Showing papers in "Annals of the New York Academy of Sciences in 2008"

The Brain's Default Network Anatomy, Function, and Relevance to Disease

Abstract: Thirty years of brain imaging research has converged to define the brain’s default network—a novel and only recently appreciated brain system that participates in internal modes of cognition Here we synthesize past observations to provide strong evidence that the default network is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment Analysis of connectional anatomy in the monkey supports the presence of an interconnected brain system Providing insight into function, the default network is active when individuals are engaged in internally focused tasks including autobiographical memory retrieval, envisioning the future, and conceiving the perspectives of others Probing the functional anatomy of the network in detail reveals that it is best understood as multiple interacting subsystems The medial temporal lobe subsystem provides information from prior experiences in the form of memories and associations that are the building blocks of mental simulation The medial prefrontal subsystem facilitates the flexible use of this information during the construction of self-relevant mental simulations These two subsystems converge on important nodes of integration including the posterior cingulate cortex The implications of these functional and anatomical observations are discussed in relation to possible adaptive roles of the default network for using past experiences to plan for the future, navigate social interactions, and maximize the utility of moments when we are not otherwise engaged by the external world We conclude by discussing the relevance of the default network for understanding mental disorders including autism, schizophrenia, and Alzheimer’s disease

The Adolescent Brain

Abstract: Adolescence is a developmental period characterized by suboptimal decisions and actions that are associated with an increased incidence of unintentional injuries, violence, substance abuse, unintended pregnancy, and sexually transmitted diseases. Traditional neurobiological and cognitive explanations for adolescent behavior have failed to account for the nonlinear changes in behavior observed during adolescence, relative to both childhood and adulthood. This review provides a biologically plausible model of the neural mechanisms underlying these nonlinear changes in behavior. We provide evidence from recent human brain imaging and animal studies that there is a heightened responsiveness to incentives and socioemotional contexts during this time, when impulse control is still relatively immature. These findings suggest differential development of bottom-up limbic systems, implicated in incentive and emotional processing, to top-down control systems during adolescence as compared to childhood and adulthood. This developmental pattern may be exacerbated in those adolescents prone to emotional reactivity, increasing the likelihood of poor outcomes.

Chronic Stress, Drug Use, and Vulnerability to Addiction

Abstract: Stress is a well-known risk factor in the development of addiction and in addiction relapse vulnerability. A series of population-based and epidemiological studies have identified specific stressors and individual-level variables that are predictive of substance use and abuse. Preclinical research also shows that stress exposure enhances drug self-administration and reinstates drug seeking in drug-experienced animals. The deleterious effects of early life stress, child maltreatment, and accumulated adversity on alterations in the corticotropin releasing factor and hypothalamic-pituitary-adrenal axis (CRF/HPA), the extrahypothalamic CRF, the autonomic arousal, and the central noradrenergic systems are also presented. The effects of these alterations on the corticostriatal-limbic motivational, learning, and adaptation systems that include mesolimbic dopamine, glutamate, and gamma-amino-butyric acid (GABA) pathways are discussed as the underlying pathophysiology associated with stress-related risk of addiction. The effects of regular and chronic drug use on alterations in these stress and motivational systems are also reviewed, with specific attention to the impact of these adaptations on stress regulation, impulse control, and perpetuation of compulsive drug seeking and relapse susceptibility. Finally, research gaps in furthering our understanding of the association between stress and addiction are presented, with the hope that addressing these unanswered questions will significantly influence new prevention and treatment strategies to address vulnerability to addiction.

Poverty and access to health care in developing countries.

Abstract: People in poor countries tend to have less access to health services than those in better-off countries, and within countries, the poor have less access to health services. This article documents disparities in access to health services in low- and middle-income countries (LMICs), using a framework incorporating quality, geographic accessibility, availability, financial accessibility, and acceptability of services. Whereas the poor in LMICs are consistently at a disadvantage in each of the dimensions of access and their determinants, this need not be the case. Many different approaches are shown to improve access to the poor, using targeted or universal approaches, engaging government, nongovernmental, or commercial organizations, and pursuing a wide variety of strategies to finance and organize services. Key ingredients of success include concerted efforts to reach the poor, engaging communities and disadvantaged people, encouraging local adaptation, and careful monitoring of effects on the poor. Yet governments in LMICs rarely focus on the poor in their policies or the implementation or monitoring of health service strategies. There are also new innovations in financing, delivery, and regulation of health services that hold promise for improving access to the poor, such as the use of health equity funds, conditional cash transfers, and coproduction and regulation of health services. The challenge remains to find ways to ensure that vulnerable populations have a say in how strategies are developed, implemented, and accounted for in ways that demonstrate improvements in access by the poor.

