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1.
Nature ; 627(8004): 564-571, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38418889

RESUMEN

Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10-12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.


Asunto(s)
Biodiversidad , Bosques , Mapeo Geográfico , Árboles , Modelos Biológicos , Especificidad de la Especie , Árboles/clasificación , Árboles/fisiología , Clima Tropical
2.
Proc Natl Acad Sci U S A ; 120(28): e2220918120, 2023 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-37406098

RESUMEN

Understanding the claustrum's functions has recently progressed thanks to new anatomical and behavioral studies in rodents, which suggest that it plays an important role in attention, salience detection, slow-wave generation, and neocortical network synchronization. Nevertheless, knowledge about the origin and development of the claustrum, especially in primates, is still limited. Here, we show that neurons of rhesus macaque claustrum primordium are generated between embryonic day E48 and E55 and express some neocortical molecular markers, such as NR4A2, SATB2, and SOX5. However, in the early stages, it lacks TBR1 expression, which separates it from other surrounding telencephalic structures. We also found that two waves of neurogenesis (E48 and E55) in the claustrum, corresponding to the birthdates of layers 6 and 5 of the insular cortex, establish a "core" and "shell" cytoarchitecture, which is potentially a basis for differential circuit formation and could influence information processing underlying higher cognitive functions of the claustrum. In addition, parvalbumin-positive interneurons are the dominant interneuron type in the claustrum in fetal macaque, and their maturation is independent of that in the overlaying neocortex. Finally, our study reveals that the claustrum is likely not a continuance of subplate neurons of the insular cortex, but an independent pallial region, suggesting its potentially unique role in cognitive control.


Asunto(s)
Claustro , Neocórtex , Animales , Macaca mulatta , Neuronas/metabolismo , Interneuronas
3.
Proc Natl Acad Sci U S A ; 120(1): e2210967120, 2023 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-36574666

RESUMEN

The convolutions of the mammalian cerebral cortex allow the enlargement of its surface and addition of novel functional areas during evolution while minimizing expansion of the cranium. Cognitive neurodevelopmental disorders in humans, including microcephaly and lissencephaly, are often associated with impaired gyrification. In the classical model of gyrification, surface area is initially set by the number of radial units, and the forces driving cortical folding include neuronal growth, formation of neuropil, glial cell intercalation, and the patterned growth of subcortical white matter. An alternative model proposes that specified neurogenic hotspots in the outer subventricular zone (oSVZ) produce larger numbers of neurons that generate convexities in the cortex. This directly contradicts reports showing that cortical neurogenesis and settling of neurons into the cortical plate in primates, including humans, are completed well prior to the formation of secondary and tertiary gyri and indeed most primary gyri. In addition, during the main period of gyrification, the oSVZ produces mainly astrocytes and oligodendrocytes. Here we describe how rapid growth of intracortical neuropil, addition of glial cells, and enlargement of subcortical white matter in primates are the primary forces responsible for the post-neurogenic expansion of the cortical surface and formation of gyri during fetal development. Using immunohistochemistry for markers of proliferation and glial and neuronal progenitors combined with transcriptomic analysis, we show that neurogenesis in the ventricular zone and oSVZ is phased out and transitions to gliogenesis prior to gyral development. In summary, our data support the classical model of gyrification and provide insight into the pathogenesis of congenital cortical malformations.


Asunto(s)
Corteza Cerebral , Primates , Humanos , Animales , Corteza Cerebral/metabolismo , Neuronas , Neuroglía , Neurópilo , Mamíferos
5.
Langmuir ; 40(35): 18760-18772, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39171356

RESUMEN

The air-water interface is a highly prevalent phase boundary impacting many natural and artificial processes. The significance of this interface arises from the unique properties of water molecules within the interfacial region, with a crucial parameter being the thickness of its structural anisotropy, or "healing depth". This quantity has been extensively assessed by various simulations which have converged to a prediction of a remarkably short length of ∼6 Å. Despite the absence of any direct experimental measurement of this quantity, this predicted value has surprisingly become widely accepted as fact. Using an advancement in nonlinear vibrational spectroscopy, we provide the first measurement of this thickness and, indeed, find it to be ∼6-8 Å, finally confirming the prior predictions. Lastly, by combining the experimental results with depth-dependent second-order spectra calculated from ab initio parametrized molecular dynamics simulations, which are also in excellent agreement with this experimental result, we shed light on this surprisingly short correlation length of molecular orientations at the interface.

