Sex differences in longevity and aging are seen throughout the animal kingdom. These are likely to result, in part, from sex differences in endocrinology. In the nematode C. elegans, males are the longer-lived sex. Here we explore the possibility that sex differences in insulin/IGF-1 and steroid endocrinology contribute to this sex difference in aging, studying C. elegans populations in liquid culture. We report that in hermaphrodite populations, mutational loss of the DAF-12 steroid receptor affected lifespan as in previous plate culture studies: mutant longevity is suppressed in a weak daf-2 insulin/IGF-1 receptor mutant, but enhanced in a stronger daf-2 mutant. However, in males mutation of daf-12 had little effect on aging in either weak or strong daf-2 mutants. Moreover, while mutation of daf-12 marginally reduced lifespan in daf-2(+) hermaphrodites, as in plate cultured populations, it did not in daf-2(+) males. These results could imply that in C. elegans, as in mammals, sex differences in steroid endocrinology contribute to sex differences in aging.
C. elegans; aging; gender; steroid; insulin/IGF-1 signaling
There has been renewed interest in the role of strategies in sensorimotor learning. The combination of new behavioral methods and computational methods has begun to unravel the interaction between processes related to strategic control and processes related to motor adaptation. These processes may operate on very different error signals. Strategy learning is sensitive to goal-based performance error. In contrast, adaptation is sensitive to prediction errors between the desired and actual consequences of a planned movement. The former guides what the desired movement should be, whereas the latter guides how to implement the desired movement. Whereas traditional approaches have favored serial models in which an initial strategy-based phase gives way to more automatized forms of control, it now seems that strategic and adaptive processes operate with considerable independence throughout learning, although the relative weight given the two processes will shift with changes in performance. As such, skill acquisition involves the synergistic engagement of strategic and adaptive processes.
motor learning; motor adaptation; motor skills; cognition
In this paper, we will argue that (1) four classes of norm can be distinguished from a neuro-cognitive perspective; (2) learning the prohibitive power of these norms relies on relatively independent emotional systems; (3) individuals with psychopathy show selective impairment for one of these emotional learning systems and two classes of norm: care-based and justice-based; and (4) while emotional learning systems are necessary for appropriate moral development/reasoning, they are not sufficient for moral development/reasoning.
Deep brain stimulation was introduced as a treatment for patients with Parkinsonism and other movement disorders in the early 1990s. The technique rapidly became the treatment of choice for these conditions, and is now also being explored for other diseases, including Tourette syndrome, gait disorders, epilepsy, obsessive-compulsive disorder, and depression. Although the mechanism of action of DBS remains unclear, it is recognized that DBS works through focal modulation of functionally specific circuits. The fact that that the same DBS parameters and targets can be used in multiple diseases suggests that DBS does not counteract the pathophysiology of any specific disorder, but acts to replace pathologic activities in disease-affected brain circuits with activity that is more easily tolerated. Despite the progress made in the use of DBS, much remains to be done to fully realize the potential of this therapy. We describe some of the most active areas of research in this field, both in terms of exploration of new targets and stimulation parameters, and in terms of new electrode or stimulator designs.
Parkinson’s disease; dystonia; subthalamic nucleus; internal pallidal segment; pedunculopontine nucleus; segregated circuits
Scientific interest in the relationship between cognition and action has increased markedly in the past several years, fueled by the discovery of mirror neurons in monkey prefrontal and parietal cortex and by the emergence of a movement in cognitive psychology, termed the embodied cognition framework, which emphasizes the role of simulation in cognitive representations. Guided by a functional neuroanatomic model called the Two Action Systems account, which posits numerous points of differentiation between structure- and function-based actions, we focus on two of the major issues under recent scrutiny: the relationship between representations for action production and recognition, and the role of action in object representations. We suggest that mirror neurons in humans are not critical for full action understanding, and that only function-based (and not structure-based) action is a component of embodied object concepts.