Metabolic, phylogenetic, and ecological diversity of the methanogenic archaea.

Abstract: Although of limited metabolic diversity, methanogenic archaea or methanogens possess great phylogenetic and ecological diversity. Only three types of methanogenic pathways are known: CO(2)-reduction, methyl-group reduction, and the aceticlastic reaction. Cultured methanogens are grouped into five orders based upon their phylogeny and phenotypic properties. In addition, uncultured methanogens that may represent new orders are present in many environments. The ecology of methanogens highlights their complex interactions with other anaerobes and the physical and chemical factors controlling their function.

Ecosystem Services Provided by Birds

Abstract: Ecosystem services are natural processes that benefit humans. Birds contribute the four types of services recognized by the UN Millennium Ecosystem Assessment-provisioning, regulating, cultural, and supporting services. In this review, we concentrate primarily on supporting services, and to a lesser extent, provisioning and regulating services. As members of ecosystems, birds play many roles, including as predators, pollinators, scavengers, seed dispersers, seed predators, and ecosystem engineers. These ecosystem services fall into two subcategories: those that arise via behavior (like consumption of agricultural pests) and those that arise via bird products (like nests and guano). Characteristics of most birds make them quite special from the perspective of ecosystem services. Because most birds fly, they can respond to irruptive or pulsed resources in ways generally not possible for other vertebrates. Migratory species link ecosystem processes and fluxes that are separated by great distances and times. Although the economic value to humans contributed by most, if not all, of the supporting services has yet to be quantified, we believe they are important to humans. Our goals for this review are 1) to lay the groundwork on these services to facilitate future efforts to estimate their economic value, 2) to highlight gaps in our knowledge, and 3) to point to future directions for additional research.

Sleep Deprivation and Vigilant Attention

Abstract: Sleep deprivation severely compromises the ability of human beings to respond to stimuli in a timely fashion. These deficits have been attributed in large part to failures of vigilant attention, which many theorists believe forms the bedrock of the other more complex components of cognition. One of the leading paradigms used as an assay of vigilant attention is the psychomotor vigilance test (PVT), a high signal-load reaction-time test that is extremely sensitive to sleep deprivation. Over the last twenty years, four dominant findings have emerged from the use of this paradigm. First, sleep deprivation results in an overall slowing of responses. Second, sleep deprivation increases the propensity of individuals to lapse for lengthy periods (>500ms), as well as make errors of commission. Third, sleep deprivation enhances the time-on-task effect within each test bout. Finally, PVT results during extended periods of wakefulness reveal the presence of interacting circadian and homeostatic sleep drives. A theme that links these findings is the interplay of “top-down” and “bottom-up” attention in producing the unstable and unpredictable patterns of behavior that are the hallmark of the sleep-deprived state.

Oxidative Stress in Parkinson's Disease

Abstract: Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, time-course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death-related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.

Toll-like Receptor and RIG-1-like Receptor Signaling

Abstract: Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) constitute distinct families of pattern-recognition receptors that sense nucleic acids derived from viruses and trigger antiviral innate immune responses. TLR3, TLR7, and TLR9 are membrane proteins localized to the endosome that recognize viral double-stranded RNA, single-stranded RNA, and DNA, respectively, while RLRs, including RIG-I, Mda5, and LGP2, are cytoplasmic proteins that recognize viral RNA. Upon recognition of these nucleic acid species, TLRs and RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways culminating in activation of NF-κB, MAP kinases, and IRFs that control the transcription of genes encoding type I interferon and other inflammatory cytokines, which are important for eliminating viruses. Here, we review recent insights into the signaling pathways initiated by TLR and RLR and their roles in innate and adaptive immune responses.

