Showing papers in "Annals of the New York Academy of Sciences in 1999"
TL;DR: This paper examines the data regarding the SES‐health gradient, addressing causal direction, generalizability across populations and diseases, and associations with health for different indicators of SES.
Abstract: In the past 15 years, we have seen a marked increase in research on socioeconomic status (SES) and health. Research in the first part of this era examined the nature of the relationship of SES and health, revealing a graded association; SES is important to health not only for those in poverty, but at all levels of SES. On average, the more advantaged individuals are, the better their health. In this paper we examine the data regarding the SES-health gradient, addressing causal direction, generalizability across populations and diseases, and associations with health for different indicators of SES. In the most recent era, researchers are increasingly exploring the mechanisms by which SES exerts an influence on health. There are multiple pathways by which SES determines health; a comprehensive analysis must include macroeconomic contexts and social factors as well as more immediate social environments, individual psychological and behavioral factors, and biological predispositions and processes.
1,518 citations
TL;DR: McEwen et al. as discussed by the authors pointed out that stress is not just the dramatic stressful events that exact their toll but rather the many events of daily life that elevate activities of physiological systems to cause some measure of wear and tear.
Abstract: Stress is a condition of human existence and a factor in the expression of disease. A broader view of stress is that it is not just the dramatic stressful events that exact their toll but rather the many events of daily life that elevate activities of physiological systems to cause some measure of wear and tear. We call this wear and tear "allostatic load," and it reflects not only the impact of life experiences but also of genetic load; individual habits reflecting items such as diet, exercise, and substance abuse; and developmental experiences that set life-long patterns of behavior and physiological reactivity (see McEwen). Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation, but in the long run allostatic load causes changes in the body that lead to disease. This will be illustrated for the immune system and brain. Among the most potent of stressors are those arising from competitive interactions between animals of the same species, leading to the formation of dominance hierarchies. Psychosocial stress of this type not only impairs cognitive function of lower ranking animals, but it can also promote disease (e.g. atherosclerosis) among those vying for the dominant position. Social ordering in human society is also associated with gradients of disease, with an increasing frequency of mortality and morbidity as one descends the scale of socioeconomic status that reflects both income and education. Although the causes of these gradients of health are very complex, they are likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources and negative life events and the allostatic load that this burden places on the physiological systems involved in coping and adaptation.
1,479 citations
TL;DR: The complex ways in which race and socioeconomic status (SES) combine to affect health are considered, which accounts for much of the observed racial disparities in health.
Abstract: Higher disease rates for blacks (or African Americans) compared to whites are pervasive and persistent over time, with the racial gap in mortality widening in recent years for multiple causes of death. Other racial/ethnic minority populations also have elevated disease risk for some health conditions. This paper considers the complex ways in which race and socioeconomic status (SES) combine to affect health. SES accounts for much of the observed racial disparities in health. Nonetheless, racial differences often persist even at “equivalent” levels of SES. Racism is an added burden for nondominant populations. Individual and institutional discrimination, along with the stigma of inferiority, can adversely affect health by restricting socioeconomic opportunities and mobility. Racism can also directly affect health in multiple ways. Residence in poor neighborhoods, racial bias in medical care, the stress of experiences of discrimination and the acceptance of the societal stigma of inferiority can have deleterious consequences for health.
1,411 citations
TL;DR: This chapter attempts to give an overview of the different genes coding for K+ channel principal and accessory subunits and their genealogical relationships, and discusses the possible correlation of different principal sub units with native K+ channels, the biophysical and pharmacological properties of channels formed when principal subunits are expressed in heterologous expression systems, and their patterns of tissue expression.
Abstract: K+ channel principal subunits are by far the largest and most diverse of the ion channels. This diversity originates partly from the large number of genes coding for K+ channel principal subunits, but also from other processes such as alternative splicing, generating multiple mRNA transcripts from a single gene, heteromeric assembly of different principal subunits, as well as possible RNA editing and posttranslational modifications. In this chapter, we attempt to give an overview (mostly in tabular format) of the different genes coding for K+ channel principal and accessory subunits and their genealogical relationships. We discuss the possible correlation of different principal subunits with native K+ channels, the biophysical and pharmacological properties of channels formed when principal subunits are expressed in heterologous expression systems, and their patterns of tissue expression. In addition, we devote a section to describing how diversity of K+ channels can be conferred by heteromultimer formation, accessory subunits, alternative splicing, RNA editing and posttranslational modifications. We trust that this collection of facts will be of use to those attempting to compare the properties of new subunits to the properties of others already known or to those interested in a comparison between native channels and cloned candidates.
