The monoaminergic neuron, in particular the dopaminergic neuron, is central to mediating the hedonic and addictive properties of drugs of abuse. The effects of amphetamine (AMPH) and cocaine (COC), for example, depend on the ability to increase dopamine in the synapse, by effects on either the plasma membrane transporter DAT or the vesicular transporter for monoamine storage, VMAT2. The potential role of DAT as a target for AMPH and COC has been reviewed extensively. Here, we present VMAT2 as a target that enables the rewarding and addictive actions of these drugs, based on imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence. The presence of VMAT2 in noradrenergic, serotoninergic, histaminergic, and potentially trace aminergic neurons invites consideration of a wider role for aminergic neurotransmission in AMPH and COC abuse and addiction.
VMAT2; amphetamine; cocaine; addiction; monoamines; vesicular transporter
Significant progress has been made in the last few decades using animal models to recreate the esophagitis–metaplasia–carcinoma sequence similar to that seen in human Barrett’s esophagus (BE) and EAC. More recent works focus on molecular pathways associated with intestinal metaplasia and carcinogenesis, as well as similarities between genetic mutations occurring in humans and animal models, mouse, rat, pig, rabbit, guinea pig, dog, cat, ferret, and possum.
Despite the lack of a perfect model, there is still significant potential in using these models to clarify the contribution of different types of reflux (gastric, biliary, and pancreatic) to esophageal adenocarcinoma and to determine how the different types of refluxate interact.
Refluxed duodenal contents cause gastric and esophageal carcinoma in rats without exposure to carcinogens, and several rat duodenal contents reflux models have been developed. BE in the animal models has well-developed goblet cells positive forMUC2, gastric pyloric-type mucins positive for MUC6, and sometimes intermingled with gastric foveolar-type mucins positive for MUC5AC.
A gut regenerative cell lineage, characterized by pyloric–foveolar metaplasia followed by the appearance of goblet cells, occurs in the regenerative process in response to chronic inflammation.
High animal-fat dietary intake causes severe obesity, resulting in the development of increased abdominal pressure and increased refluxate, particularly of the duodenal contents. The N-nitroso bile acid conjugates, which have mutagenecity, play an important role in Barrett’s carcinogenesis, and are stabilized by gastric acid.
Experiments have been made in a rodent duodeno-esophageal reflux model using thioproline or cyclooxygenase-2 inhibitor to prevent the inflammation–metaplasia– adenocarcinoma sequence. Thioproline is one of the nitrite scavengers, which reduce the production of carcinogenic nitroso-compounds. Celecoxib could postpone the sequence itself, whereas thioproline could only prevent the evolution of Barrett’s esophagus to cancer.
The Levrat’s surgical model of esophago-duodenal anatomosis in rats has been shown to induce gastroduodenojejunal reflux. This in vivo model reproduces the sequence of histologic and molecular events that lead to the development of BE and esophageal adenocarcinoma in humans and, as such, provides a realistic and translatable model for development of therapeutics for EAC.
A pilot study using proteomics to evaluate for differentially expressed markers in the progression from metaplasia to dysplasia and ultimately adenocarcinoma in human tissues has been conducted.
Differential expression of cytokeratin 20 in specimens from human patients and the Levrat’s model substantiated the hypothesis that the animal model is representative of human cancer and, hence, further supporting the basis for its utilization.
Furthermore, if this data is confirmed, the Levrat’s approach may serve as a model for preclinical drug development. Up to ten potential novel target regimens identified and selected through the proteomics screen will be tested in a multi-arm study in rats.
esophageal neoplasm; Barrett’s esophagus; duodenogastric reflux; bile reflux; carcinoma; histogenesis; gut regenerative cell lineage; pyloric–foveolar metaplasia; fat intake; DNA adducts; N-nitroso bile acids; chemoprevention; duodenoesophageal reflux; thioproline; cyclooxygenase-2 inhibitor
The Knockout Mouse Project (KOMP) Repository archives and distributes vectors, embryonic stem cell clones, frozen germplasm, and live mutant mice for 8,500 knockout genes. Here, we describe the creation and functions of the KOMP Repository.
genetically altered mice; knockouts; gene targeting; ES cells
Visual acuity and motion perception are degraded during head movements unless the eyes counter-rotate so as to stabilize the line of sight and the retinal image. The vestibulo-ocular reflex (VOR) is assumed to produce this ocular counter-rotation. Consistent with this assumption, oscillopsia is a common complaint of patients with bilateral vestibular weakness.
