Nektaria Nicolakakis

TOOLS AND BRAINS IN BIRDS

Tools are traditionally defined as objects that are used as an extension of the body and held directly in the hand or mouth. By these standards, a vulture breaking an egg by hitting it with a stone uses a tool, but a gull dropping an egg on a rock does not. This distinction between true and borderline (or proto-tool) cases has been criticized for its arbitrariness and anthropocentrism. We show here that relative size of the neostriatum and whole brain distinguish the true and borderline categories in birds using tools to obtain food or water. From two sources, the specialized literature on tools and an innovation data base gathered in the short note sections of 68 journals in 7 areas of the world, we collected 39 true (e.g. use of probes, hammers, sponges, scoops) and 86 borderline (e.g. bait fishing, battering and dropping on anvils, holding with wedges and skewers) cases of tool use in 104 species from 15 parvorders. True tool users have a larger mean residual brain size (regressed against body weight) than do users of borderline tools, confirming the distinction in the literature. In multiple regressions, residual brain size and residual size of the neostriatum (one of the areas in the avian telencephalon thought to be equivalent to the mammalian neocortex) are the best predictors of true tool use reports per taxon. Innovation rate is the best predictor of borderline tool use distribution. Despite the strong concentration of true tool use cases in Corvida and Passerida, independent constrasts suggest that common ancestry is not responsible for the association between tool use and size of the neostriatum and whole brain. Our results demonstrate that birds are more frequent tool users than usually thought and that the complex cognitive processes involved in tool use may have repeatedly co-evolved with large brains in several orders of birds.

Complete Rescue of Cerebrovascular Function in Aged Alzheimer's Disease Transgenic Mice by Antioxidants and Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimers disease (AD). Using aged (∼16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-β (Aβ) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-l-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor γ agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Aβ levels or Aβ plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.

Behavioural flexibility predicts species richness in birds, but not extinction risk

The number of species varies greatly among taxa. In birds, for example, the parvorder Passerida contains 3556 species while the Odontophorida contains only six species. This uneven distribution of species among bird groups is not a consequence of random branching patterns and therefore warrants an explanation. According to the behavioural drive hypothesis, behavioural innovation coupled with social transmission of the new skill to other members of the population may lead to accelerated rates of evolution, and could therefore account for differences in species richness. In this paper, we test the behavioural drive hypothesis by examining the link between behavioural flexibility and the number of species per taxon. We estimate flexibility with relative brain size and feeding innovation rate and predict that both will be positively associated with the number of species per taxon. Since the number of species at any given time results from a balance between speciation and extinction rates, we also examine the link between flexibility and the number of species threatened with extinction. We predict that the two flexibility correlates will be negatively associated with the number of species at risk. In simple regressions, both flexibility correlates were significantly associated with species number per taxon. However, only innovation rate remained in the final model. Relative brain weight dropped out of the multiple regression due to its association with innovation rate. Relative brain weight, innovation rate and species number per taxon were all significantly correlated with the number of threatened species in the simple regression, but only the latter remained significant in the final model. The same results were obtained on independent contrasts, indicating that behavioural flexibility predicts richness but not extinction risk in birds.  2003 Published by Elsevier Science Ltd on behalf of The Association for the Study of Animal Behaviour.

Vascular Remodeling versus Amyloid β-Induced Oxidative Stress in the Cerebrovascular Dysfunctions Associated with Alzheimer's Disease

The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimers disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-β1 (TGF+). Age-related impairments and their in vitro reversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+ mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+ mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+ mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+ mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+ mice but had no effect in those of TGF+ mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+ mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.