1,141 citations
TL;DR: Accumulated behavioral, neuroanatomical, and neuroendocrine data in hamsters, other rodents, and other mammals indicate that this circuit is embedded in a larger integrated network that controls not only male mating behavior, but female sexual behavior, parental behavior, and various forms of aggression.
Abstract: Hormonal and chemosensory signals regulate social behaviors in a wide variety of mammals. In the male Syrian hamster, these signals are integrated in nuclei of the medial extended amygdala, where olfactory and vomeronasal system transmission is modulated by populations of androgen- and estrogen-sensitive neurons. Evidence from behavioral changes following lesions and from immediate early gene expression supports the hypothesis that the medial extended amygdala and medial preoptic area belong to a circuit that functions selectively in male sexual behavior. However, accumulated behavioral, neuroanatomical, and neuroendocrine data in hamsters, other rodents, and other mammals indicate that this circuit is embedded in a larger integrated network that controls not only male mating behavior, but female sexual behavior, parental behavior, and various forms of aggression. In this context, perhaps an individual animal's social responses can be more easily understood as a repertoire of closely interrelated, hormone-regulated behaviors, shaped by development and experience and modulated acutely by the environmental signals and the hormonal milieu of the brain.
1,011 citations
TL;DR: Chronic stress may capture much of the variance in health and social outcomes associated with harmful aspects of lower social status and research targeting this hypothesis is needed to determine the extent to which stress is a pathway linking SES and health.
Abstract: Socioeconomic status (SES) is an important predictor of a range of health and illness outcomes. Research seeking to identify the extent to which this often-reported effect is due to protective benefits of higher SES or to toxic elements of lower social status has not yielded consistent or conclusive findings. A relatively novel hypothesis is that these effects are due to chronic stress that is associated with SES; lower SES is reliably associated with a number of important social and environmental conditions that contribute to chronic stress burden, including crowding, crime, noise pollution, discrimination, and other hazards or stressors. In other words, chronic stress may capture much of the variance in health and social outcomes associated with harmful aspects of lower social status. Low SES is generally associated with distress, prevalence of mental health problems, and with health-impairing behaviors that are also related to stress. Research targeting this hypothesis is needed to determine the extent to which stress is a pathway linking SES and health.
721 citations
TL;DR: Understanding of the special role of the ventral striatum is enriched in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal‐directed behavior, through different forms of associative learning.
Abstract: Only recently have the functional implications of the organization of the ventral striatum, amygdala, and related limbic-cortical structures, and their neuroanatomical interactions begun to be clarified. Processes of activation and reward have long been associated with the NAcc and its dopamine innervation, but the precise relationships between these constructs have remained elusive. We have sought to enrich our understanding of the special role of the ventral striatum in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal-directed behavior, through different forms of associative learning. Such appetitive behavior comprises many subcomponents, some of which we have isolated in these experiments to reveal that, not surprisingly, the mechanisms by which an animal sequences responding to reach a goal are complex. The data reveal how the different components, pavlovian approach (or sign-tracking), conditioned reinforcement (whereby pavlovian stimuli control goal-directed action), and also more general response-invigorating processes (often called "activation," "stress," or "drive") may be integrated within the ventral striatum through convergent interactions of the amygdala, other limbic cortical structures, and the mesolimbic dopamine system to produce coherent behavior. The position is probably not far different when considering aversively motivated behavior. Although it may be necessary to employ simplified, even abstract, paradigms for isolating these mechanisms, their concerted action can readily be appreciated in an adaptive, functional setting, such as the responding by rats for intravenous cocaine under a second-order schedule of reinforcement. Here, the interactions of primary reinforcement, psychomotor activation, pavlovian conditioning, and the control that drug cues exert over the integrated drug-seeking response can be seen to operate both serially and concurrently. The power of our analytic techniques for understanding complex motivated behavior has been evident for some time. However, the crucial point is that we are now able to map these components with increasing certainty onto discrete amygdaloid, and other limbic cortical-ventral striatal subsystems. The neural dissection of these mechanisms also serves an important theoretical purpose in helping to validate the various hypothetical constructs and further developing theory. Major challenges remain, not the least of which is an understanding of the operation of the ventral striatum together with its dopaminergic innervation and its interactions with the basolateral amygdala, hippocampal formation, and prefrontal cortex at a more mechanistic, neuronal level.
695 citations
TL;DR: The results support the idea that the nucleus accumbens may consist of a collection of neuronal ensembles with different input‐output relationships and, presumably, different functional characteristics.