apraxia; praxis; objects; attention; dorso-dorsal; dorso-ventral
The development of disease-modifying treatments for Alzheimer's disease (AD) faces a number of barriers. Among these are the lack of surrogate biomarkers, the exceptional size and duration of clinical trials, difficulties in identifying appropriate populations for clinical trials, and the limitations of monotherapies in addressing such a complex multifactorial disease. This study sets out to first estimate the consequent impact on the expected cost of developing disease-modifying treatments for AD and then to estimate the potential benefits of bringing together industry, academic, and government stakeholders to co-invest in, for example, developing better biomarkers and cognitive assessment tools, building out advanced registries and clinical trial-readiness cohorts, and establishing clinical trial platforms to investigate combinations of candidate drugs and biomarkers from the portfolios of multiple companies. Estimates based on interviews with experts on AD research and development suggest that the cost of one new drug is now $5.7 billion (95% confidence interval (CI) $3.7–9.5 billion) and could be reduced to $2.0 billion (95% CI $1.5–2.9 billion). The associated acceleration in the arrival of disease-modifying treatments could reduce the number of case years of dementia by 7.0 million (95% CI 4.4–9.4 million) in the United States from 2025 through 2040.
Alzheimer's disease; dementia; biomarkers; drug development; R&D; efficiency; infrastructure; public–private partnership
Remarkable advances in the technological capacity of modern medicine now permit the use of mechanical organ failure support deployed primarily to save life. Such technology serves as a bridge to either recovery or, when feasible, organ transplantation. However, when effective treatment options are exhausted, technological advances can be burdensome bridges to death. This paper briefly reviews the principles of management of life-threatening critical illness and the corresponding biological aspects of life, death, and organ donation, which are both informed and complicated by these technological and scientific achievements.
end-of-life care; organ donation; transplantation; death; determination of death; life-sustaining treatments; withdrawal of life support; ECMO
Buddhist meditation practices have become a topic of widespread interest in both science and medicine. Traditional Buddhist formulations describe meditation as a state of relaxed alertness that must guard against both excessive hyperarousal (restlessness) and excessive hypoarousal (drowsiness, sleep). Modern applications of meditation have emphasized the hypoarousing and relaxing effects without as much emphasis on the arousing or alertness-promoting effects. In an attempt to counterbalance the plethora of data demonstrating the relaxing and hypoarousing effects of Buddhist meditation, this interdisciplinary review aims to provide evidence of meditation’s arousing or wake-promoting effects by drawing both from Buddhist textual sources and from scientific studies, including subjective, behavioral, and neuroimaging studies during wakefulness, meditation, and sleep. Factors that may influence whether meditation increases or decreases arousal are discussed, with particular emphasis on dose, expertise, and contemplative trajectory. The course of meditative progress suggests a nonlinear multiphasic trajectory such that early phases that are more effortful may produce more fatigue and sleep propensity, while later stages produce greater wakefulness as a result of neuroplastic changes and more efficient processing.
Buddhist meditation; relaxation; sleep; arousal; alertness; wakefulness
Children need to be protected in intergenerational networks, with parents who have positive mood, resources to feed their children, and skills to promote early childhood development (ECD). Globally, more than 200 million children are raised annually without these resources. This article reviews the potential contributions of increasing coverage and penetration of services for these children, challenges to achieving penetration of services in high risk families, the opportunities created by bundling multiple services within one provider, the potential leveraging of paraprofessionals to deliver care, and mobilizing communities to support children in households at high risk for negative outcomes. We end with a number of suggestions for how to ensure the equitable scale up of integrated ECD and nutrition services that take into account current global priorities, as well as coverage and penetration of services.
A central issue when designing multi-dimensional biological and psychosocial interventions for children who are exposed to multiple developmental risks is identification of the age period(s) in which such interventions will have the strongest and longest lasting impact (sensitive periods). In this paper we review nutritional, neuroscience and psychological evidence on this issue. Nutritional evidence is used to identify nutrient sensitive periods of age-linked dimensions of brain development, with specific reference to iron deficiency. Neuroscience evidence is used to assess the importance of timing of exposures to environmental stressors for maintaining neural, neuroendocrine and immune systems integrity. Psychological evidence illustrates the sensitivity of cognitive and social-emotional development to contextual risk and protective influences encountered at different ages. Evidence reviewed documents that the early years of life are a sensitive period where biological or psychosocial interventions or exposure to risk or protective contextual influences can produce unique long-term influences upon human brain, neuroendocrine and cognitive or psychosocial development. However, the evidence does not identify the early years as the sole sensitive time period within which to have a significant influence upon development. Choice of age(s) to initiate interventions should be based on what outcomes are targeted and what interventions are used.