Associations between sleep loss and increased risk of obesity and diabetes

Abstract: During the past few decades, sleep curtailment has become a very common in industrialized countries. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity and diabetes. Evidence is rapidly accumulating to indicate that chronic partial sleep loss may increase the risk of obesity and diabetes. Laboratory studies in healthy volunteers have shown that experimental sleep restriction is associated with an adverse impact on glucose homeostasis. Insulin sensitivity decreases rapidly and markedly without adequate compensation in beta cell function, resulting in an elevated risk of diabetes. Prospective epidemiologic studies in both children and adults are consistent with a causative role of short sleep in the increased risk of diabetes. Sleep curtailment is also associated with a dysregulation of the neuroendocrine control of appetite, with a reduction of the satiety factor, leptin, and an increase in the hunger-promoting hormone, ghrelin. Thus, sleep loss may alter the ability of leptin and ghrelin to accurately signal caloric need, acting in concert to produce an internal misperception of insufficient energy availability. The adverse impact of sleep deprivation on appetite regulation is likely to be driven by increased activity in neuronal populations expressing the excitatory peptides orexins that promote both waking and feeding. Consistent with the laboratory evidence, multiple epidemiologic studies have shown an association between short sleep and higher body mass index after controlling for a variety of possible confounders.

Episodic simulation of future events: concepts, data, and applications.

Abstract: This article focuses on the neural and cognitive processes that support imagining or simulating future events, a topic that has recently emerged in the forefront of cognitive neuroscience. We begin by considering concepts of simulation from a number of areas of psychology and cognitive neuroscience in order to place our use of the term in a broader context. We then review neuroimaging, neuropsychological, and cognitive studies that have examined future-event simulation and its relation to episodic memory. This research supports the idea that simulating possible future events depends on much of the same neural machinery, referred to here as a core network, as does remembering past events. After discussing several theoretical accounts of the data, we consider applications of work on episodic simulation for research concerning clinical populations suffering from anxiety or depression. Finally, we consider other aspects of future-oriented thinking that we think are related to episodic simulation, including planning, prediction, and remembering intentions. These processes together comprise what we have termed "the prospective brain," whose primary function is to use past experiences to anticipate future events.

The Role of Mitochondria in Reactive Oxygen Species Metabolism and Signaling

Abstract: Oxidative stress is considered a major contributor to the etiology of both "normal" senescence and severe pathologies with serious public health implications. Several cellular sources, including mitochondria, are known to produce significant amounts of reactive oxygen species (ROS) that may contribute to intracellular oxidative stress. Mitochondria possess at least 10 known sites that are capable of generating ROS, but they also feature a sophisticated multilayered ROS defense system that is much less studied. This review summarizes the current knowledge about major components involved in mitochondrial ROS metabolism and factors that regulate ROS generation and removal at the level of mitochondria. An integrative systemic approach is applied to analysis of mitochondrial ROS metabolism, which is "dissected" into ROS generation, ROS emission, and ROS scavenging. The in vitro ROS-producing capacity of several mitochondrial sites is compared in the metabolic context and the role of mitochondria in ROS-dependent intracellular signaling is discussed.

Cognitive Neuroscience of Aging

Abstract: The number of reports on the cognitive neuroscience of aging has increased in recent years, and most of these studies have found many similarities in the patterns of activity in young and old adults, indicating that basic neural mechanisms are maintained into older age. Despite these overall similarities, older adults often have less activity in some regions, such as medial temporal areas during memory processing and visual regions across a variety of cognitive domains. It seems clear that age reductions in cognitive function can be tied, at least in part, to these reductions in brain activity. On the other hand, older adults typically also overrecruit some brain areas, mainly the ventral or dorsal prefrontal cortex during memory tasks, as well as both the frontal and parietal regions during tasks engaging cognitive control processes, such as attention. Sometimes this overrecruitment appears to be in response to altered function in other brain regions and is often seen in those older adults who perform better on the task at hand. These findings have provided rather convincing support for the idea that overrecruitment can be compensatory in the elderly. Nevertheless, not all age increases can be interpreted as compensatory, and some are more indicative of neural inefficiency. The challenge facing future research will be to understand the task conditions that promote compensation in older adults, the role of the various brain areas in aiding cognitive function, and how these compensatory mechanisms can be elicited to enhance quality of life in the elderly.

