Transgenic mice expressing a human mutant beta1 thyroid receptor are hyperactive, impulsive, and inattentive

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed childhood psychiatric disorder. We have found that a transgenic mouse bearing a human mutant thyroid receptor (TRbeta1) expresses all of the defining symptoms of ADHD--inattention, hyperactivity, and impulsivity--as well as a 'paradoxical' response to methylphenidate (MPH). As with ADHD, the behavioral phenotypes expressed by the TRbeta transgenic mice are dynamic and sensitive to changes in environmental conditions, stress, and reinforcement. TRbeta transgenic mice are euthyroid except for a brief period during postnatal development, but the behavioral phenotypes, elevated dopamine turnover, and paradoxical response to MPH persist into adulthood. Thus, like the vast majority of children with ADHD, the TRbeta transgenic mice exhibit the symptoms of ADHD in the complete absence of thyroid abnormalities. This suggests that even transient perturbations in developmental thyroid homeostasis can have long-lasting behavioral and cognitive consequences, including producing the full spectrum of symptoms of ADHD.     

The evolution of nonhuman primate social behavior

A review of the recent literature concerning evolutionary mechanisms and possible genetic contributions to social behavior reveals a concentration on function rather than mechanism. Although functional consequences may influence future genetic changes in a population, they do not necessarily reflect evolutionary history. More important, genes cannot code for functions. Only when the anatomical structures and behavioral patterns of individuals are described can we study genetic contributions to social organization. Discussions of function in the abstract, without specification of mechanism, do not fall within the realm of scientific testing.     

Is obesity un-American? Disease concerns bias implicit perceptions of national identity

The current research examined whether Americans incorporate obesity into their national identity, and further investigated the role an evolved behavioral immune system plays in shaping Americans' perceptions of obesity and national identity. Two studies revealed that obesity is not, on the whole, incorporated into the American identity at an implicit level. Moreover, when disease concerns were salient, either because of an experimental priming manipulation (Study 1) or due to recent illness (Study 2), thin individuals (for whom obesity may represent a particularly atypical morphology and thus a heuristic cue to disease) implicitly excluded obesity from the American identity to a greater degree. Thus, implicitly categorizing a subgroup of people as an outgroup pathogen threat may promote behavioral avoidance, exclusion, or stigmatization. This behavioral avoidance, could, in turn lead to less risk of fitness-reducing disease contraction. Further implications for evolutionary theories of disease avoidance, group identity, and discrimination are discussed.     

Neurobiology of Mice Selected for High Voluntary Wheel-running Activity

Selective breeding of house mice has been used to study theevolution of locomotor behavior. Our model consists of 4 replicatelines selectively bred for high voluntary wheel running (High-Runner)and 4 bred randomly (Control). The major changes in High-Runnerlines appear to have taken place in the brain rather than incapacities for exercise. Their neurobiological profile resemblesfeatures of human Attention Deficit Hyperactivity Disorder (ADHD)and is also consistent with high motivation for exercise asa natural reward. Both ADHD and motivation for natural rewards(such as food and sex), as well as drugs of abuse, have beenassociated with alterations in function of the neuromodulatordopamine, and High-Runner mice respond differently to dopaminedrugs. In particular, drugs that block the dopamine transporterprotein (such as Ritalin and cocaine) reduce the high-intensityrunning of High-Runner mice but have little effect on Controlmice. In preliminary studies of mice exercised on a treadmill,brain dopamine concentrations did not differ, suggesting thatchanges in the dopamine system may have occurred downstreamof dopamine production (e.g., receptor expression or transduction).Brain imaging by immunohistochemical detection of c-Fos identifiedseveral key regions (prefrontal cortex, nucleus accumbens, caudate-putamen,lateral hypothalamus) that appear to play a role in the differentialresponse to Ritalin and in the increased motivation for runningin High-Runner mice. The activation of other brain regions,such as the hippocampus, was closely associated with wheel runningitself. Chronic wheel running (several weeks) also increasedthe production of new neurons to apparently maximal levels inthe hippocampus, but impaired learning in High-Runner mice.We discuss the biomedical implications of these findings.     

