Prenatal corticosteroid exposure affects hippocampal plasticity and reduces lifespan

Synthetic corticosteroids, such as dexamethasone, are frequently administered to pregnant women at risk for preterm delivery. Endogenous corticosteroids are essential for normal development, but exposure to therapeutic doses at critical developmental stages may have adverse effects on the central nervous system. Major concern has arisen about long-term effects of corticosteroid treatment on brain plasticity, particularly in the hippocampus. Therefore, we analyzed the molecular, cellular, and behavioral effects of prenatal dexamethasone treatment on the adult hippocampus. Pregnant mice were treated at embryonic day 15.5 with a single dose of dexamethasone or saline. Adult offspring was analyzed for hippocampal neuron loss, cell proliferation, and NMDA receptor subunit expression. Hippocampal function was assessed in the Morris water maze and synaptic plasticity in the CA1 field by determining frequency dependence of LTP and LTD in hippocampal slices. Prenatal dexamethasone treatment decreased hippocampal cell proliferation in the dentate gyrus. Treated mice showed reduced LTD, impaired spatial learning, and a marked reduction in lifespan. Our data show long-term adverse effects of prenatal dexamethasone treatment on hippocampal function in mice and suggest accelerated aging. These findings indicate that it is important to be restrictive with corticosteroid administration during fetal development because of the lifelong consequences.     

Word learning and lexical development across the lifespan

Word learning is one of the core components of language acquisition. In this article, we provide an overview of the theme issue on word learning, describing some of the ways in which research in the area has progressed and diverged. In recent years, word learning has become central in a wider range of research areas, and is important to research on adult, as well as child and infant language. We introduce 10 papers that cover the recent developments from a wide range of perspectives, focusing on developmental research, the influence of reading skills, neuroimaging and the relationship between word learning and general models of memory.     

Estrogen and hippocampal synaptic plasticity

During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system,including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.     

Interplay between VGLUT isoforms and endophilin A1 regulates neurotransmitter release and short-term plasticity

Vesicular glutamate transporters (VGLUTs) are essential for filling synaptic vesicles with glutamate and mammals express three VGLUT isoforms (VGLUT1-3) with distinct spatiotemporal expression patterns. Here, we find that neurons expressing VGLUT1 have lower release probability and less short-term depression than neurons expressing VGLUT2 or VGLUT3. Investigation of the underlying mechanism identified endophilin A1 as a positive regulator of exocytosis whose expression levels are positively correlated with release efficiency and showed that the differences in release efficiency between VGLUT1- and VGLUT2-expressing neurons are due to VGLUT1's ability to bind endophilin A1 and inhibit endophilin-induced enhancement of release probability.     

Determinants of time allocation across the lifespan

This paper lays the groundwork for a theory of time allocation across the life course, based on the idea that strength and skill vary as a function of age, and that return rates for different activities vary as a function of the combination of strength and skills involved in performing those tasks. We apply the model to traditional human subsistence patterns. The model predicts that young children engage most heavily in low-strength/low-skill activities, middle-aged adults in high-strength/high-skill activities, and older adults in low-strength/high-skill activities. Tests among Machiguenga and Piro forager-horticulturalists of southeastern Peru show that males and females focus on low-strength/low-skill tasks early in life (domestic tasks and several forms of fishing), switch to higher-strength/higher-skill activities in their twenties and thirties (hunting, fishing, and gardening for males; fishing and gardening for females), and shift focus to high-skill activities late in life (manufacture/repair, food processing). Michael Gurven is an assistant professor of anthropology at the University of California-Santa Barbara. He received his Ph.D. from the University of New Mexico in 2000. He has conducted fieldwork in Paraguay and Bolivia with Ache and Tsimane forager-horticulturalists. His research interests include intragroup cooperation and problems of collective action, and the application of life history theory to explaining human longevity, cognitive development, delayed maturation, and sociality. Since 2002, Gurven and Kaplan have co-directed the Tsimane Health and Life History Initiative, a five-year project to develop theory and test implications of different models of human life history evolution. Hillard Kaplan is a professor of anthropology at University of New Mexico. He received his Ph.D. from the University of Utah in 1983. He has conducted fieldwork in Paraguay, Brazil, Botswana, and Bolivia. His research interests include evolutionary perspectives on life course development and senescence, and brain evolution. He has launched theoretical and empirical investigations into each of these areas, uniting evolutionary and economic approaches. He has applied human capital theory toward explaining human life history evolution, and the proximate physiological and psychological mechanisms governing fertility and parental investment in both traditional, high-fertility, subsistence economies and modern, low-fertility, industrial societies.     