Early Intervention; sensitive periods; iron deficiency; stress; developmental risk; brain
Nutritional and developmental insults in the first few years of life have profound public health implications, including substantial contributions to neonatal, infant, and early childhood morbidity and mortality, as well as longer term impacts on cognitive development, school achievement, and worker productivity. Optimal development that can lead to the attainment of the individual's fullest potential therefore requires a combination of genetic capacity, adequate nutrition, psychosocial stimulation, and safe, clean physical environments. Researchers and policymakers have called for integrated child nutrition and development interventions for more than twenty years, yet there are only a handful of efficacy trials and even fewer examples of integrated interventions that have been taken to scale. While a critical component to the design of such interventions is formative research, there is a dearth of information in both the literature and policy arenas to guide this phase of the process. To move the field forward, this paper first provides an overview of formative research methods with a focus on qualitative inquiry, a description of the critical domains to be assessed (infant and young child feeding, responsive feeding, and child development), and currently available resources. Application of these methods is provided through a real-world case study—the design of an integrated nutrition and child development efficacy trial in Andhra Pradesh, India. Recommendations for next steps are discussed, the most important of which is the need for a comprehensive set of formative guidelines for designing locally tailored, culturally appropriate integrated interventions.
The immune toxicity of the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to as dioxin, has been studied for over 35 years but only recently has the profound immune suppression induced by TCDD exposure been linked to induction of regulatory T cells (Tregs). The effects of TCDD are mediated through its binding to the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. The subsequent AHR-dependent effects on immune responses are determined by the cell types involved, their activation status, and the type of antigenic stimulus. Collectively, studies indicate that TCDD inhibits CD4+ T cell differentiation into T helper (Th)1, Th2, and Th17 effector cells, while inducing Foxp3-negative and/or preserving Foxp3+ Tregs. Although it is not yet clear how activation of AHR by TCDD induces Tregs, there is a potential therapeutic role for alternative AHR ligands in the treatment of immune-mediated disorders.
2,3,7,8 tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; regulatory T cells; dendritic cells; indoleamine 2,3-dioxygenase; Foxp3; NF-κB
Accelerated apoptosis of erythroid progenitors in β-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin–inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with β+-thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one β0 -globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin–inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of β-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of β-thalassemia.
thalassemia; short-chain fatty acid; erythropoietin; fetal hemoglobin; apoptosis; molecular signaling
Robotic and automation technologies have played a huge role in in vitro biological science, having proved critical for scientific endeavors such as genome sequencing and high-throughput screening. Robotic and automation strategies are beginning to play a greater role in in vivo and in situ sciences, especially when it comes to the difficult in vivo experiments required for understanding the neural mechanisms of behavior and disease. In this perspective, we discuss the prospects for robotics and automation to impact neuroscientific and intact-system biology fields. We discuss how robotic innovations might be created to open up new frontiers in basic and applied neuroscience, and present a concrete example with our recent automation of in vivo whole cell patch clamp electrophysiology of neurons in the living mouse brain.
robotics; neuroscience; patch clamping
Recent advances in our understanding of the community structure and function of the human microbiome have implications for the potential role of probiotics and prebiotics in promoting human health. A group of experts recently met to review the latest advances in microbiota/microbiome research and discuss the implications for development of probiotics and prebiotics, primarily as they relate to effects mediated via the intestine. The goals of the meeting were to share recent advances in research on the microbiota, microbiome, probiotics, and prebiotics, and to discuss these findings in the contexts of regulatory barriers, evolving healthcare environments, and potential effects on a variety of health topics, including the development of obesity and diabetes; the long term consequences of exposure to antibiotics early in life to the gastrointestinal (GI) microbiota; lactose intolerance; and the relationship between the GI microbiota and the central nervous system, with implications for depression, cognition, satiety, and mental health for people living in developed and developing countries. This report provides an overview of these discussions.