Abstract: The ventral striatum, which prominently includes the nucleus accumbens (Acb), is a heterogeneous area. Within the Acb of rats, a peripherally located shell and a centrally situated core can be recognized that have different connectional, neurochemical, and functional identities. Although the Acb core resembles in many respects the dorsally adjacent caudate-putamen complex in its striatal character, the Acb shell has, in addition to striatal features, a more diverse array of neurochemical characteristics, and afferent and efferent connections. Inputs and outputs of the Acb, in particular of the shell, are inhomogeneously distributed, resulting in a mosaical arrangement of concentrations of afferent fibers and terminals and clusters of output neurons. To determine the precise relationships between the distributional patterns of various afferents (e.g., from the prefrontal cortex, the basal amygdaloid complex, the hippocampal formation, and the midline/intralaminar thalamic nuclei) and efferents to the ventral pallidum and mesencephalon, neuroanatomical anterograde and retrograde tracing experiments were carried out. The results of the double anterograde, double retrograde, and anterograde/retrograde tracing experiments indicate that various parts of the shell (dorsomedial, ventromedial, ventral, and lateral) and the core (medial and lateral) have different input-output characteristics. Furthermore, within these Acb regions, various populations of neurons can be identified, arranged in a cluster-like fashion, onto which specific sets of afferents converge and that project to particular output stations, distinct from the input-output relationships of neighboring, cluster-like neuronal populations. These results support the idea that the nucleus accumbens may consist of a collection of neuronal ensembles with different input-output relationships and, presumably, different functional characteristics.
673 citations
TL;DR: It is shown that people who have accumulated intra‐abdominal visceral fat frequently have multiple risks and vascular diseases, and “visceral fat syndrome” is a clinical entity compatible with Syndrome X.
Abstract: Syndrome X is a clinical syndrome in which multiple risks cluster in an individual, and it is a common basis of vascular disease in the industrial countries. The molecular basis of Syndrome X, however, has not been elucidated. We have analyzed body fat distribution using CT scan and have shown that people who have accumulated intra-abdominal visceral fat frequently have multiple risks and vascular diseases. Thus, “visceral fat syndrome” is a clinical entity compatible with Syndrome X. To clarify the molecular mechanism of the disorders in visceral fat syndrome, we analyzed the expressed genes in adipose tissue by a large-scale random sequencing. Unexpectedly, visceral fat expressed a variety of the genes for secretory proteins including various bioactive substances; we designated them adipocytokines. One of them, plasminogen activator inhibitor-1, was overproduced in accumulated visceral fat and might contribute to the development of vascular disease. We have also cloned a novel adipose-specific gene named adiponectin. Adiponectin is a collagen-like plasma protein which has an inhibitory effect on proliferation of vascular smooth muscle cells; its plasma levels are paradoxically decreased in obesity. Adipocytokines may play important roles in the development of the disorders in Syndrome X.
612 citations
TL;DR: A neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli is suggested, which may compensate for this dysfunction by inhibiting pathological limbic activity.
Abstract: Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correlated with both depression severity and "stressed" plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala-driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli. Antidepressant drugs may compensate for this dysfunction by inhibiting pathological limbic activity.
545 citations
TL;DR: The hypothesis that best fits current evidence is that the gradient is an “emergent property” of the interaction between the developmental status of people and the material and psychosocial conditions they encounter over their life course.
Abstract: Explanations of the socioeconomic gradient in health status must account for the observations that the gradient cuts across a wide range of disease processes and is capable of replicating itself on new disease processes as they emerge in society. Understanding this pattern requires an understanding of how human organisms can become generally vulnerable or resilient to disease over time: a huge collation task across different disciplines. The hypothesis that best fits current evidence is that the gradient is an "emergent property" of the interaction between the developmental status of people and the material and psychosocial conditions they encounter over their life course. Within this broad formulation, special attention is given to child development, and the prospect that socioeconomic differences in the quality of early life experiences contribute to subsequent gradients in health status through socioeconomic differences in brain sculpting and the conditioning of host defense systems that depend on communication with the developing brain. The contribution to the gradient in health is theorized to occur through a combination of latent effects, pathway effects, and cumulative disadvantage.
TL;DR: In preliminary analyses, the higher the stocks of social capital (as indicated by measures of trust and reciprocity in social surveys), the higher appear to be the health achievement of a given area.
Abstract: Social capital refers to those features of social relationships--such as levels of interpersonal trust and norms of reciprocity and mutual aid--that facilitate collective action for mutual benefit. Social capital is believed to play an important role in the functioning of community life across a variety of domains, ranging from the prevention of juvenile delinquency and crime, the promotion of successful youth development, and the enhancement of schooling and education to the encouragement of political participation. More recently, researchers have begun to apply the concept to explain variations in health status across geographic localities. In preliminary analyses, the higher the stocks of social capital (as indicated by measures of trust and reciprocity in social surveys), the higher appear to be the health achievement of a given area. Strengthening the social capital within communities may provide an important avenue for reducing socioeconomic disparities in health.