6.
Nature ; 564(7735): 207-212, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30429613

RESUMEN

Global warming is forcing many species to shift their distributions upward, causing consequent changes in the compositions of species that occur at specific locations. This prediction remains largely untested for tropical trees. Here we show, using a database of nearly 200 Andean forest plot inventories spread across more than 33.5° latitude (from 26.8° S to 7.1° N) and 3,000-m elevation (from 360 to 3,360 m above sea level), that tropical and subtropical tree communities are experiencing directional shifts in composition towards having greater relative abundances of species from lower, warmer elevations. Although this phenomenon of 'thermophilization' is widespread throughout the Andes, the rates of compositional change are not uniform across elevations. The observed heterogeneity in thermophilization rates is probably because of different warming rates and/or the presence of specialized tree communities at ecotones (that is, at the transitions between distinct habitats, such as at the timberline or at the base of the cloud forest). Understanding the factors that determine the directions and rates of compositional changes will enable us to better predict, and potentially mitigate, the effects of climate change on tropical forests.


Asunto(s)
Aclimatación , Altitud , Biodiversidad , Bosques , Calentamiento Global , Temperatura , Árboles/clasificación , Árboles/fisiología , Bases de Datos Factuales , Planificación en Desastres/tendencias , Desastres/prevención & control , Predicción/métodos , Especificidad de la Especie , Clima Tropical
7.
Cereb Cortex ; 33(24): 11501-11516, 2023 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-37874022

RESUMEN

Alzheimer's disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a "signature of flexibility" near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar "signature of flexibility" expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology.


Asunto(s)
Enfermedad de Alzheimer , Animales , Humanos , Enfermedad de Alzheimer/patología , Corteza Entorrinal/patología , Macaca mulatta/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Calcio , Calbindinas , Glutamatos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo
8.
Alzheimers Dement ; 20(4): 2843-2860, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38445818

RESUMEN

INTRODUCTION: Tau phosphorylated at threonine-217 (pT217-tau) is a novel fluid-based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217-tau arises in the brain, as soluble pT217-tau is dephosphorylated post mortem in humans. METHODS: We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217-tau levels in plasma. RESULTS: pT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217-tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION: These data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.


Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Animales , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Corteza Prefontal Dorsolateral , Macaca mulatta/metabolismo , Proteínas tau/líquido cefalorraquídeo
9.
Glob Chang Biol ; 29(12): 3409-3420, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36938951

RESUMEN

Accurate estimates of forest biomass stocks and fluxes are needed to quantify global carbon budgets and assess the response of forests to climate change. However, most forest inventories consider tree mortality as the only aboveground biomass (AGB) loss without accounting for losses via damage to living trees: branchfall, trunk breakage, and wood decay. Here, we use ~151,000 annual records of tree survival and structural completeness to compare AGB loss via damage to living trees to total AGB loss (mortality + damage) in seven tropical forests widely distributed across environmental conditions. We find that 42% (3.62 Mg ha-1 year-1 ; 95% confidence interval [CI] 2.36-5.25) of total AGB loss (8.72 Mg ha-1 year-1 ; CI 5.57-12.86) is due to damage to living trees. Total AGB loss was highly variable among forests, but these differences were mainly caused by site variability in damage-related AGB losses rather than by mortality-related AGB losses. We show that conventional forest inventories overestimate stand-level AGB stocks by 4% (1%-17% range across forests) because assume structurally complete trees, underestimate total AGB loss by 29% (6%-57% range across forests) due to overlooked damage-related AGB losses, and overestimate AGB loss via mortality by 22% (7%-80% range across forests) because of the assumption that trees are undamaged before dying. Our results indicate that forest carbon fluxes are higher than previously thought. Damage on living trees is an underappreciated component of the forest carbon cycle that is likely to become even more important as the frequency and severity of forest disturbances increase.