microbiome; probiotics; prebiotics; intestinal microbiota; health disorders
Poverty increases maternal stress by heightening exposure to negative life events, job loss, chronic strains, poor housing, dangerous neighborhoods, and conflict with partners, culminating in crippling depressive symptoms, the most prevalent mental health threat. Depressive symptoms interfere with the provision of the strong maternal support needed to counter the hardships of poverty, thus placing infants and toddlers at risk for delayed language, social, and emotional development. Initial clinical trials in high-risk mothers have shown promise, and successive tests of interventions will be strengthened if mothers who have mental health risks can be accurately targeted for inclusion. This article reports on a sequential, data-driven process by which high-risk mothers were targeted for intervention in two trials currently in progress to reduce depressive symptoms. An iterative process of using data to identify at-risk mothers and validate the presence of risk factors helped hone the recruitment and design of the intervention trials. This report also offers guidance for further study.
mothers; depression; poverty; low income; infants/toddlers; targeting; intervention trials
Signaling by H2O2, α,β-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (HNE) and related chemical species, is thought to differ from signaling by other second messengers because the oxidants and other electrophiles can readily undergo nonenzymatic reactions and are therefore classified as “reactive.” This brief review will describe how and when the chemistry of signaling is similar or differs from classic second messengers, such as cyclic AMP, or posttranslational signaling, such as farnesylation or ubiquitination. The chemistry of cysteine provides a common factor that underlies signaling by H2O2 and HNE. Nonetheless, as H2O2 and HNE are rapidly metabolized in vivo, spatial considerations are extremely important in their actions. Therefore, the locations of sources of H2O2 and α,β-unsaturated aldehydes, the NADPH oxidases, mitochondria, membrane lipids, and redox cycling toxicants, as well as their targets, are key factors. The activation of the JNK pathway by HNE and endogenously generated H2O2 illustrates these principles.
hydrogen peroxide; superoxide; 4-hydroxynonenal; thiol; thiolate; protein tyrosine phosphatase; glutathionylation; thioredoxin
Consumers of marijuana typically feel a strong compulsive desire to consume food. Although past research revealed that the CB1 cannabinoid receptor is a potent regulator of food intake, the functional presence of neuronal CB2 cannabinoid receptors in the brain had been controversial. The role of CB2 receptors in food and alcohol consumption and the behavioral effects of CB2 receptor ligands are not well characterized. This is because CB2 cannabinoid receptors were thought to be absent from the brain and expressed primarily in immune cells and in the periphery. We tested the effects of peripheral injections of CB2 antagonist AM 630, CB2 agonist PEA and CB1 antagonist AM 251 on male C57BL/6, Balb/c, and DBA/2 mice at the beginning of the night cycle and after overnight 12-hour fasts. We also investigated the effects of the putative CB2 agonist, JWH015, and CB2 antagonist SR144528 in mouse motor function tests and in the two compartment black and white box. Under standard conditions, the CB2 antagonist AM 630 inhibited food consumption in C57BL/6 mice and DBA/2 mice, but failed to block food intake of Balb/c mice. The CB2 agonist PEA had no significant effect on food consumption in Balb/c mice, and reduced food intake in C57BL/6 and DBA mice. The CB1 antagonist AM 251 inhibited food ingestion in the three mouse strains at variable times. After 12-hour food deprivation, the CB2 antagonist AM 630 increased food consumption in C57Bl/6 mice, but failed to produce significant changes in food intake for Balb/c and DBA/2 mice. The CB2 agonist PEA also reduced food consumption in all three mice strains at variable times. In comparison to the CB2 ligands, CB1 antagonist AM 251 inhibited food ingestion in the mouse strains. A general pattern of depression in locomotor activity was induced by JWH 015 in both males and females in the three mouse strains tested as the dose was increased. The development and enhancement of alcohol preference was observed following chronic treatment with CB2 agonist JWH 015 in stressed mice but not in controls. Using the DBA/2 strain the spontaneous locomotor activity and stereotype behavior was enhanced by acute administration of low doses of SR144528. There was a reduction in CNR2 gene expression in the ventral mid-brain region of mice that developed alcohol preference but not in those that did not develop alcohol preference. These effects of CB2 cannabinoid receptor ligands in in vivo behavioral tests are provided as functional evidence that CB2-Rs in the brain plays a role in food and alcohol consumption and in the modification of mouse behavior.