Shanidze et al. (2010b) described compensatory eye movements in normal guinea pigs that appear to anticipate self-generated head movements. These responses effectively stabilize gaze and occur independently of the vestibular system. These new findings suggest that the VOR stabilizes gaze during passive perturbations of the head in space, but anticipatory responses may supplement or even supplant the VOR during actively generated head movements. This report reviews these findings, potential neurophysiological mechanisms, and their potential application to human clinical treatment of patients with vestibular disease.
vestibulo-ocular reflex (VOR); efference copy; cervico-ocular reflex (COR); vestibular nuclei; oscillopsia; guinea pigs
Although drug craving has received considerable research attention over the past several decades, to date there has been no systematic review of the general clinical significance of craving. This paper presents an overview of measurement issues of particular relevance to a consideration of use of craving in clinical settings. The paper then considers the relevance of craving across a broad array of clinical domains, including diagnosis, prognostic utility, craving as an outcome measure, and the potential value of craving as a direct target of intervention. The paper is both descriptive and prescriptive, informed by the current state of the science on craving with recommendations for the definition of craving, assessment practices, future research, and clinical applications. We conclude that craving has considerable utility for diagnosis and as a clinical outcome, and that findings from future research will likely expand the clinical potential of the craving construct in the domains of prognosis and craving as a treatment target.
craving; clinical significance; diagnosis; prognosis; clinical outcomes
The primate orbitofrontal cortex (OFC) is often treated as a single entity, but architectonic and connectional neuroanatomy indicates that it has distinguishable parts. Nevertheless, few studies have attempted to dissociate the functions of its subregions. Here we review findings from recent neuropsychological and neurophysiological studies that do so. The lateral OFC seems to be important for learning, representing and updating specific object–reward associations. Medial OFC seems to be important for value comparisons and choosing among objects on that basis. Rather than viewing this dissociation of function in terms of learning versus choosing, however, we suggest that it reflects the distinction between contrasts and comparisons: differences versus similarities. Making use of high-dimensional representations that arise from the convergence of several sensory modalities, the lateral OFC encodes contrasts among outcomes. The medial MFC reduces these contrasting representations of value to a single dimension, a common currency, in order to compare alternative choices.
Orbitofrontal cortex; macaque; reward; reversal learning
Patients with primary immunodeficiency (PID) provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. Alterations in B cell receptor and Toll-like receptor signaling pathways result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. In contrast, CD40L- and MHC class II–deficient patients only displayed peripheral B cell tolerance defects, suggesting that decreased numbers of regulatory T cells and increased concentration of B cell activating factor (BAFF) may interfere with the peripheral removal of autoreactive B cells. The pathways regulating B cell tolerance identified in PID patients are likely to be affected in patients with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes who display defective central and peripheral B cell tolerance checkpoints. Indeed, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of these diseases, interfere with the removal of developing autoreactive B cells. Hence, insights into B cell selection from PID patients are highly relevant to the understanding of the etiology of autoimmune conditions.
B cell tolerance; B cell receptor; Toll-like receptors; receptor editing
Neocortex is an important part of the mammalian brain that is quite different from its homologue of the dorsal cortex in the reptilian brain. Whereas dorsal cortex is small, thin, and composed of a single layer of neurons, neocortex is thick and has six layers, while being variable across species in size, number of functional areas, and architectonic differentiation. Early mammals had little neocortex, with perhaps 20 areas of poor structural differentiation. Many extant mammals continue to have small brains with little neocortex, but they often have sensory specializations reflected in the organization of sensory areas in neocortex. In primates, neocortex is variously enlarged and characterized by structural and other specializations, including those of cortical networks devoted to vision and visuomotor processing.In humans, neocortex occupies 80% of the volume of the brain, where as many as 200 areas may exist.