Large-scale cortical functional organization and speech perception across the lifespan

Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor (i.e., underlying physiological decline). To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic (functional MRI) responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global (but not local) efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas (bilateral superior and middle temporal cortex), further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains.     

Vitellogenin hormonal control in the green frog, Rana esculenta. Interplay between estradiol and pituitary hormones

1. The effect of estradiol and pituitary hormones on the titre of serum vitellogenin has been studied in Rana esculenta by rocket immunoelectrophoresis. 2. Hepatic synthesis of vitellogenin depends on physiological doses of estradiol. 3. Gonadotrophins enhance the uptake, presumably by acting directly on the oocyte plasma membrane. 4. In addition, our data support direct pituitary intervention on liver synthesis and/or release of vitellogenin. 5. Hormonal response, as evaluated by vitellogenin serum titres, tends to increase from November to July. This could be the expression of a modification, throughout the sexual cycle, of liver sensitivity to the hormones.     

Proteomics in the study of hippocampal plasticity

Synaptic plasticity is the dynamic regulation of the strength of synaptic communication between nerve cells. It is central to neuronal development as well as experience-dependent remodeling of the adult nervous system as occurs during memory formation. Aberrant forms of synaptic plasticity also accompany a variety of neurological and psychiatric diseases, and unraveling the biological basis of synaptic plasticity has been a major goal in neurobiology research. The biochemical and structural mechanisms underlying different forms of synaptic plasticity are complex, involving multiple signaling cascades, reconfigurations of structural proteins and the trafficking of synaptic proteins. As such, proteomics should be a valuable tool in dissecting the molecular events underlying normal and disease-related forms of plasticity. In fact, progress in this area has been disappointingly slow. We discuss the particular challenges associated with proteomic interrogation of synaptic plasticity processes and outline ways in which we believe proteomics may advance the field over the next few years. We pay particular attention to technical advances being made in small sample proteomics and the advent of proteomic imaging in studying brain plasticity.     

The spatiotemporal dynamics of microglia across the human lifespan

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Born this way: Hippocampal neurogenesis across the lifespan

The capability of the mammalian brain to generate new neurons through the lifespan has gained much attention for the promise of new therapeutic possibilities especially for the aging brain. One of the brain regions that maintains a neurogenesis‐permissive environment is the dentate gyrus of the hippocampus. Here, new neurons are generated from a pool of multipotent neural progenitor cells to become fully functional neurons that are integrated into the brain circuitry. A growing body of evidence points to the fact that neurogenesis in the adult hippocampus is necessary for certain memory processes, and in mood regulation, while alterations in hippocampal neurogenesis have been associated with a myriad of neurological and psychiatric disorders. More recently, evidence has come to light that new neurons may differ in their vulnerability to environmental and disease‐related influences depending on the time during the life course at which they are exposed. Thus, it has been the topic of intense research in recent years. In this review, we will discuss the complex process and associated functional relevance of hippocampal neurogenesis during the embryonic/postnatal period and in adulthood. We consider the implications of hippocampal neurogenesis during the developmentally critical periods of adolescence and older age. We will further consider the literature surrounding hippocampal neurogenesis and its functional role during these critical periods with a view to providing insight into the potential of harnessing neurogenesis for health and therapeutic benefit.     