Molecular genetics of attention-deficit hyperactivity disorder (ADHD): an update

Attention-deficit hyperactivity disorder (ADHD) is a heritable and behavioral condition of childhood, affecting 5-10% of school-age children worldwide. Affected patients exhibit various behavioral problems such as carelessness, restlessness, disobedience and failure to stay quiet in class. The etiology of ADHD is not known. However, family, twin and adoption studies have provided strong evidence for a genetic etiology of the disorder. A genome-wide scan has identified six chromosomal loci with LOD scores suggestive of linkage. Animal studies suggest the involvement of the brain dopamine pathway and its alteration in ADHD but there is no direct evidence to support this hypothesis. In addition, there are at least 20 candidate genes of small effect that have been studied but none of them appear to be the major gene causing ADHD. Medical intervention along with psychosocial therapy proved to be beneficial for controlling ADHD, although some undesirable side effects have been encountered during medical treatment. In the future, identification of environmental factors, study of additive gene effects and the interaction of genes and environmental factors may provide better insight into the pathophysiology of ADHD. This may lead to an effective new treatment strategy.     

The evolution of ADHD: a disorder of communication?

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric condition. Many believe that the central disability is impaired inhibition, which leads to reduced abilities in social skills, self-control, organization and time management. The behaviors identified by clinicians as problematic--inattention, hyperactivity and impulsivity--have been incorporated into several evolutionary models as selectively adaptive cognitive skills for surviving the challenges of a variable Pleistocene environment. We propose that the "disabilities" exhibited by individuals with ADHD are maladaptive, and we concur with Barkley that there is a central impairment in the behavioral inhibition system. The underlying neural anatomy and physiology support the possibility that neurotransmitter pathology may have an impact on other interlinked systems (including language), and may also account for the frequent comorbidity of aggression, anxiety, depression, and learning disabilities (many of which are language-related). Language skills compete with other cognitive activities for the attentional system, and thus the evolution of language could not in fact be independent of the evolution of attention. If language represents the ultimate expression of the attentional system, and some individuals with ADHD are seriously impaired in the coordination of interlinked neural systems (including language), then ADHD fits Jerome Wakefield's definition of "harmful dysfunction," and communication impairments should be investigated more thoroughly by clinicians.     

ADHD-Type Behavior and Harmful Dysfunction in Childhood: A Cross-Cultural Model

Cross-cultural studies of psychiatric phenomena allow testing of assumptions of biological consistency and improved understanding of how disorders are culturally formulated. We used a comparative approach to test for population variation in degrees of harmful academic and social dysfunction associated with children's display of behaviors considered symptomatic of Attention Deficit Hyperactivity Disorder (ADHD). Teacher ratings on psychometric scales described behavior and functioning in population-representative samples of Colombian and United States schoolchildren. Mean levels of the behaviors were similar across populations, including a constant gender difference. A multiple regression model showed remarkably consistent relationships of hyperactivity and inattention to harmful dysfunction across populations and genders. Increasing inattention was associated with increasing harmful dysfunction. Increased hyperactivity was associated with improved functioning to a uniform threshold, beyond which more hyperactivity was associated with greater harmful dysfunction. Patterns of relationships between ADHD-associated behaviors and their consequences may prove useful as a basis for cross-cultural investigation of ADHD. The idea of ADHD as psychiatric disease concept or construct with some cross-cultural (external) validity is supported by these data, [cross-cultural psychology, ADHD (Attention deficit hyperactivity disorder), child behavioral disorders, Colombia]     

Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion

High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were measured in the blood of individuals who had concurrently used cocaine and ethanol. Since the powerful reinforcing effects of cocaine appear to be dependent on inhibition of dopamine reuptake in brain, we compared the effects of EC on the dopamine uptake system and its behavioral effects with those of cocaine. EC was equipotent to cocaine with respect to inhibition of binding of [3H]GBR 12935 to the dopamine reuptake complex, inhibition of [3H]dopamine uptake into synaptosomes and in its ability to increase extracellular dopamine concentration in the nucleus accumbens following its systemic administration to rats. Moreover, in rats, EC and cocaine each increased locomotor activity and rearing to the same extent following i.p. administration. In self-administration studies in primates, EC was approximately equipotent to cocaine in maintaining responding. The in vivo formation of this active, transesterified ethyl homolog of cocaine may contribute to the effects and consequences of combined cocaine and ethanol abuse.     

