age-dependent cognitive decline and a slight difference in lifespan (16% for median, 15% for maximum lifespan) between these lines. Finally, we observed shorter lifespan and accelerated expression of age-related markers in the inbred laboratory strain compared to these wild-derived lines. Conclusions/Significance Owing to large differences in aging phenotypes in different lines, N. furzeri could represent a model system for studying the genetic control of life-history traits in natural populations.

Temperature affects longevity and age-related locomotor and cognitive decay in the short-lived fish Nothobranchius furzeri

Temperature variations are known to modulate aging and life‐history traits in poikilotherms as different as worms, flies and fish. In invertebrates, temperature affects lifespan by modulating the slope of age‐dependent acceleration in death rate, which is thought to reflect the rate of age‐related damage accumulation. Here, we studied the effects of temperature on aging kinetics, aging‐related behavioural deficits, and age‐associated histological markers of senescence in the short‐lived fish Nothobranchius furzeri. This species shows a maximum captive lifespan of only 3 months, which is tied with acceleration in growth and expression of aging biomarkers. These biological peculiarities make it a very convenient animal model for testing the effects of experimental manipulations on life‐history traits in vertebrates. Here, we show that (i) lowering temperature from 25 °C to 22 °C increases both median and maximum lifespan; (ii) life extension is due to reduction in the slope of the age‐dependent acceleration in death rate; (iii) lowering temperature from 25 °C to 22 °C retards the onset of age‐related locomotor and learning deficits; and (iv) lowering temperature from 25 °C to 22 °C reduces the accumulation of the age‐related marker lipofuscin. We conclude that lowering water temperature is a simple experimental manipulation which retards the rate of age‐related damage accumulation in this short‐lived species.

Brain-derived neurotrophic factor plasma levels in patients suffering from post-traumatic stress disorder

In both animals and humans, stress has been demonstrated to reduce the expression of the Brain-Derived Neurotrophic Factor (BDNF), a neurotrophin (NT) which promotes the proliferation, survival and differentiation of neurons. Although traumatic events have been found to be associated with lower BDNF plasma levels in affective disorders, no study has explored this parameter in patients with post-traumatic stress disorder (PTSD). We, therefore, measured BDNF plasma level in 18 patients with PTSD and in 18 healthy control subjects. Diagnoses were assessed by the Structured Clinical Interview for DSM-IV, while the specific symptoms were examined in the patients by means of the Impact of Event Scale for PTSD and the traumas experienced were assessed by using the Life Events Checklist. BDNF plasma levels were evaluated by means of a standardized Elisa method. The results, while showing significantly lower BDNF levels in PTSD patients, as compared with those of healthy subjects (p=0.001), although obtained in a small sample size, would suggest that this NT may be involved in the pathophysiology of PTSD.

Plasma Brain-Derived Neurotrophic Factor in treatment-resistant depressed patients receiving electroconvulsive therapy

There is an increasing evidence that the Brain-Derived Neurotrophic Factor (BDNF) could be involved in the mode of action of antidepressants and, perhaps, of ECT. This study aimed to investigate whether the clinical course of medication-resistant depressed patients following a course of ECT might be associated with changes of plasma BDNF concentrations. Our findings showed that at T0 (baseline) plasma BDNF levels of patients were significantly lower than those of control subjects, and that at T2 (after ECT) were significantly increased in parallel with the decrease of the Hamilton Rating Scale for Depression (HRSD) total score. However, only remitter patients who showed higher baseline BDNF levels than non-remitters reached normalized BDNF levels after ECT. These findings would suggest the potential usefulness of baseline plasma BDNF levels as predictors of response to ECT in treatment-resistant depressed patients.

Antibodies to nerve growth factor (NGF) prolong the sensitive period for monocular deprivation in the rat

Neural plasticity in the visual cortex, as tested by changes in its functional organization induced by monocular deprivation (MD), is present only during a restricted period of postnatal development (critical period). To investigate whether this process of synapse strengthening depends upon NGF, we antagonized endogenous NGF during the critical period by implanting anti-NGF producing cells. Anti-NGF treated and control rats were monocularly deprived after the end of the critical period. In anti-NGF treated but not in control rats MD was still effective. We conclude that antagonism of endogenous NGF prolongs the critical period, possibly by delaying the process of synapse consolidation in the visual cortex.