TL;DR: A byproduct of normal aerobic metabolism is the generation of dangerously reactive intermediates of the reduction of O2, which pose a role for such oxidative damage in aging and neurodegenerative diseases.
Abstract: A byproduct of normal aerobic metabolism is the generation of dangerously reactive intermediates of the reduction of O2. These include O2-, H2O2, and HO. and arise because of the predisposition of O2 for univalent reductions. These reactive oxygen species (ROS), and others that they can engender, threaten all cellular macromolecules, and defenses are needed. Among those known to date are: superoxide dismutases to convert O2- into O2 + H2O2; catalases to dismute H2O2 into O2 + H2O; and peroxidases to reduce H2O2 into 2H2O) and to reduce ROOH into ROH and H2O. These defenses are aided by enzymes that repair or recycle oxidatively damaged nucleic acids and proteins. A role for such oxidative damage in aging and neurodegenerative diseases is well supported.
TL;DR: A research strategy that explores their coherence as a psychosocial profile that promotes resilience to stress is tenable and merits empirical examination.
Abstract: Psychosocial resources, which include optimism, coping style, a sense of mastery or personal control, and social support, influence the relationship between SES and health. To varying degrees, these resources appear to be differentially distributed by social class and related to health outcomes. Such resources may partially mediate the impact of SES on health. For example, environments that undermine personal control may have an impact on chronic arousal and the corresponding development of disease, such as CHD. Psychosocial resources may also moderate the impact of SES on health. For example, a large number of positive social relationships and a few conflictual ones may buffer individuals against the adverse effects of SES-related stress. These psychosocial resources are moderately intercorrelated, and so a research strategy that explores their coherence as a psychosocial profile that promotes resilience to stress is tenable and merits empirical examination. The erosion of these resources as one moves lower on the SES scale and specific factors that contribute to such erosion are discussed.
TL;DR: At least twenty‐two architectonic areas can be distinguished within the orbital and medial prefrontal cortex (OMPFC), and this system appears to be involved in guiding behavior and regulation of mood.
Abstract: At least twenty-two architectonic areas can be distinguished within the orbital and medial prefrontal cortex (OMPFC). Although each of these areas has a distinct structure and connections, they can be grouped into two “networks,” defined by cortico-cortical connections that primarily interconnect areas within each network. The networks also have different connections to the striatum, medial thalamus, and other brain regions. The orbital network consists of most of the areas in the orbital cortex. It receives several sensory inputs (olfactory, gustatory, visceral afferent, somatic sensory, and visual) that appear to be related to feeding. It also receives many limbic inputs from the amygdala, entorhinal and perirhinal cortex, and subiculum, including a specific projection from the ventrolateral part of the basal amygdaloid nucleus. The orbital network may therefore serve as a substrate to integrate viscerosensory information with affective signals. The medial network consists of areas on the medial frontal surface together with a few select areas in the orbital cortex. These areas have few direct sensory inputs, and their limbic inputs are somewhat different than those to the orbital network (e.g., from the ventromedial part of the basal amygdaloid nucleus). However, they provide the major output from the OMPFC to the hypothalamus and brain stem (especially the periaqueductal gray). The medial network may therefore serve as a visceromotor system to provide frontal cortical influence over autonomic and endocrine function. Connections between the networks presumably allow information flow from viscerosensory to visceromotor systems. In addition to a probable role in eating behavior, this system appears to be involved in guiding behavior and regulation of mood. Lesions of the ventromedial prefrontal cortex result in sociopathic behavior and difficulty in making appropriate choices, whereas functional imaging studies indicate that subjects with unipolar and bipolar depression have abnormal activity in medial and orbital prefrontal areas. Many of these areas also show volume changes and decreased glial number and density in mood-disordered subjects.
TL;DR: This paper summarizes experiments performed over the last decade in slice preparations that address the site of expression of LTP and argues that, while numerous experiments fail to support a presynaptic expression mechanism, many experiments do point to a post synapse expression mechanism.