Neurovascular function in Alzheimer's disease patients and experimental models

The ability of the brain to locally augment glucose delivery and blood flow during neuronal activation, termed neurometabolic and neurovascular coupling, respectively, is compromised in Alzheimers disease (AD). Since perfusion deficits may hasten clinical deterioration and have been correlated with negative treatment outcome, strategies to improve the cerebral circulation should form an integral element of AD therapeutic efforts. These efforts have yielded several experimental models, some of which constitute AD models proper, others which specifically recapture the AD cerebrovascular pathology, characterized by anatomical alterations in brain vessel structure, as well as molecular changes within vascular smooth muscle cells and endothelial cells forming the blood– brain barrier. The following paper will present the elements of AD neurovascular dysfunction and review the in vitro and in vivo model systems that have served to deepen our understanding of it. It will also critically evaluate selected groups of compounds, the FDA-approved cholinesterase inhibitors and thiazolidinediones, for their ability to correct neurovascular dysfunction in AD patients and models. These and several others are emerging as compounds with pleiotropic actions that may positively impact dysfunctional cerebrovascular, glial, and neuronal networks in AD.

Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice.

Cerebrovascular dysfunctions appear to contribute to Alzheimers disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Abeta) levels and the number of Abeta plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Abeta plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.

Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease

Several factors have been implicated in Alzheimers disease (AD) but there is no definite conclusion as to the main pathogenic agents. Mutations in the amyloid precursor protein (APP) that lead to increased production of amyloid β peptide (Aβ) are associated with the early‐onset, familial forms of AD. However, in addition to ageing, the most common risk factors for the sporadic, prevalent form of AD are hypertension, hypercholesterolaemia, ischaemic stroke, the ApoE4 allele and diabetes, all characterized by a vascular pathology. In AD, the vascular pathology includes accumulation of Aβ in the vessel wall, vascular fibrosis, and other ultrastructural changes in constituent endothelial and smooth muscle cells. Moreover, the ensuing chronic cerebral hypoperfusion has been proposed as a determinant factor in the accompanying cognitive deficits. In transgenic mice that overexpress mutated forms of the human APP (APP mice), the increased production of Aβ results in vascular oxidative stress and loss of vasodilatory function. The culprit molecule, superoxide, triggers the synthesis of other reactive oxygen species and the sequestration of nitric oxide (NO), thus impairing resting cerebrovascular tone and NO‐dependent dilatations. The Aβ‐induced cerebrovascular dysfunction can be completely abrogated in aged APP mice with antioxidant therapy. In contrast, in mice that overproduce an active form of the cytokine transforming growth factor‐β1 and recapitulate the vascular structural changes seen in AD, antioxidants have no beneficial effect on the accompanying cerebrovascular deficits. This review discusses the beneficial role and limitations of antioxidant therapy in AD cerebrovascular pathology.

FOREBRAIN SIZE AND INNOVATION RATE IN EUROPEAN BIRDS: FEEDING, NESTING AND CONFOUNDING VARIABLES

Previous work has shown a positive correlation between relative forebrain size and feeding innovation frequency, corrected for species number, over different taxonomic groups of birds. Several confounding variables could account for this relationship: ornithologists could notice and report innovations more often in certain taxa because of biased expectations, greater research effort, editorial bias in journals or large population sizes of the taxa. The innovationforebrain correlation could also be spuriously caused by phylogeny or juvenile development mode. We examined these possibilities by entering species number per taxon, population size, number of full length papers, expectations (assessed by a questionnaire), journal source and development mode in multiple regressions that also included relative forebrain size. We did this with and without phylogenetic corrections and tested two behavioural categories, feeding and nesting, where flexibility and learning are clearly thought to differ, but confounds should have similar effects. Through an exhaustive survey covering 30 years in 11 journals, a total of 683 innovations was gathered for the northwestern part of Europe, 507 for feeding and 176 for nesting. Species number per taxon was the only significant confound for both feeding and nesting reports; as predicted, forebrain size was a second significant predictor for feeding innovations, but not for nesting. The frequency of feeding innovations in the short notes of ornithology journals thus appears to be a valid and reliable way to operationalise behavioural flexibility in birds.

Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimers disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.

The nuclear receptor PPARγ as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer's disease

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (α, γ, β/δ), and synthetic ligands for PPARα (fibrates) and PPARγ (Thiazolidinediones, TZDs) are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARγ, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARγ ligands in the treatment of brain disorders such as Alzheimers disease (AD), leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARγ agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.