Asunto(s)
Árboles , Clima Tropical , Biomasa , Bosques , Carbono
10.
Mol Psychiatry ; 27(1): 377-382, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34667259

RESUMEN

In sub-mammalian vertebrates like fishes, amphibians, and reptiles, new neurons are produced during the entire lifespan. This capacity diminishes considerably in birds and even more in mammals where it persists only in the olfactory system and hippocampal dentate gyrus. Adult neurogenesis declines even more drastically in nonhuman primates and recent evidence shows that this is basically extinct in humans. Why should such seemingly useful capacity diminish during primate evolution? It has been proposed that this occurs because of the need to retain acquired complex knowledge in stable populations of neurons and their synaptic connections during many decades of human life. In this review, we will assess critically the claim of significant adult neurogenesis in humans and show how current evidence strongly indicates that humans lack this trait. In addition, we will discuss the allegation of many rodent studies that adult neurogenesis is involved in psychiatric diseases and that it is a potential mechanism for human neuron replacement and regeneration. We argue that these reports, which usually neglect significant structural and functional species-specific differences, mislead the general population into believing that there might be a cure for a variety of neuropsychiatric diseases as well as stroke and brain trauma by genesis of new neurons and their incorporation into existing synaptic circuitry.


Asunto(s)
Primates , Roedores , Animales , Hipocampo/fisiología , Humanos , Neurogénesis/fisiología , Neuronas/fisiología , Especificidad de la Especie
11.
Mol Psychiatry ; 27(10): 4252-4263, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35732693

RESUMEN

Glutamate carboxypeptidase-II (GCPII) expression in brain is increased by inflammation, e.g. by COVID19 infection, where it reduces NAAG stimulation of metabotropic glutamate receptor type 3 (mGluR3). GCPII-mGluR3 signaling is increasingly linked to higher cognition, as genetic alterations that weaken mGluR3 or increase GCPII signaling are associated with impaired cognition in humans. Recent evidence from macaque dorsolateral prefrontal cortex (dlPFC) shows that mGluR3 are expressed on dendritic spines, where they regulate cAMP-PKA opening of potassium (K+) channels to enhance neuronal firing during working memory. However, little is known about GCPII expression and function in the primate dlPFC, despite its relevance to inflammatory disorders. The present study used multiple label immunofluorescence and immunoelectron microscopy to localize GCPII in aging macaque dlPFC, and examined the effects of GCPII inhibition on dlPFC neuronal physiology and working memory function. GCPII was observed in astrocytes as expected, but also on neurons, including extensive expression in dendritic spines. Recordings in dlPFC from aged monkeys performing a working memory task found that iontophoresis of the GCPII inhibitors 2-MPPA or 2-PMPA markedly increased working memory-related neuronal firing and spatial tuning, enhancing neural representations. These beneficial effects were reversed by an mGluR2/3 antagonist, or by a cAMP-PKA activator, consistent with mGluR3 inhibition of cAMP-PKA-K+ channel signaling. Systemic administration of the brain penetrant inhibitor, 2-MPPA, significantly improved working memory performance without apparent side effects, with largest effects in the oldest monkeys. Taken together, these data endorse GCPII inhibition as a potential strategy for treating cognitive disorders associated with aging and/or neuroinflammation.