primates; reptiles; dorsal cortex; visual cortex; marsupials; monotremes
Research on consumer decision making and aging is especially important for fostering a better understanding of ways to maintain consumer satisfaction and high decision quality across the life span. We provide a review of extant research on the effects of normal aging on cognition and decision processes and how these age-related processes are influenced by task environment, meaningfulness of the task, and consumer expertise. We consider how research centered on these topics generates insights about changes in consumption decisions that occur with aging and identify a number of gaps and directions for future research.
aging; decision making; consumers
The following on esophageal disease in pediatrics contains commentaries on acquisition of neuromuscular maturation; physiology of esophageal peristaltic and sphincteric reflexes; implications for clinical practice; and conditions that predispose to severe gastroesophageal reflux disease (GERD) in children with potential risk for esophageal cancer.
embryology; peristalsis; sphincteric reflexes; fetal swallowing; airway protection; Barrett's esophagus; GERD
Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, “Advancing Drug Discovery for Schizophrenia” was held March 9–11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, all of which contribute to the overarching goal of enhancing the pharmaceutical armamentarium for treating schizophrenia. This report surveys work by the vanguard of schizophrenia research in such topics as genetic and epigenetic approaches; small molecule therapeutics; and the relationships between target genes, neuronal function, and symptoms of schizophrenia.
schizophrenia; genetics; GWAS; neuronal function; small molecules; therapeutics
Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, “Behavioral Epigenetics” was held on October 29–30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level.
behavior; epigenetics; chromosome; gene regulation; transcription; methylation
In this paper, we review the current literature to highlight relations between age-associated declines in dopaminergic and serotonergic neuromodulation and adult age differences in adaptive goal-directed behavior. Specifically, we focus on evidence suggesting that deficits in neuromodulation contribute to older adults’ behavioral disadvantages in learning and decision making. These deficits are particularly pronounced when reward information is uncertain or the task context requires flexible adaptations to changing stimulus–reward contingencies. Moreover, emerging evidence points to age-related differences in the sensitivity to rewarding and aversive outcomes during learning and decision making if the acquisition of behavior critically depends on outcome processing. These age-related asymmetries in outcome valuation may be explained by age differences in the interplay of dopaminergic and serotonergic neuromodulation. This hypothesis is based on recent neurocomputational and psychopharmacological approaches, which suggest that dopamine and serotonin serve opponent roles in regulating the balance between approach behavior and inhibitory control. Studying adaptive regulation of behavior across the adult life span may shed new light on how the aging brain changes functionally in response to its diminishing resources.
aging; neuromodulation; motivation; cognitive control
Mutations in genes encoding the Calcium-Release Activated Calcium (CRAC)
channel abolish calcium influx in cells of the immune system and cause severe
congenital immunodeficiency. Patients with autosomal recessive mutations in the
CRAC channel gene ORAI1, its activator Stromal
Interaction Molecule 1 (STIM1) and mice with
targeted deletion of Orai1, Stim1 and Stim2
genes reveal important roles for CRAC channels in adaptive and innate immune
responses to infection and in autoimmunity. Since CRAC channels have important
functions outside the immune system, ORAI1 and STIM1 deficiency are associated
with a unique clinical phenotype. This review will give an overview of CRAC
channel function in the immune system, examine the consequences of CRAC channel
deficiency for immunity in human patients and mice and discuss genetic defects
in immunoreceptor-associated signaling molecules that compromise calcium influx
and cause immunodeficiency.