Abstract: Long-term potentiation (LTP) is currently the best available cellular model for learning and memory in the mammalian brain. In the CA1 region of the hippocampus, as well as in many other areas of the CNS, its induction requires a rise in postsynaptic Ca2+ via activation of NMDA receptors. What happens after the rise in postsynaptic Ca2+ is less clear. This paper summarizes experiments performed over the last decade in slice preparations that address the site of expression of LTP. While a large number of laboratories have contributed importantly to this issue, this review will rely primarily on experiments performed in the authors' laboratory. The experiments to be discussed can be broadly divided into two groups: those designed to determine if an increase in glutamate release occurs during LTP and those designed to determine if a change in postsynaptic sensitivity to glutamate occurs during LTP. Experiments in the first category include the analysis of dual-component excitatory postsynaptic currents (EPSCs), paired-pulse facilitation, saturating release probability, the use of MK-801 to measure release probability, and glial glutamate transporter currents to measure directly the synaptic release of glutamate. Experiments in the second category include analysis of miniature EPSC amplitudes, measurements of synaptic potency, the consequences of loading cells with the constitutively activated form of CaM kinase II, and the evidence that during LTP postsynaptically silent synapses become functional. We will argue that, while numerous experiments fail to support a presynaptic expression mechanism, many experiments do point to a postsynaptic expression mechanism. The decrease in synaptic failures during LTP, the only generally accepted experimental result that supports a presynaptic expression mechanism, can be explained by postsynaptically silent synapses. Future directions for research in this field include activity-dependent targeting of glutamate receptors and the functional consequences of phosphorylation of AMPA receptors.
TL;DR: The main reasons why populations with narrower income differences tend to have lower mortality rates are to be found in the psychosocial impact of low social status, and causal pathways are likely to center on the influence that the quality of social relations has on neuroendocrine pathways.
Abstract: This paper suggests that the main reasons why populations with narrower income differences tend to have lower mortality rates are to be found in the psychosocial impact of low social status. There is now substantial evidence showing that where income differences are greater, violence tends to be more common, people are less likely to trust each other, and social relations are less cohesive. The growing impression that social cohesion is beneficial to health may be less a reflection of its direct effects than of its role as a marker for the underlying psychological pain of low social status. Low social status affects patterns of violence, disrespect, shame, poor social relations, and depression. In its implications for feelings of inferiority and insecurity, it interacts with other powerful health variables such as poor emotional attachment in early childhood and patterns of friendship and social support. Causal pathways are likely to center on the influence that the quality of social relations has on neuroendocrine pathways.
TL;DR: The molecular basis of the hyperpolarization‐activated cation channels that underlie the anomalous rectifying current variously termed Ih, Iq, or If is discussed and an initial attempt at defining the identity and subunit composition of channels underlying native Ih is undertaken.
Abstract: The molecular basis of the hyperpolarization-activated cation channels that underlie the anomalous rectifying current variously termed Ih, Iq, or If is discussed. On the basis of the expression patterns and biophysical properties of the newly cloned HCN ion channels, an initial attempt at defining the identity and subunit composition of channels underlying native Ih is undertaken. By comparing the sequences of HCN channels to other members of the K channel superfamily, we discuss how channel opening may be coupled to membrane hyperpolarization and to direct binding of cyclic nucleotide. Finally, we consider some of the questions in cardiovascular physiology and neurobiology that can be addressed as a result of the demonstration that Ih is encoded by the HCN gene family.
TL;DR: Evidence is presented that the multisensory parieto‐insular vestibular cortex is the human homologue of the Parieto-insular Vestibular Cortex (PIVC) in the monkey and is involved in the perception of verticality and self‐motion.
Abstract: The two major cortical functions of the vestibular system are spatial orientation and self-motion perception. These functions, however, are not exclusively vestibular; they also rely on visual and somatosensory input. All three systems (vestibular, visual and somatosensory) provide us with redundant information about the position and motion of our body relative to the external space. Although the vestibular cortex function is distributed among several multisensory areas in the parietal and temporal cortices, it is also integrated in a larger network for spatial attention and sensorimotor control of eye and body motion in space.
TL;DR: The nucleus accumbens, a major part of the ventral striatum, comprises numerous subterritories and compartments, of which the core and shell appear to be dominant, and it is hypothesized that core‐shell has a feed‐forward functional organization.
Abstract: The nucleus accumbens, a major part of the ventral striatum, comprises numerous subterritories and compartments, of which the core and shell appear to be dominant. Shell exhibits greater chemical neuroanatomical diversity than core and is rather directly connected to it by a robust, feed-forward, striatopallido-thalamocortico-striatal pathway. Shell and extended amygdala share afferents, but the two are distinguished by their outputs, strongly toward cortex for shell and descendent toward brain stem effector sites for extended amygdala. Shell responds independently to stimulation by excitatory amino acids and dopamine, which are more mutually permissive in the core. Accordingly, the shell responds to a broad variety of physiological and pharmacological stimuli, including psychomotor and opioid drugs. Whereas locomotion and oro-facial movements are elicitable from the shell, lesions and blockade of EAA transmission in the core reduce locomotion. It is hypothesized that core-shell has a feed-forward functional organization.