Food intake; alcohol consumption; cannabinoids; CB1 and CB2 cannabinoid receptors; CB2-R gene expression; locomotor activity; stereotypy
Memory plays an important role in everyday life but does not provide an exact and unchanging record of experience: research has documented that memory is a constructive process that is subject to a variety of errors and distortions. Yet these memory “sins” also reflect the operation of adaptive aspects of memory. Memory can thus be characterized as an adaptive constructive process, which plays a functional role in cognition but produces distortions, errors, or illusions as a consequence of doing so.
memory; cognition; experience; brain; neuroscience
Anxiety disorders are the most common of the psychiatric disorders affecting as many as 10% of youth, with a peak during adolescence. A core component of these disorders is an unremitting fear in the absence of present threat. One of the most commonly used therapies to treat these disorders is exposure-based cognitive behavioral therapy that identifies the source of the fear and anxiety and then desensitizes the individual to it. This treatment builds on basic principles of fear extinction learning. A number of patients improve with this therapy, but 40–50% do not. This paper provides an overview of recent empirical studies employing both human imaging and cross-species behavioral genetics to examine how fear regulation varies across individuals and across development, especially during adolescence. These studies have important implications for understanding who may be at risk for anxiety disorders and for whom and when during development exposure-based therapies may be most effective.
anxiety; fear regulation; development; individual differences
The transition into and out of adolescence represents a unique developmental period during which neuronal circuits are particularly susceptible to modification by experience. Adolescence is associated with an increased incidence of anxiety disorders in humans,1–3 and an estimated 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents.4,5 Conserved neural circuitry between rodents and humans has facilitated neurodevelopmental studies of behavioral and molecular processes associated with fear learning and memory, which lie at the heart of many anxiety disorders. Here, we review the non-linear developmental aspects of fear learning and memory during a transition period into and out of adolescence and provide a discussion of the molecular mechanisms that may underlie these alterations in behavior. We provide a model that may help to inform novel treatment strategies for children and adolescents with fear-related disorders.
adolescence; anxiety; fear; memory; extinction; retrieval
Multiple subsets of nociceptive, parasympathetic, and sympathetic nerves innervate human nasal mucosa. These play carefully coordinated roles in regulating glandular, vascular, and other processes. These functions are vital for cleaning and humidifying ambient air before it is inhaled into the lungs. The recent identification of distinct classes of nociceptive nerves with unique patterns of transient receptor potential sensory receptor ion channel proteins may account for the polymodal, chemo- and mechanicosensitivity of many trigeminal neurons. Modulation of these families of proteins, excitatory and inhibitory autoreceptors, and combinations of neurotransmitters introduces a new level of complexity and subtlety to nasal innervation. These findings may provide a rational basis for responses to air-temperature changes, culinary and botanical odorants (“aromatherapy”), and inhaled irritants in conditions as diverse as allergic and nonallergic rhinitis, occupational rhinitis, hyposmia, and multiple chemical sensitivity.
transient receptor potential; TRPV1; nociceptive axon response; nociception
The neuronal dendritic tree is a key determinant of how neurons receive, compute, and transmit information. During early postnatal life, synaptic activity promotes dendrite elaboration. Spinal motor neurons utilize GluA1-containing AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptors (AMPA-R) to control this process. This form of developmental dendrite growth can occur independently of N-methyl-D-aspartate receptors (NMDA-R). This review focuses on the mechanism by which the GluA1 subunit of AMPA-R transforms synaptic activity into dendrite growth, and describes the essential role of the GluA1 binding partner SAP97 (synapse-associated protein of 97 kDa molecular weight) in this process. This work defines a new mechanism of activity-dependent development, which might be harnessed to stimulate the recovery of function following insult to the central nervous system.
dendrite; activity dependent; AMPA; GluA1; growth; development