Immunodeficiency; T cells; CRAC channels; ORAI1; STIM1
With life expectancy dramatically increasing throughout much of the world, people have to make choices with a longer future in mind than they ever had to before. Yet, many indicators suggest that undersaving for the long term often occurs: in America, for instance, many individuals will not be able to maintain their preretirement standard of living in retirement. Previous research has tried to understand problems with intertemporal choice by focusing on the ways in which people treat present and future rewards. In this paper, the author reviews a burgeoning body of theoretical and empirical work that takes a different viewpoint, one that focuses on how perceptions of the self over time can dramatically affect decision making. Specifically, when the future self shares similarities with the present self, when it is viewed in vivid and realistic terms, and when it is seen in a positive light, people are more willing to make choices today that may benefit them at some point in the years to come.
future self-continuity; behavioral economics; intertemporal choice; temporal discounting; retirement saving
Time and time perceptions are integral to decision making because any meaningful choice is embedded in a temporal context and requires the evaluation of future preferences and outcomes. The present review examines the influence of chronological age on time perceptions and horizons and discusses implications for decision making across the life span. Time influences and interacts with decision making in multiple ways. Specifically, this review examines the following topic areas: (1) processing speed and decision time, (2) internal clocks and time estimation, (3) mental representations of future time and intertemporal choice, and (4) global time horizons. For each aspect, patterns of age differences and implications for decision strategies and quality are discussed. The conclusion proposes frameworks to integrate different lines of research and identifies promising avenues for future inquiry.
We outline a contextual and motivational model of judgment and decision-making (JDM) biases across the life span. Our model focuses on abilities and skills that correspond to deliberative, experiential, and affective decision-making processes. We review research that addresses links between JDM biases and these processes as represented by individual differences in specific abilities and skills (e.g., fluid and crystallized intelligence, executive functioning, emotion regulation, personality traits). We focus on two JDM biases—the sunk-cost fallacy (SCF) and the framing effect. We trace the developmental trajectory of each bias from preschool through middle childhood, adolescence, early adulthood, and later adulthood. We conclude that life-span developmental trajectories differ depending on the bias investigated. Existing research suggests relative stability in the framing effect across the life span and decreases in the SCF with age, including in later life. We highlight directions for future research on JDM biases across the life span, emphasizing the need for process-oriented research and research that increases our understanding of JDM biases in people’s everyday lives.
sunk costs; framing effect; dual processes; heuristics; biases
Everyday problem solving involves examining the solutions that individuals generate when faced with problems that take place in their everyday experiences. Problems can range from medication adherence and meal preparation to disagreeing with a physician over a recommended medical procedure or compromising with extended family members over where to host Thanksgiving dinner. Across the life span, research has demonstrated divergent patterns of change in performance based on the type of everyday problems used as well as based on the way that problem-solving efficacy is operationally defined. Advancing age is associated with worsening performance when tasks involve single-solution or fluency-based definitions of effectiveness. However, when efficacy is defined in terms of the diversity of strategies used, as well as by the social and emotional impact of solution choice on the individual, performance is remarkably stable and sometimes even improves in the latter half of life. This article discusses how both of these approaches to everyday problem solving inform research on the influence that aging has on everyday functioning.
everyday problem solving; aging; coping; practical intelligence; decision making
The orbital frontal cortex (OFC) has been implicated in a number of psychiatric disorders, including depression, anxiety, phobia, and obsessive-compulsive disorder. Thus, a better understanding of its functions will likely provide critical information to understand the specific behavioral and cognitive processes affected in these human disorders. In recent years, a growing number of studies have provided evidence for anatomical and functional differentiation within the OFC. Here we discuss the effects of selective OFC (areas 11/13) lesions on social behavior, emotional regulation, and behavioral adaptation. Damage to these specific OFC subfields in adult monkeys resulted in profound changes in the flexible modulation of responses guided by reward value that could explain the poor fear regulation and disturbed social interactions observed in the same animals. A similar pattern of results was found when the OFC lesions were done in infancy. Thus, in monkeys, self-regulation abilities mediated by OFC areas 11/13 emerge from midinfancy through adolescence.
orbitofrontal cortex; rhesus; behavior; emotion; flexibility
Major well-defined medical problems that are, in part, the unfortunate outcome of a negative social environment may include specific addictive diseases and other mental health disorders, in particular the affective disorders of anxiety, depression, social phobia, and post-traumatic stress syndrome. This overview touches on the topic of extreme marginalization associated with addiction and other mental health disorders, along with arrest, imprisonment, and parole. All of these are characterized by lasting stigma that hauntingly continues to impact upon each person suffering from any of these problems.