TL;DR: It is clear that a richer animal model of human anxiety disorders would include measures of both stimulus‐specific fear and something less stimulus specific, more akin to anxiety.
Abstract: Although there is a close correspondence between fear and anxiety, and the study of fear in animals has been extremely valuable for under-standing the neural basis of anxiety, it is also clear that a richer animal model of human anxiety disorders would include measures of both stimulus-specific fear and something less stimulus specific, more akin to anxiety. Patients with posttraumatic stress syndrome seem to show normal fear reactions but abnormal anxiety measured with the acoustic startle reflex. Studies in rats, also using the startle reflex, indicate that highly processed explicit cue information (lights, tones) activates the central nucleus of the amygdala, which projects to and modulates the acoustic startle pathway in the brain stem. Less explicit information, such as that produced by exposure to a threating environment or by intraventricular administration of corticotropin-releasing hormone, may activate another part of the extended amygdala, the bed nucleus of the stria terminalis, which also projects to the startle pathway. Because this information may be less specific and of long duration, activation of the bed nucleus of the stria terminalis may mediate anxiety, whereas activation of the central nucleus of the amygdala may mediate stimulus-specific fear.
TL;DR: A picture is beginning to emerge of the properties conferred to receptor subtypes by the different subunits; these include different functional properties, differential modulation by protein kinases, and the targeting to different membrane compartments.
Abstract: Fast inhibitory neurotransmission in the mammalian CNS is mediated primarily by the neurotransmitter gamma-aminobutyric acid (GABA), which, upon binding to its receptor, leads to opening of the intrinsic ion channel, allowing chloride to enter the cell. Over the past 10 years it has become clear that a family of GABA-A receptor subtypes exists, generated through the coassembly of polypeptides selected from alpha 1-alpha 6, beta 1-beta 3, gamma 1-gamma 3, delta, epsilon, and pie to form what is most likely a pentomeric macromolecule. The gene transcripts, and indeed the polypeptides, show distinct patterns of temporal and spatial expression, such that the GABA-A receptor subtypes have a defined localization that presumably reflects their physiological role. A picture is beginning to emerge of the properties conferred to receptor subtypes by the different subunits; these include different functional properties, differential modulation by protein kinases, and the targeting to different membrane compartments. These properties presumably underlie the different physiological roles of the various receptor subtypes. Recently we have identified a further member of the GABA-A receptor gene family, which we have termed theta, which appears to be most closely related to the beta subunits. The structure, function, and distribution of theta-containing receptors, and receptors containing the recently reported epsilon subunit, are described.
TL;DR: This work will review the discovery and subsequent elaboration of the ventral striatopallidal system and extended amygdala, and dispel some recently published misgivings regarding the usefulness of the extended amygdaloid concept.
Abstract: The concepts of the ventral striatopallidal system and extended amygdala have significantly improved our understanding of basal forebrain organization. As a result of these and other advances during the last twenty years, many of the most prominent basal forebrain structures, including the nucleus accumbens, olfactory tubercle, and amygdaloid body, have all but lost their relevance as independent functional anatomical units. In order to appreciate the distinct differences that exist between the ventral striatopallidal system and the extended amygdala, and as a way of explaining the choice of the terms ventral striatopallidal system and extended amygdala, we will review the discovery and subsequent elaboration of these two systems. On the background of these discussions, we will then proceed to dispel some recently published misgivings regarding the usefulness of the extended amygdaloid concept.
TL;DR: Emerging evidence that dietary restriction can forestall the development of AD and PD is consistent with a major “metabolic” component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.
Abstract: Synaptic degeneration and death of nerve cells are defining features of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. In PD dopamine-producing neurons in the substantia nigra-striatum (brain regions that control body movements) selectively degenerate. Studies of postmortem brain tissue from AD and PD patients have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. Studies of animal and cell culture models of AD and PD suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive ATPases and glucose and glutamate transporters. Such oxidative and metabolic compromise may thereby render neurons vulnerable to excitotoxicity and apoptosis. Studies of the pathogenic mechanisms of AD-linked mutations in amyloid precursor protein (APP) and presenilins strongly support central roles for perturbed cellular calcium homeostasis and aberrant proteolytic processing of APP as pivotal events that lead to metabolic compromise in neurons. Specific molecular “players” in the neurodegenerative processes in AD and PD are being identified and include Par-4 and caspases (bad guys) and neurotrophic factors and stress proteins (good guys). Interestingly, while studies continue to elucidate cellular and molecular events occurring in the brain in AD and PD, recent data suggest that both AD and PD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD and PD is consistent with a major “metabolic” component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.