Sex differences in interest in infants across the lifespan

This study investigated sex differences in interest in infants among children, adolescents, young adults, and older individuals. Interest in infants was assessed with responses to images depicting animal and human infants versus adults, and with verbal responses to questionnaires. Clear sex differences, irrespective of age, emerged in all visual and verbal tests, with females being more interested in infants than males. Male interest in infants remained fairly stable across the four age groups, whereas female interest in infants was highest in childhood and adolescence and declined thereafter, particularly for the responses to visual stimuli. The observed developmental changes in female interest in infants are consistent with the hypothesis that they represent a biological adaptation for parenting. This study was supported by NIH grants R01-MH57249, R01-MH62577, and K02-MH63097. Dario Maestripieri, Ph.D., is an assistant professor of Human Development and Evolutionary Biology at the University of Chicago. He has broad research interests in behavior, development, and evolution, and conducted research on primate parenting and development at the University of Cambridge and at the Yerkes Regional Primate Research Center before moving to Chicago. Suzanne Pelka is a graduate student in Human Development at the University of Chicago.     

Non-coding RNA networks underlying cognitive disorders across the lifespan

Non-coding RNAs (ncRNAs) and their associated regulatory networks are increasingly being implicated in mediating a complex repertoire of neurobiological functions. Cognitive and behavioral processes are proving to be no exception. In this review, we discuss the emergence of many novel, diverse and rapidly expanding classes and subclasses of short and long ncRNAs. We briefly review the life cycles and molecular functions of these ncRNAs. We also examine how ncRNA circuitry mediates brain development, plasticity, stress responses and aging, and highlight its potential roles in the pathophysiology of cognitive disorders, including neural developmental and age-associated neurodegenerative diseases, as well as those that manifest throughout the lifespan.     

PDGF-responsive progenitors persist in the subventricular zone across the lifespan

The SVZ (subventricular zone) contains neural stem cells and progenitors of various potentialities. Although initially parsed into A, B, and C cells, this germinal zone is comprised of a significantly more diverse population of cells. Here, we characterized a subset of postnatal PRPs (PDGF-AA-responsive precursors) that express functional PDGFα and β receptors from birth to adulthood. When grown in PDGF-AA, dissociated neonatal rat SVZ cells divided to produce non-adherent clusters of progeny. Unlike the self-renewing EGF/FGF-2-responsive precursors that produce neurospheres, these PRPs failed to self-renew after three passages; therefore, we refer to the colonies they produce as spheroids. Upon differentiation these spheroids could produce neurons, type 1 astrocytes and oligodendrocytes. When maintained in medium supplemented with BMP-4 they also produced type 2 astrocytes. Using lineage tracing methods, it became evident that there were multiple types of PRPs, including a subset that could produce neurons, oligodendrocytes, and type 1 and type 2 astrocytes; thus some of these PRPs represent a unique population of precursors that are quatropotential. Spheroids also could be generated from the newborn neocortex and they had the same potentiality as those from the SVZ. By contrast, the adult neocortex produced less than 20% of the numbers of spheroids than the adult SVZ and spheroids from the adult neocortex only differentiated into glial cells. Interestingly, SVZ spheroid producing capacity diminished only slightly from birth to adulthood. Altogether these data demonstrate that there are PRPs that persist in the SVZ that includes a unique population of quatropotential PRPs.     