Ocean acidification and its potential effects on marine ecosystems.

Abstract: Ocean acidification is rapidly changing the carbonate system of the world oceans. Past mass extinction events have been linked to ocean acidification, and the current rate of change in seawater chemistry is unprecedented. Evidence suggests that these changes will have significant consequences for marine taxa, particularly those that build skeletons, shells, and tests of biogenic calcium carbonate. Potential changes in species distributions and abundances could propagate through multiple trophic levels of marine food webs, though research into the long-term ecosystem impacts of ocean acidification is in its infancy. This review attempts to provide a general synthesis of known and/or hypothesized biological and ecosystem responses to increasing ocean acidification. Marine taxa covered in this review include tropical reef-building corals, cold-water corals, crustose coralline algae, Halimeda, benthic mollusks, echinoderms, coccolithophores, foraminifera, pteropods, seagrasses, jellyfishes, and fishes. The risk of irreversible ecosystem changes due to ocean acidification should enlighten the ongoing CO(2) emissions debate and make it clear that the human dependence on fossil fuels must end quickly. Political will and significant large-scale investment in clean-energy technologies are essential if we are to avoid the most damaging effects of human-induced climate change, including ocean acidification.

Detecting awareness in the vegetative state.

Abstract: The assessment of residual brain function in the vegetative state, is extremely difficult and depends frequently on subjective interpretations of observed spontaneous and volitional behaviors. For those patients who retain peripheral motor function, rigorous behavioral assessment supported by structural imaging and electrophysiology is usually sufficient to establish a patient's level of wakefulness and awareness. However, it is becoming increasingly apparent that, in some patients, damage to the peripheral motor system may prevent overt responses to command, even though the cognitive ability to perceive and understand such commands may remain intact. Advances in functional neuroimaging suggest a novel solution to this problem; in several recent cases, so-called "activation" studies have been used to identify residual cognitive function and even conscious awareness in patients who are assumed to be vegetative, yet retain cognitive abilities that have evaded detection using standard clinical methods.

Regulation of endothelial junctional permeability.

Abstract: The endothelium is a semi-permeable barrier that regulates the flux of liquid and solutes, including plasma proteins, between the blood and surrounding tissue. The permeability of the vascular barrier can be modified in response to specific stimuli acting on endothelial cells. Transport across the endothelium can occur via two different pathways: through the endothelial cell (transcellular) or between adjacent cells, through interendothelial junctions (paracellular). This review focuses on the regulation of the paracellular pathway. The paracellular pathway is composed of adhesive junctions between endothelial cells, both tight junctions and adherens junctions. The actin cytoskeleton is bound to each junction and controls the integrity of each through actin remodeling. These interendothelial junctions can be disassembled or assembled to either increase or decrease paracellular permeability. Mediators, such as thrombin, TNF-alpha, and LPS, stimulate their respective receptor on endothelial cells to initiate signaling that increases cytosolic Ca2+ and activates myosin light chain kinase (MLCK), as well as monomeric GTPases RhoA, Rac1, and Cdc42. Ca2+ activation of MLCK and RhoA disrupts junctions, whereas Rac1 and Cdc42 promote junctional assembly. Increased endothelial permeability can be reversed with "barrier stabilizing agents," such as sphingosine-1-phosphate and cyclic adenosine monophosphate (cAMP). This review provides an overview of the mechanisms that regulate paracellular permeability.

Glutamate and neurotrophic factors in neuronal plasticity and disease.

Abstract: Glutamate’s role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis and neuron survival in the developing and adult mammalian nervous system. Cell surface glutamate receptors are coupled to Ca2+ influx and release from endoplasmic reticulum stores which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF) which, in turn, modifies neuronal glutamate sensitivity, Ca2+ homeostasis and plasticity. Neurotrophic factors may modify glutamate signalling directly, by changing the expression of glutamate receptor subunits and Ca2+-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins and anti-apoptotic Bcl2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer’s disease to psychiatric disorders. By enhancing neurotrophic factor signalling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signalling and protect against neurological disorders.