TL;DR: It is suggested that these cortical inputs may be important for cognitive, mnemonic, and affective aspects of emotional and motivated behavior.
Abstract: The projections of the cerebral cortex to the extended amygdala were studied in the rat using anterograde and retrograde tract-tracing techniques. Most cortical areas with strong projections to the extended amygdala preferentially targeted either the medial extended amygdala (including the medial amygdalar nucleus, ventromedial substantia innominata, and the medial part of the bed nucleus the stria terminalis) or the central extended amygdala (including the central amygdalar nucleus, dorsolateral substantia innominata, and the lateral part of the bed nucleus of the stria terminalis). Some cortical areas, however, had equal projections to both medial and central portions. The main areas projecting preferentially to the medial extended amygdala were the ventral subiculum, infralimbic cortex, ventral agranular insular area, and the rostral part of the ventrolateral entorhinal area. The main areas projecting preferentially to the central extended amygdala were the prefrontal cortex, viscerosensory and somatosensory portions of the insular cortex, and the amygdalopiriform transitional area. It is suggested that these cortical inputs may be important for cognitive, mnemonic, and affective aspects of emotional and motivated behavior.
TL;DR: Experimental evidence has now become available showing that Kv3.2 channels play critical roles in the generation of fast‐spiking properties in cortical GABAergic interneurons and to help regulate the fidelity of synaptic transmission.
Abstract: Four mammalian Kv3 genes have been identified, each of which generates, by alternative splicing, multiple protein products differing in their C-terminal sequence. Products of the Kv3.1 and Kv3.2 genes express similar delayed-rectifier type currents in heterologous expression systems, while Kv3.3 and Kv3.4 proteins express A-type currents. All Kv3 currents activate relatively fast at voltages more positive than -10 mV, and deactivate very fast. The distribution of Kv3 mRNAs in the rodent CNS was studied by in situ hybridization, and the localization of Kv3.1 and Kv3.2 proteins has been studied by immunohistochemistry. Most Kv3.2 mRNAs (approximately 90%) are present in thalamic-relay neurons throughout the dorsal thalamus. The protein is expressed mainly in the axons and terminals of these neurons. Kv3.2 channels are thought to be important for thalamocortical signal transmission. Kv3.1 and Kv3.2 proteins are coexpressed in some neuronal populations such as in fast-spiking interneurons of the cortex and hippocampus, and neurons in the globus pallidus. Coprecipitation studies suggest that in these cells the two types of protein form heteromeric channels. Kv3 proteins appear to mediate, in native neurons, similar currents to those seen in heterologous expression systems. The activation voltage and fast deactivation rates are believed to allow these channels to help repolarize action potentials fast without affecting the threshold for action potential generation. The fast deactivating current generates a quickly recovering after hyperpolarization, thus maximizing the rate of recovery of Na+ channel inactivation without contributing to an increase in the duration of the refractory period. These properties are believed to contribute to the ability of neurons to fire at high frequencies and to help regulate the fidelity of synaptic transmission. Experimental evidence has now become available showing that Kv3.1-Kv3.2 channels play critical roles in the generation of fast-spiking properties in cortical GABAergic interneurons.
TL;DR: Findings suggest that variations in parental care mediate, in part at least, the effects of environmental adversity on child development, and that maternal depression associated with environmental conditions not only compromises parent–child interactions, but also limits the efficacy of early intervention programs.
Abstract: The quality of family life influences the development of individual differences in vulnerability to illness throughout later life. As adults, victims of childhood physical or sexual abuse are at considerably greater risk for mental illness, as well as for diabetes and heart disease (e.g., Refs. 1–3). Children need not be beaten to be compromised. Persistent emotional neglect or conditions of harsh, inconsistent discipline serve to increase the risk of depression and anxiety disorders to a level comparable to that observed in cases of abuse. 4 Indeed, for certain outcomes, the consequences of persistent neglect exceed those of abuse. 5,6 More subtle relationships exist. Low scores on parental bonding scales, reflecting cold, distant parent–child relationships, significantly increase the risk of depression and anxiety in later life (e.g., Refs. 7,8). And the risk is not unique to mental health. Russak and Schwartz 9 found that by midlife those individuals who, as undergraduate students, rated their relationship with parents as cold and detached, had a fourfold greater risk of chronic illness, including depression and alcoholism as well as heart disease and diabetes. Parental factors also serve to mediate the effects of environmental adversity on development. For example, the effects of poverty on emotional and cognitive development are mediated by parental factors, to the extent that if such factors are controlled, there is no discernible effect of poverty on child development. 10,11 Moreover, treatment outcomes associated with early intervention programs are routinely correlated with changes in parental behavior: In cases where parental behavior proves resistant to change, treatment outcomes are seriously limited. These findings suggest that variations in parental care mediate, in part at least, the effects of environmental adversity on child development. One of the more common findings here is that maternal depression associated with environmental conditions not only compromises parent–child interactions, but also limits the efficacy of early intervention programs.