Down on one knee: soft tissue knee injuries across the lifespan

Joint injury is a potent risk factor for osteoarthritis, the most important musculoskeletal disease affecting humankind. Yet the population incidence of soft tissue knee injury is not well documented. Using health-care register data from Sweden, Peat and colleagues report that soft tissue knee injuries are common, peak in adolescence and early adulthood, have a second spike in women who are 35 to 49 years old, and continue throughout the lifespan. The study highlights the need for more knowledge on the natural history of knee injuries, their impact on knee osteoarthritis development and progression, and the potential for prevention programs to reduce the incidence of these injuries.Joint injury is a potent risk factor for osteoarthritis (OA), the most important musculoskeletal disease affecting humankind. Although evidence is mounting that knee joint injury rates are high and increasing, it is also perhaps the lowest hanging fruit for primary OA prevention; several randomized clinical trials have shown that knee injuries can be dramatically reduced with relatively straightforward interventions. Yet outside of anterior cruciate ligament (ACL) injury and despite its potential public health impact, the population incidence of soft tissue knee injury requiring medical attention is not well documented: we have not known the extent or the nature of the problem, until now.In a recent issue of Arthritis Research & Therapy, Peat and colleagues [1] provided population-wide estimates of clinically diagnosed soft tissue knee injuries across all ages on the basis of an entire region of Sweden (approximately 1.3 million people). The opportunity to report and classify all clinically diagnosed knee injuries across the lifespan arises from unique and detailed health-care registries typical to Scandinavian countries. This overcomes weaknesses of previous epidemiological evaluations of knee injuries, which are limited to specific health-care settings, subgroups of people, and specific injury types. Of note, the findings of Peat and colleagues [1] have convergent validity - largely agreeing with previous reports of incidence for specific injury types and subgroups where data overlap.What emerges is that population exposure to soft tissue knee injury is a common problem; the annual incidences for males and females are 766 and 676 per 100,000 persons per year, respectively. This is approximately 10 times higher than ACL injuries alone. If these ‘less catastrophic’ but more common injuries are a risk for OA development (as risk factor studies measuring self-reported injury suggest [2]), then this study may be uncovering and detailing critical new exposure data. They are clearly more numerous though more difficult to accurately diagnose. This study begins to shed light on this challenge.Also revealed is new information on age and gender differences. The incidence of soft tissue knee injuries peaks in adolescence and early adulthood and is likely sports-related, matching seasonal fluctuations in popular sports in Sweden. The rates after this period decline over the lifespan with a notable exception: females from 35 to 49 experience a second peak. This is intriguing and the reasons are not clear, although the authors propose that the previously reported link between parity/child-bearing and knee OA may be mediated by injury. Although the reasons remain obscure, the finding is compelling and may help elucidate the consistently reported, but unexplained, higher prevalence of knee OA in females.Peat and colleagues [1] show that, although incidence rates are highest in the second and third decades of life, considerable rates of contusion, collateral ligament sprain, and other soft tissue strains continue into middle and old age. These injuries coincide with the age of onset of knee OA symptoms and illustrate the challenge of differentiating what is truly an injury from what is part of a previously latent or degenerative process or both. This also applies to meniscal injuries. Surgeries for meniscal tears peak in the mid to late 40s [3–5]. In contrast, Peat and colleagues [1] report a high incidence of meniscal tears in adolescents and young adults. As acknowledged by the authors, less severe injuries such as meniscal tears likely suffer from some misclassification. However, the relationship between diagnosis and surgery for meniscal tears requires further investigation.The high injury incidence among adolescents and young adults, together with the known risk of OA incidence from ACL and meniscal injuries, provides further impetus for implementing knee injury prevention programs, for which there is a strong body of level 1 evidence [6–11]. Efficacy has been demonstrated primarily in the sports team setting, implemented as novel 10- to 15-minute team warm-ups consisting of neuromuscular exercises to train athletes to land, decelerate, and push off with better lower limb alignment and improved trunk control, balance, and proprioception. The reported risk reductions range from 41% to 88% [7,8,11]. Given the age and frequency at which these injuries most often occur and their potential sequelae, perhaps targeting injury prevention programs to physical education classes in public schools could address a growing public health problem.The study by Peat and colleagues highlights several areas for further study. Knowledge is needed on the natural history of knee injuries in the development of knee OA as well as the potential for prevention programs to reduce the incidence. The spike of injuries in females between 35 and 49 requires confirmation and further investigation as to its causes, prevention, and potential role in OA development or progression. The same is true for injuries that occur in middle and older age, often coinciding with a time when knee OA has been diagnosed. Further clarity is needed around meniscal injury: what is traumatic injury and what is degenerative knee disease? There is still much to discover about the different knee injury types throughout the lifespan and the initiation and progression of knee OA. The study by Peat and colleagues [1] provides a good platform for this to be pursued.     

Modulation of hippocampal plasticity in learning and memory

Synaptic plasticity plays a central role in the study of neural mechanisms of learning and memory. Plasticity rules are not invariant over time but are under neuromodulatory control, enabling behavioral states to influence memory formation. Neuromodulation controls synaptic plasticity at network level by directing information flow, at circuit level through changes in excitation/inhibition balance, and at synaptic level through modulation of intracellular signaling cascades. Although most research has focused on modulation of principal neurons, recent progress has uncovered important roles for interneurons in not only routing information, but also setting conditions for synaptic plasticity. Moreover, astrocytes have been shown to both gate and mediate plasticity. These additional mechanisms must be considered for a comprehensive mechanistic understanding of learning and memory.