Biodiversity Conservation in Tropical Agroecosystems

Abstract: It is almost certainly the case that many populations have always existed as metapopulations, leading to the conclusion that local extinctions are common and normally balanced by migrations. This conclusion has major consequences for biodiversity conservation in fragmented tropical forests and the agricultural matrices in which they are embedded. Here we make the argument that the conservation paradigm that focuses on setting aside pristine forests while ignoring the agricultural landscape is a failed strategy in light of what is now conventional wisdom in ecology. Given the fragmented nature of most tropical ecosystems, agricultural landscapes should be an essential component of any conservation strategy. We review the literature on biodiversity in tropical agricultural landscapes and present evidence that many tropical agricultural systems have high levels of biodiversity (planned and associated). These systems represent, not only habitat for biodiversity, but also a high-quality matrix that permits the movement of forest organisms among patches of natural vegetation. We review a variety of agroecosystem types and conclude that diverse, low-input systems using agroecological principles are probably the best option for a high-quality matrix. Such systems are most likely to be constructed by small farmers with land titles, who, in turn, are normally the consequence of grassroots social movements. Therefore, the new conservation paradigm should incorporate a landscape approach in which small farmers, through their social organizations, work with conservationists to create a landscape matrix dominated by productive agroecological systems that facilitate interpatch migration while promoting a sustainable and dignified livelihood for rural communities.

The Nrf2–ARE Pathway

Abstract: Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative, stress-related, neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress-induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes, suggesting that Nrf2 activation in astrocytes somehow confers resistance to naive neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE-mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.

The Neural Correlates of Consciousness An Update

Abstract: This review examines recent advances in the study of brain correlates of consciousness. First, we briefly discuss some useful distinctions between consciousness and other brain functions. We then examine what has been learned by studying global changes in the level of consciousness, such as sleep, anesthesia, and seizures. Next we consider some of the most common paradigms used to study the neural correlates for specific conscious percepts and examine what recent findings say about the role of different brain regions in giving rise to consciousness for that percept. Then we discuss dynamic aspects of neural activity, such as sustained versus phasic activity, feedforward versus reentrant activity, and the role of neural synchronization. Finally, we briefly consider how a theoretical analysis of the fundamental properties of consciousness can usefully complement neurobiological studies.

Classifications of Atmospheric Circulation Patterns

Abstract: We review recent advances in classifications of circulation patterns as a specific research area within synoptic climatology. The review starts with a general description of goals of classification and the historical development in the field. We put circulation classifications into a broader context within climatology and systematize the varied methodologies and approaches. We characterize three basic groups of classifications: subjective (also called manual), mixed (hybrid), and objective (computer-assisted, automated). The roles of cluster analysis and principal component analysis in the classification process are clarified. Several recent methodological developments in circulation classifications are identified and briefly described: the introduction of nonlinear methods, objectivization of subjective catalogs, efforts to optimize classifications, the need for intercomparisons of classifications, and the progress toward an optimum, if possible unified, classification method. Among the recent tendencies in the applications of circulation classifications, we mention a more extensive use in climate studies, both of past, present, and future climates, innovative applications in the ensemble forecasting, increasing variety of synoptic-climatological investigations, and steps above from the troposphere. After introducing the international activity within the field of circulation classifications, the COST733 Action, we briefly describe outputs of the inventory of classifications in Europe, which was carried out within the Action. Approaches to the evaluation of classifications and their mutual comparisons are also reviewed. A considerable part of the review is devoted to three examples of applications of circulation classifications: in historical climatology, in analyses of recent climate variations, and in analyses of outputs from global climate models.

Spatial cognition and the brain.