TL;DR: Evidence will be presented to show that BL afferents form synaptic complexes with cortical, GABAergic, and TH‐immunoreactive terminal boutons on GABAergic dendritic spines, which may be a key element in control of CEA output activity.
Abstract: The central component of the extended amygdala (CEA) comprises the central amygdaloid nucleus (Ce), the dorsal substantia innominata (SI), and the bed nucleus of the stria terminalis (BNST). Anatomical studies have suggested the presence of an intrinsic system of GABAergic neurons that not only connects homologous subareas of the Ce, SI, and BNST but that also acts as an interface between sensory afferents and brain stem-projecting neurons. CEA outputs, with a few exceptions, arise from separate populations of neurons, but all, including GABAergic neurons themselves, are heavily innervated by GABAergic terminals. GABAergic neurons may serve to integrate output activity of the CEA, though GABAergic neurons form a heterogeneous population whose differential intrinsic connections appear related to their peptide content. Afferents from the dysgranular insular cortex and lateral parabrachial complex preferentially innervate GABAergic neurons, suggesting these neurons may also integrate afferent activity. Afferents from the basolateral amygdala (BL) appear to innervate both output neurons and intrinsic GABAergic neurons. Evidence will be presented to show that BL afferents form synaptic complexes with cortical, GABAergic, and TH-immunoreactive terminal boutons on GABAergic dendritic spines. These complexes may be a key element in control of CEA output activity.
TL;DR: Evidence suggests that the acute reinforcing actions of drugs of abuse may be mediated by specific elements of the striatopallidal and extended amygdala systems, including the shell of the Nucleus accumbens, the central nucleus of hte amygdala, and the sublenticular extended amygdala.
Abstract: Evidence suggests that the acute reinforcing actions of drugs of abuse may be mediated by specific elements of the striatopallidal and extended amygdala systems These include the shell of the nucleus accumbens, the central nucleus of the amygdala, and the sublenticular extended amygdala Chronic administration of drugs of abuse, including cocaine, amphetamines, nicotine, alcohol, and tetrahydrocannabinol leads to an increasing dysregulation of brain reward systems that is characterized by decreases in reward function Withdrawal from chronic administration of cocaine, amphetamine, nicotine, alcohol, and tetrahydrocannabinol raises thresholds for brain stimulation reward Neurochemical elements in the extended amygdala may mediate these changes, including decreases in dopamine and serotonin neurotransmission in the nucleus accumbens and increases in the brain-stress neurotransmitter, corticotropin-releasing factor, in the central nucleus of the amygdala The combination of decreases in function of neurotransmitters involved in the positive-reinforcing properties of drugs of abuse with recruitment of brain-stress systems within the extended amygdala provides a powerful mechanism for allostatic changes in hedonic set point that can lead to the compulsive drug-seeking and drug-taking behavior characteristic of addiction
TL;DR: A local (transtympanic) strategy against cochlear excitotoxicity may, in the near future, prove to be helpful in ischemic‐ or noise‐induced sudden deafness, as well as in the related tinnitus.
Abstract: Besides its fast excitatory properties, glutamate is known to have neurotoxic properties when released in large amounts or when incompletely recycled. This so-called excitotoxicity is involved in a number of acute and/or degenerative forms of neuropathology such as epilepsy, Alzheimer's, Parkinson's, stroke, and retinal ischemia. In the cochlea, excitotoxicity may occur in two pathological conditions: anoxia and noise trauma. It is characterized by a two-step mechanism: (1) An acute swelling, which primarily depends on the AMPA/kainate type of receptors, together with a disruption of the postsynaptic structures (type I afferent dendrites) resulting in a loss of function. Within the next 5 days, synaptic repair may be observed with a full or a partial (acoustic trauma) recovery of cochlear potentials. (2) The second phase of excitotoxicity, which may develop after strong and/or repetitive injury, consists of a cascade of metabolic events triggered by the entry of Ca2+, which leads to neuronal death in the spiral ganglion. Ongoing experiments in animals, tracking the molecular basis of both these processes, presages the development of new pharmacological strategies to help neurites to regrow and reconnect properly to the IHCs, and to prevent or delay neuronal death in the spiral ganglion. Human applications should follow, and a local (transtympanic) strategy against cochlear excitotoxicity may, in the near future, prove to be helpful in ischemic- or noise-induced sudden deafness, as well as in the related tinnitus.