Expression of dopaminergic receptors in the hypothalamus of lean and obese Zucker rats and food intake

As revealed by previous microdialysis studies, basal and food intake-accompanied dopamine release significantly differs in the hypothalamus of obese vs. lean Zucker rats. In the present study, we determined whether dopaminergic receptors are also compromised in obesity. Dopaminergic D(1) and D(2) receptor mRNA expression was studied in the ventromedial hypothalamus (VMH), lateral hypothalamic area (LHA), and the adenohypophysis (AH) of obese and lean Zucker rats using RT-PCR technique. In obese Zucker rats, we found an upregulation of D(1) receptor mRNA in the VMH and AH and a downregulation in the LHA, whereas D(2) receptor mRNA was downregulated in both the VMH and LHA, but not changed in the AH, compared with lean rats. Also, an increase of D(1) receptor staining was seen in the paraventricular nucleus of obese rats by immunohistochemistry. We selected the VMH to test if the observed changes in the dopamine receptor expression of obese rats induce behavioral sensitization to dopamine as expressed by hyperphagia. The overnight food-deprived rats received a single VMH injection (10 nmol) of sulpiride (D(2) receptor antagonist) or saline as control, then food was provided and 1-h food intake was measured. Food intake after sulpiride vs. saline injection was greater in obese rats but was not different in lean rats. Our data suggest that downregulation of D(2) receptor in the hypothalamus at least in the VMH induces behavior sensitization for having large meals. Low D(2) receptor expression may be causal for an exaggerated dopamine release observed in obese rats during food ingestion and for reduced satiety feedback effect of dopamine. High level of D(1) receptor expression in the VMH and low in the LHA may also contribute to the specific feeding pattern in obese rats represented by large meal size and low meal number.     

Paradoxical striatal cellular signaling responses to psychostimulants in hyperactive mice

Recent investigations have shown that three major striatal-signaling pathways (protein kinase A/DARPP-32, Akt/glycogen synthase kinase 3, and ERK) are involved in the regulation of locomotor activity by the monoaminergic neurotransmitter dopamine. Here we used dopamine transporter knock-out mice to examine which particular changes in the regulation of these cell signaling mechanisms are associated with distinct behavioral responses to psychostimulants. In normal animals, amphetamine and methylphenidate increase extracellular levels of dopamine, leading to an enhancement of locomotor activity. However, in dopamine transporter knock-out mice that display a hyperactivity phenotype resulting from a persistent hyperdopaminergic state, these drugs antagonize hyperactivity. Under basal conditions, dopamine transporter knock-out mice show enhanced striatal DARPP-32 phosphorylation, activation of ERK, and inactivation of Akt as compared with wild-type littermates. However, administration of amphetamine or methylphenidate to these mice reveals that inhibition of ERK signaling is a common determinant for the ability of these drugs to antagonize hyperactivity. In contrast, psychostimulants activate ERK and induce hyperactivity in normal animals. In hyperactive mice psychostimulant-mediated behavioral inhibition and ERK regulation are also mimicked by the serotonergic drugs fluoxetine and 5-carboxamidotryptamine, thereby revealing the involvement of serotonin-dependent inhibition of striatal ERK signaling. Furthermore, direct inhibition of the ERK signaling cascade in vivo using the MEK inhibitor SL327 recapitulates the actions of psychostimulants in hyperactive mice and prevents the locomotor-enhancing effects of amphetamine in normal animals. These data suggest that the inhibitory action of psychostimulants on dopamine-dependent hyperactivity results from altered regulation of striatal ERK signaling. In addition, these results illustrate how altered homeostatic state of neurotransmission can influence in vivo signaling responses and biological actions of pharmacological agents used to manage psychiatric conditions such as Attention Deficit Hyperactivity Disorder (ADHD).     

Maternal high-fat diet programming of the neuroendocrine system and behavior

This article is part of a Special Issue “SBN 2014”.Maternal obesity, metabolic state, and diet during gestation have profound effects on offspring development. The prevalence of neurodevelopmental and mental health disorders has risen rapidly in the last several decades in parallel with the rise in obesity rates. Evidence from epidemiological studies indicates that maternal obesity and metabolic complications increase the risk of offspring developing behavioral disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and schizophrenia. Animal models show that a maternal diet high in fat similarly disrupts behavioral programming of offspring, with animals showing social impairments, increased anxiety and depressive behaviors, reduced cognitive development, and hyperactivity. Maternal obesity, metabolic conditions, and high fat diet consumption increase maternal leptin, insulin, glucose, triglycerides, and inflammatory cytokines. This leads to increased risk of placental dysfunction, and altered fetal neuroendocrine development. Changes in brain development that likely contribute to the increased risk of behavioral and mental health disorders include increased inflammation in the brain, as well as alterations in the serotonergic system, dopaminergic system and hypothalamic–pituitary–adrenal (HPA) axis.     