Abstract: Recent advances in the understanding of spatial cognition are reviewed, focusing on memory for locations in large-scale space and on those advances inspired by single-unit recording and lesion studies in animals. Spatial memory appears to be supported by multiple parallel representations, including egocentric and allocentric representations, and those updated to accommodate self-motion. The effects of these representations can be dissociated behaviorally, developmentally, and in terms of their neural bases. It is now becoming possible to construct a mechanistic neural-level model of at least some aspects of spatial memory and imagery, with the hippocampus and medial temporal lobe providing allocentric environmental representations, the parietal lobe egocentric representations, and the retrosplenial cortex and parieto-occipital sulcus allowing both types of representation to interact. Insights from this model include a common mechanism for the construction of spatial scenes in the service of both imagery and episodic retrieval and a role for the remainder of Papez's circuit in orienting the viewpoint used. In addition, it appears that hippocampal and striatal systems process different aspects of environmental layout (boundaries and local landmarks, respectively) and do so using different learning rules (incidental learning and associative reinforcement, respectively).

Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress

Abstract: The hypothalamo-pituitary-adrenocortical (HPA) axis is responsible for initiation of glucocorticoid stress responses in all vertebrate animals. Activation of the axis is regulated by diverse afferent input to the hypothalamic paraventricular nucleus (PVN). This review discusses brain mechanisms subserving generation and inhibition of stress responses focusing on the contribution of the limbic system and highlighting recent conceptual advances regarding organization of stress response pathways in the brain. First, control of HPA axis responses to psychogenic stimuli is exerted by a complex neurocircuitry that involves oligosynaptic networks between limbic forebrain structures and the PVN. Second, individual stress-modulatory structures can have a heterogeneous impact on HPA axis responses, based on anatomical micro-organization and/or stimulus properties. Finally, HPA axis hyperactivity pursuant to chronic stress involves a substantial functional and perhaps anatomical reorganization of central stress-integrative circuits. Overall, the data suggest that individual brain regions do not merely function as monolithic activators or inhibitors of the HPA axis and that network approaches need be taken to fully understand the nature of the neuroendocrine stress response.

Brain Glucose Hypometabolism and Oxidative Stress in Preclinical Alzheimer's Disease

Abstract: One of the main features of Alzheimer’s disease (AD) is the severe reduction of the cerebral metabolic rate for glucose (CMRglc). In vivo imaging using positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG–PET) demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. Increasing evidence suggests that CMRglc reductions occur at the preclinical stages of AD. CMRglc reductions were observed on FDG–PET before the onset of disease in several groups of at-risk individuals, including patients with mild cognitive impairment (MCI), often a prodrome to AD; presymptomatic individuals carrying mutations responsible for early-onset familial AD; cognitively normal elderly individuals followed for several years until they declined to MCI and eventually to AD; normal, middle-aged individuals who expressed subjective memory complaints and were carriers of the apolipoprotein E epsilon-4 allele, a strong genetic risk factor for late-onset AD. However, the causes of the early metabolic dysfunction forerunning the onset of AD are not known. An increasing body of evidence indicates a deficient or altered energy metabolism that could change the overall oxidative microenvironment for neurons during the pathogenesis and progression of AD, leading to alterations in mitochondrial enzymes and in glucose metabolism in AD brain tissue. The present paper reviews findings that implicate hypometabolism and oxidative stress as crucial players in the initiation and progression of synaptic pathology in AD.

Old Acetogens, New Light

Abstract: Acetogens utilize the acetyl-CoA Wood-Ljungdahl pathway as a terminal electron-accepting, energy-conserving, CO(2)-fixing process. The decades of research to resolve the enzymology of this pathway (1) preceded studies demonstrating that acetogens not only harbor a novel CO(2)-fixing pathway, but are also ecologically important, and (2) overshadowed the novel microbiological discoveries of acetogens and acetogenesis. The first acetogen to be isolated, Clostridium aceticum, was reported by Klaas Tammo Wieringa in 1936, but was subsequently lost. The second acetogen to be isolated, Clostridium thermoaceticum, was isolated by Francis Ephraim Fontaine and co-workers in 1942. C. thermoaceticum became the most extensively studied acetogen and was used to resolve the enzymology of the acetyl-CoA pathway in the laboratories of Harland Goff Wood and Lars Gerhard Ljungdahl. Although acetogenesis initially intrigued few scientists, this novel process fostered several scientific milestones, including the first (14)C-tracer studies in biology and the discovery that tungsten is a biologically active metal. The acetyl-CoA pathway is now recognized as a fundamental component of the global carbon cycle and essential to the metabolic potentials of many different prokaryotes. The acetyl-CoA pathway and variants thereof appear to be important to primary production in certain habitats and may have been the first autotrophic process on earth and important to the evolution of life. The purpose of this article is to (1) pay tribute to those who discovered acetogens and acetogenesis, and to those who resolved the acetyl-CoA pathway, and (2) highlight the ecology and physiology of acetogens within the framework of their scientific roots.

Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates.

Abstract: Lesions of the cerebral white matter (WM) result in focal neurobehavioral syndromes, neuropsychiatric phenomena, and dementia. The cerebral WM contains fiber pathways that convey axons linking cerebral cortical areas with each other and with subcortical structures, facilitating the distributed neural circuits that subserve sensorimotor function, intellect, and emotion. Recent neuroanatomical investigations reveal that these neural circuits are topographically linked by five groupings of fiber tracts emanating from every neocortical area: (1) cortico-cortical association fibers; (2) corticostriatal fibers; (3) commissural fibers; and cortico-subcortical pathways to (4) thalamus and (5) pontocerebellar system, brain stem, and/or spinal cord. Lesions of association fibers prevent communication between cortical areas engaged in different domains of behavior. Lesions of subcortical structures or projection/striatal fibers disrupt the contribution of subcortical nodes to behavior. Disconnection syndromes thus result from lesions of the cerebral cortex, subcortical structures, and WM tracts that link the nodes that make up the distributed circuits. The nature and the severity of the clinical manifestations of WM lesions are determined, in large part, by the location of the pathology: discrete neurological and neuropsychiatric symptoms result from focal WM lesions, whereas cognitive impairment across multiple domains—WM dementia—occurs in the setting of diffuse WM disease. We present a detailed review of the conditions affecting WM that produce these neurobehavioral syndromes, and consider the pathophysiology, clinical effects, and broad significance of the effects of aging and vascular compromise on cerebral WM, in an attempt to help further the understanding, diagnosis, and treatment of these disorders.

Drug addiction and the memory systems of the brain.

Abstract: We review drug addiction from the perspective of the hypothesis that drugs of abuse interact with distinct brain memory systems. We focus on emotional and procedural forms of memory, encompassing Pavlovian and instrumental conditioning, both for action-outcome and for stimulus-response associations. Neural structures encompassed by these systems include the amygdala, hippocampus, nucleus accumbens, and dorsal striatum. Additional influences emanate from the anterior cingulate and prefrontal cortex, which are implicated in the encoding and retrieval of drug-related memories that lead to drug craving and drug use. Finally, we consider the ancillary point that chronic abuse of many drugs may impact directly on neural memory systems via neuroadaptive and neurotoxic effects that lead to cognitive impairments in which memory dysfunction is prominent.

Food security, poverty, and human development in the United States.

Abstract: Access to food is essential to optimal development and function in children and adults. Food security, food insecurity, and hunger have been defined and a U.S. Food Security Scale was developed and is administered annually by the Census Bureau in its Current Population Survey. The eight child-referenced items now make up a Children's Food Security Scale. This review summarizes the data on household and children's food insecurity and its relationship with children's health and development and with mothers' depressive symptoms. It is demonstrable that food insecurity is a prevalent risk to the growth, health, cognitive, and behavioral potential of America's poor and near-poor children. Infants and toddlers in particular are at risk from food insecurity even at the lowest levels of severity, and the data indicate an "invisible epidemic" of a serious condition. Food insecurity is readily measured and rapidly remediable through policy changes, which a country like the United States, unlike many others, is fully capable of implementing. The food and distribution resources exist; the only constraint is political will.

The Effect of Poverty on Child Development and Educational Outcomes

Abstract: Poverty affects a child's development and educational outcomes beginning in the earliest years of life, both directly and indirectly through mediated, moderated, and transactional processes. School readiness, or the child's ability to use and profit from school, has been recognized as playing a unique role in escape from poverty in the United States and increasingly in developing countries. It is a critical element but needs to be supported by many other components of a poverty-alleviation strategy, such as improved opportunity structures and empowerment of families. The paper reviews evidence from interventions to improve school readiness of children in poverty, both in the United States and in developing countries, and provides recommendations for future research and action.