Asunto(s)
COVID-19 , Corteza Prefontal Dorsolateral , Humanos , Animales , Haplorrinos , Macaca , Cognición , Glutamatos
12.
J Chem Phys ; 159(16)2023 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-37873965

RESUMEN

Second-order nonlinear spectroscopy is becoming an increasingly important technique in the study of interfacial systems owing to its marked ability to study molecular structures and interactions. The properties of such a system under investigation are contained within their intrinsic second-order susceptibilities which are mapped onto the measured nonlinear signals (e.g. sum-frequency generation) through the applied experimental settings. Despite this yielding a plethora of information, many crucial aspects of molecular systems typically remain elusive, for example the depth distributions, molecular orientation and local dielectric properties of its constituent chromophores. Here, it is shown that this information is contained within the phase of the measured signal and, critically, can be extracted through measurement of multiple nonlinear pathways (both the sum-frequency and difference-frequency output signals). Furthermore, it is shown that this novel information can directly be correlated to the characteristic vibrational spectra, enabling a new type of advanced sample characterization and a profound analysis of interfacial molecular structures. The theory underlying the different contributions to the measured phase of distinct nonlinear pathways is derived, after which the presented phase disentanglement methodology is experimentally demonstrated for model systems of self-assembled monolayers on several metallic substrates. The obtained phases of the local fields are compared to the corresponding phases of the nonlinear Fresnel factors calculated through the commonly used theoretical model, the three-layer model. It is found that, despite its rather crude assumptions, the model yields remarkable similarity to the experimentally obtained values, thus providing validation of the model for many sample classes.

13.
New Phytol ; 233(2): 705-721, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34716605

RESUMEN

The relative importance of tree mortality risk factors remains unknown, especially in diverse tropical forests where species may vary widely in their responses to particular conditions. We present a new framework for quantifying the importance of mortality risk factors and apply it to compare 19 risks on 31 203 trees (1977 species) in 14 one-year periods in six tropical forests. We defined a condition as a risk factor for a species if it was associated with at least a doubling of mortality rate in univariate analyses. For each risk, we estimated prevalence (frequency), lethality (difference in mortality between trees with and without the risk) and impact ('excess mortality' associated with the risk, relative to stand-level mortality). The most impactful risk factors were light limitation and crown/trunk loss; the most prevalent were light limitation and small size; the most lethal were leaf damage and wounds. Modes of death (standing, broken and uprooted) had limited links with previous conditions and mortality risk factors. We provide the first ranking of importance of tree-level mortality risk factors in tropical forests. Future research should focus on the links between these risks, their climatic drivers and the physiological processes to enable mechanistic predictions of future tree mortality.


Asunto(s)
Árboles , Clima Tropical , Bosques , Factores de Riesgo , Árboles/fisiología
14.
New Phytol ; 234(5): 1664-1677, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35201608

RESUMEN

Tree size shapes forest carbon dynamics and determines how trees interact with their environment, including a changing climate. Here, we conduct the first global analysis of among-site differences in how aboveground biomass stocks and fluxes are distributed with tree size. We analyzed repeat tree censuses from 25 large-scale (4-52 ha) forest plots spanning a broad climatic range over five continents to characterize how aboveground biomass, woody productivity, and woody mortality vary with tree diameter. We examined how the median, dispersion, and skewness of these size-related distributions vary with mean annual temperature and precipitation. In warmer forests, aboveground biomass, woody productivity, and woody mortality were more broadly distributed with respect to tree size. In warmer and wetter forests, aboveground biomass and woody productivity were more right skewed, with a long tail towards large trees. Small trees (1-10 cm diameter) contributed more to productivity and mortality than to biomass, highlighting the importance of including these trees in analyses of forest dynamics. Our findings provide an improved characterization of climate-driven forest differences in the size structure of aboveground biomass and dynamics of that biomass, as well as refined benchmarks for capturing climate influences in vegetation demographic models.