Inhibition in Adults with Attention Deficit/Hyperactivity Disorder: Event-Related Potentials in the Stop Task

The core deficit in Attention Deficit/Hyperactivity Disorder (ADHD) may be a deficiency in executive functions, particularly the processes that are associated with the inhibition of predominant responses. To test this notion in the adult population, healthy undergraduate volunteers and students with ADHD symptoms performed a visual Stop Signal Task (Logan et al. J Exp Psychol: Hum Percept Perform 10:276–291, 1984) while Event-Related brain Potentials were recorded. The two groups did not differ on behavioral measures of performance, but there was a significant difference in the N2–P3 component. These results underline the robustness of an N2–P3 difference between healthy adults and people with ADHD symptoms that have persisted into young adulthood.     

Childhood obesity and parental smoking as risk factors for childhood ADHD in Liverpool children

ADHD prevalence has risen in parallel with rising prevalence of pregnancy smoking and childhood obesity. The objective was to determine the epidemiological association of pregnancy smoking and childhood obesity with ADHD. A cross-sectional community study was conducted in 2006 using a parental questionnaire. A total of 1,074 schoolchildren aged 5-11 years were enrolled from 15 primary schools in a lower socio-economic area of Merseyside. ADHD was defined by the question "does your child have Attention Deficit Hyperactivity Disorder, (ADHD), which has been diagnosed by a doctor?" The prevalence estimates for childhood obesity, maternal smoking during pregnancy and childhood ADHD were 14.9% (116/777), 28.0% (269/955), and 3.4% (32/945), respectively. ADHD prevalence increased fivefold in children with obesity (RR, 4.80, 95% CI 2.2-10.4, P < 0.001) and more than twofold in children of mothers who smoked during pregnancy (RR, 2.44, 95% CI 1.2-4.9, P = 0.02). Regression analysis adjusting for obesity, overweight, maternal smoking during pregnancy, heavy maternal smoking, household member smoking during pregnancy, doctor-diagnosed asthma, preterm birth, and low birthweight showed significant independent associations of ADHD prevalence with obesity (AOR, 4.66, 95% CI 1.57-13.89, P = 0.006) and pregnancy smoking (AOR, 3.19, 95% CI 1.08-9.49, P = 0.04). There was a positive dose-response association of ADHD with the number of maternal cigarettes smoked during pregnancy. Measures to reduce both smoking among pregnant women and childhood obesity might reduce prevalence of childhood ADHD.     

Unusual increase of Scd1 and Elovl6 expression in rat inguinal adipose tissue

It is generally accepted that the location of body fat deposits may play an important role in the risk of developing some endocrine and metabolic diseases. We have studied the effect of food restriction and food restriction/refeeding, often practiced by individuals trying to lose body weight, on the expression of genes which are associated with obesity and certain metabolic disorders in inguinal, epididymal, and perirenal rat white adipose tissues. Gene expression was analyzed by real time semi-quantitative polymerase chain reaction and by Western blot. We found that prolonged food restriction caused a significant decrease of body and adipose tissue mass as well as the increase of Scd1 and Elovl6 gene expressions in all main rat adipose tissue deposits. Food restriction/refeeding caused increases of: a) Scd1 and Elovl6 mRNA levels in adipose tissue, b) Scd1 protein level and c) desaturation index in adipose tissue. The increased expression of both genes was unusually high in inguinal adipose tissue. The results suggest that the increase of Scd1 and Elovl6 gene expressions in white adipose tissue by prolonged food restriction and prolonged food restriction/refeeding may contribute to accelerated fat recovery that often occurs in individuals after food restriction/refeeding.     

Anticipatory Electrodermal Response as a Differentiating Somatic Marker Between Children with ADHD and Controls

Six children with Attention Deficit Hyperactivity Disorder (ADHD) and five control children between the ages of 9 and 11 years were administered an adapted version of the Iowa Gambling Task while measuring anticipatory electrodermal response (EDR). Anticipatory EDR measures were compared between groups. Results indicate that the ADHD group exhibited significantly lower autonomic reactivity to anticipated consequences, evidencing a neuropsychological profile similar to patients with lesions in the ventromedial prefrontal cortex.     