addiction; mental health disorders; stigma; imprisonment
Hofbauer cells (HBCs) are placental macrophages that are present in the villus across gestation. Despite their identification more than 100 years ago, their specific role in placental function remains largely unelucidated. We initially review aspects of their history and biology as well as evidence for putative sites of origin. To gain insight into their potential function, we then describe complications of pregnancy including villitis of unknown etiology (VUE) and histological chorioamnionitis (HCA), in which alterations in numbers, gene expression, or other characteristics of HBCs have been documented to occur. We further review methods for isolation of HBCs and in vitro studies that explore their role in relation to other major cell types in the placenta and examine their actions in cytokine-mediated inflammation. We conclude that HBCs play a key role in placental pathophysiology, and future advances in their isolation and culture would enable mechanistic insight into their villus function.
placenta; Hofbauer cells; fetal macrophages; preterm delivery; villitis of unknown etiology; chorioamnionitis
The following series of concise summaries addresses the evolution of infectious agents in relation to sex in animals and humans from the perspective of three specific questions: (1) what have we learned about the likely origin and phylogeny, up to the establishment of the infectious agent in the genital econiche, including the relative frequency of its sexual transmission; (2) what further research is needed to provide additional knowledge on some of these evolutionary aspects; and (3) what evolutionary considerations might aid in providing novel approaches to the more practical clinical and public health issues facing us currently and in the future?
evolution; infectious agents; sexual transmission; econiche
Clinical use of positron emission tomography (PET) is now well established in neurodegenerative disorders, especially in the diagnosis of dementia. Measurement of cerebral glucose metabolism is of significant value, and it facilitates early diagnosis, appropriate differential diagnosis, and the evaluation of drug treatment in patients with dementia. In addition, tracers offer new perspectives for studying the neuropathology of underlying dementia, such as the accumulation of amyloid proteins, tau-proteins, or the presence of neuroinflammation. Finally, PET tracer studies of different neurotransmitter systems in dementia may not only increase the understanding of pathophysiologic mechanisms of the different disorders, but also improve diagnostic accuracy. In conclusion, PET imaging with different tracers offers reliable biomarkers in dementia, which can assist clinicians in the diagnosis of different dementing disorders, especially in the situation of overlapping phenotypes.
PET/CT; dementia; Alzheimer’s disease
Molecular imaging with PET offers a broad variety of tools supporting the diagnosis of movement disorders. The more widely applied PET imaging techniques have focused on the assessment of neurotransmitter systems, predominantly the pre- and postsynaptic dopaminergic system. Additionally, PET imaging with [18F] fluorodeoxyglucose has been extensively used to assess local synaptic activity in the resting state and to highlight local changes in brain metabolism accompanying changes in neural activity in movement disorders. PET imaging has provided us with diagnostic agents as well as tools for evaluation of novel therapeutics, and has served as a powerful means for revealing in vivo changes at different stages of movement disorders and within the course of an individual patient’s illness.
PET/CT; movement disorders; Parkinson’s disease
Individuals weigh information about both rewarding and aversive stimuli in order to make adaptive decisions. Most studies of the orbitofrontal cortex (OFC), an area where appetitive and aversive neural subsystems might interact, have focused only on reward. Using a classical conditioning task where novel stimuli are paired with reward or aversive air-puff, we discovered that two groups of orbitofrontal neurons respond preferentially to conditioned stimuli associated with rewarding and aversive outcomes; however, information about appetitive and aversive stimuli converges on individual neurons from both populations. Therefore, neurons in OFC might participate in appetitive and aversive networks that track the motivational significance of stimuli even when they vary in valence and sensory modality. Further, we show that these networks, which also extend to the amygdala, exhibit different rates of change during reversal learning. Thus, although both networks represent appetitive and aversive associations, their distinct temporal dynamics might indicate different roles in learning processes.
orbitofrontal cortex; reinforcement learning; conditioning; reward; aversive; monkey