Asunto(s)
Carbono , Clima Tropical , Biomasa , Temperatura , Madera
15.
Glob Chang Biol ; 28(9): 2895-2909, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35080088

RESUMEN

The growth and survival of individual trees determine the physical structure of a forest with important consequences for forest function. However, given the diversity of tree species and forest biomes, quantifying the multitude of demographic strategies within and across forests and the way that they translate into forest structure and function remains a significant challenge. Here, we quantify the demographic rates of 1961 tree species from temperate and tropical forests and evaluate how demographic diversity (DD) and demographic composition (DC) differ across forests, and how these differences in demography relate to species richness, aboveground biomass (AGB), and carbon residence time. We find wide variation in DD and DC across forest plots, patterns that are not explained by species richness or climate variables alone. There is no evidence that DD has an effect on either AGB or carbon residence time. Rather, the DC of forests, specifically the relative abundance of large statured species, predicted both biomass and carbon residence time. Our results demonstrate the distinct DCs of globally distributed forests, reflecting biogeography, recent history, and current plot conditions. Linking the DC of forests to resilience or vulnerability to climate change, will improve the precision and accuracy of predictions of future forest composition, structure, and function.


Asunto(s)
Cambio Climático , Clima Tropical , Biomasa , Demografía , Ecosistema
16.
Proc Natl Acad Sci U S A ; 116(14): 7089-7094, 2019 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-30894491

RESUMEN

The primate cerebrum is characterized by a large expansion of cortical surface area, the formation of convolutions, and extraordinarily voluminous subcortical white matter. It was recently proposed that this expansion is primarily driven by increased production of superficial neurons in the dramatically enlarged outer subventricular zone (oSVZ). Here, we examined the development of the parietal cerebrum in macaque monkey and found that, indeed, the oSVZ initially adds neurons to the superficial layers II and III, increasing their thickness. However, as the oSVZ grows in size, its output changes to production of astrocytes and oligodendrocytes, which in primates outnumber cerebral neurons by a factor of three. After the completion of neurogenesis around embryonic day (E) 90, when the cerebrum is still lissencephalic, the oSVZ enlarges and contains Pax6+/Hopx+ outer (basal) radial glial cells producing astrocytes and oligodendrocytes until after E125. Our data indicate that oSVZ gliogenesis, rather than neurogenesis, correlates with rapid enlargement of the cerebrum and development of convolutions, which occur concomitantly with the formation of cortical connections via the underlying white matter, in addition to neuronal growth, elaboration of dendrites, and amplification of neuropil in the cortex, which are primary factors in the formation of cerebral convolutions in primates.


Asunto(s)
Cerebro/crecimiento & desarrollo , Cerebro/metabolismo , Ventrículos Laterales/crecimiento & desarrollo , Ventrículos Laterales/metabolismo , Neurogénesis/fisiología , Neuronas/metabolismo , Animales , Astrocitos/metabolismo , Cerebro/citología , Cerebro/embriología , Embrión de Mamíferos , Proteínas de Homeodominio/metabolismo , Ventrículos Laterales/citología , Ventrículos Laterales/embriología , Macaca , Oligodendroglía/citología , Oligodendroglía/metabolismo , Factor de Transcripción PAX6/metabolismo , Primates , Proteínas Supresoras de Tumor/metabolismo
17.
Proc Natl Acad Sci U S A ; 115(8): 1837-1842, 2018 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-29432167

RESUMEN

Knowledge about the biogeographic affinities of the world's tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world's tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.


Asunto(s)
Bosques , Filogenia , Plantas/clasificación , Plantas/genética , Clima Tropical , Biodiversidad , Conservación de los Recursos Naturales , Monitoreo del Ambiente
18.
Alzheimers Dement ; 17(6): 920-932, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33829643

RESUMEN

INTRODUCTION: The etiology of sporadic Alzheimer's disease (AD) requires non-genetically modified animal models. METHODS: The relationship of tau phosphorylation to calcium-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno-electron microscopy. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques. RESULTS: Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808-RyR2). Calcium also regulated early tau phosphorylation in vitro. Age-related reductions in the calcium-binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques. DISCUSSION: Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target.


Asunto(s)
Calcio/metabolismo , Disfunción Cognitiva/patología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Macaca mulatta , Proteínas tau/metabolismo , Envejecimiento/patología , Animales , Señalización del Calcio , Modelos Animales de Enfermedad , Humanos , Masculino , Neuronas/metabolismo , Fosforilación , Corteza Prefrontal/patología , Ratas , Canal Liberador de Calcio Receptor de Rianodina
19.
J Neurosci ; 39(14): 2722-2734, 2019 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-30755491

RESUMEN

Noradrenergic (NE) α1-adrenoceptors (α1-ARs) contribute to arousal mechanisms and play an important role in therapeutic medications such as those for the treatment of posttraumatic stress disorder (PTSD). However, little is known about how α1-AR stimulation influences neuronal firing in the dorsolateral prefrontal cortex (dlPFC), a newly evolved region that is dysfunctional in PTSD and other mental illnesses. The current study examined the effects of α1-AR manipulation on neuronal firing in dlPFC of rhesus monkeys performing a visuospatial working memory task, focusing on the "delay cells" that maintain spatially tuned information across the delay period. Iontophoresis of the α1-AR antagonist HEAT (2-{[ß-(4-hydroxyphenyl)ethyl]aminomethyl}-1-tetralone) had mixed effects, reducing firing in a majority of neurons but having nonsignificant excitatory effects or no effect in remaining delay cells. These data suggest that endogenous NE has excitatory effects in some delay cells under basal conditions. In contrast, the α1-AR agonists phenylephrine and cirazoline suppressed delay cell firing and this was blocked by coadministration of HEAT. These results indicate an inverted-U dose response for α1-AR actions, with mixed excitatory actions under basal conditions and suppressed firing with high levels of α1-AR stimulation such as with stress exposure. Immunoelectron microscopy revealed α1-AR expression presynaptically in axons and axon terminals and postsynaptically in spines, dendrites, and astrocytes. It is possible that α1-AR excitatory effects arise from presynaptic excitation of glutamate release, whereas postsynaptic actions suppress firing through calcium-protein kinase C opening of potassium channels on spines. The latter may predominate under stressful conditions, leading to loss of dlPFC regulation during uncontrollable stress.SIGNIFICANCE STATEMENT Noradrenergic stimulation of α1-adrenoceptors (α1-ARs) is implicated in posttraumatic stress disorder (PTSD) and other mental disorders that involve dysfunction of the prefrontal cortex, a brain region that provides top-down control. However, the location and contribution of α1-ARs to prefrontal cortical physiology in primates has received little attention. This study found that α1-ARs are located near prefrontal synapses and that α1-AR stimulation has mixed effects under basal conditions. However, high levels of α1-AR stimulation, as occur with stress, suppress neuronal firing. These findings help to explain why we lose top-down control under conditions of uncontrollable stress when there are high levels of noradrenergic release in brain and why blocking α1-AR, such as with prazosin, may be helpful in the treatment of PTSD.


Asunto(s)
Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/metabolismo , Desempeño Psicomotor/fisiología , Receptores Adrenérgicos alfa 1/metabolismo , Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Macaca mulatta , Imagen por Resonancia Magnética/métodos , Masculino , Norepinefrina/farmacología , Estimulación Luminosa/métodos , Desempeño Psicomotor/efectos de los fármacos
20.
J Neuroinflammation ; 17(1): 8, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31906973

RESUMEN

BACKGROUND: Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. METHODS: Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. RESULTS: C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. CONCLUSIONS: These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.


Asunto(s)
Envejecimiento/metabolismo , Complemento C1q/análisis , Complemento C1q/metabolismo , Neuronas/metabolismo , Corteza Prefrontal/química , Corteza Prefrontal/metabolismo , Animales , Macaca mulatta , Neuronas/ultraestructura , Corteza Prefrontal/ultraestructura , Ratas , Ratas Sprague-Dawley
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