Global climate change and invariable photoperiods: A mismatch that jeopardizes animal fitness

The Earth's surface temperature is rising, and precipitation patterns throughout the Earth are changing; the source of these shifts is likely anthropogenic in nature. Alterations in temperature and precipitation have obvious direct and indirect effects on both plants and animals. Notably, changes in temperature and precipitation alone can have both advantageous and detrimental consequences depending on the species. Typically, production of offspring is timed to coincide with optimal food availability; thus, individuals of many species display annual rhythms of reproductive function. Because it requires substantial time to establish or re‐establish reproductive function, individuals cannot depend on the arrival of seasonal food availability to begin breeding; thus, mechanisms have evolved in many plants and animals to monitor and respond to day length in order to anticipate seasonal changes in the environment. Over evolutionary time, there has been precise fine‐tuning of critical photoperiod and onset/offset of seasonal adaptations. Climate change has provoked changes in the availability of insects and plants which shifts the timing of optimal reproduction. However, adaptations to the stable photoperiod may be insufficiently plastic to allow a shift in the seasonal timing of bird and mammal breeding. Coupled with the effects of light pollution which prevents these species from determining day length, climate change presents extreme evolutionary pressure that can result in severe deleterious consequences for individual species reproduction and survival. This review describes the effects of climate change on plants and animals, defines photoperiod and the physiological events it regulates, and addresses the consequences of global climate change and a stable photoperiod.     

BMI Modulates Calorie-Dependent Dopamine Changes in Accumbens from Glucose Intake

Objective

Dopamine mediates the rewarding effects of food that can lead to overeating and obesity, which then trigger metabolic neuroadaptations that further perpetuate excessive food consumption. We tested the hypothesis that the dopamine response to calorie intake (independent of palatability) in striatal brain regions is attenuated with increases in weight.

Method

We used positron emission tomography with [¹¹C]raclopride to measure dopamine changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose) devoid of calories to that of glucose to assess their association with body mass index (BMI) in nineteen healthy participants (BMI range 21–35).

Results

Neither the measured blood glucose concentrations prior to the sucralose and the glucose challenge days, nor the glucose concentrations following the glucose challenge vary as a function of BMI. In contrast the dopamine changes in ventral striatum (assessed as changes in non-displaceable binding potential of [¹¹C]raclopride) triggered by calorie intake (contrast glucose – sucralose) were significantly correlated with BMI (r = 0.68) indicating opposite responses in lean than in obese individuals. Specifically whereas in normal weight individuals (BMI <25) consumption of calories was associated with increases in dopamine in the ventral striatum in obese individuals it was associated with decreases in dopamine.

Conclusion

These findings show reduced dopamine release in ventral striatum with calorie consumption in obese subjects, which might contribute to their excessive food intake to compensate for the deficit between the expected and the actual response to food consumption.     

Progressive-ratio responding for palatable high-fat and high-sugar food in mice

Foods that are rich in fat and sugar significantly contribute to over-eating and escalating rates of obesity. The consumption of palatable foods can produce a rewarding effect that strengthens action-outcome associations and reinforces future behavior directed at obtaining these foods. Increasing evidence that the rewarding effects of energy-dense foods play a profound role in overeating and the development of obesity has heightened interest in studying the genes, molecules and neural circuitry that modulate food reward. The rewarding impact of different stimuli can be studied by measuring the willingness to work to obtain them, such as in operant conditioning tasks. Operant models of food reward measure acquired and voluntary behavioral responses that are directed at obtaining food. A commonly used measure of reward strength is an operant procedure known as the progressive ratio (PR) schedule of reinforcement. In the PR task, the subject is required to make an increasing number of operant responses for each successive reward. The pioneering study of Hodos (1961) demonstrated that the number of responses made to obtain the last reward, termed the breakpoint, serves as an index of reward strength. While operant procedures that measure changes in response rate alone cannot separate changes in reward strength from alterations in performance capacity, the breakpoint derived from the PR schedule is a well-validated measure of the rewarding effects of food. The PR task has been used extensively to assess the rewarding impact of drugs of abuse and food in rats (e.g., 6-8), but to a lesser extent in mice. The increased use of genetically engineered mice and diet-induced obese mouse models has heightened demands for behavioral measures of food reward in mice. In the present article we detail the materials and procedures used to train mice to respond (lever-press) for a high-fat and high-sugar food pellets on a PR schedule of reinforcement. We show that breakpoint response thresholds increase following acute food deprivation and decrease with peripheral administration of the anorectic hormone leptin and thereby validate the use of this food-operant paradigm in mice.     

Costs of Foraging Predispose Animals to Obesity-Related Mortality when Food Is Constantly Abundant

Obesity is an important medical problem affecting humans and animals in the developed world, but the evolutionary origins of the behaviours that cause obesity are poorly understood. The potential role of occasional gluts of food in determining fat-storage strategies for avoiding mortality have been overlooked, even though animals experienced such conditions in the recent evolutionary past and may follow the same strategies in the modern environment. Humans, domestic, and captive animals in the developed world are exposed to a surplus of calorie-rich food, conditions characterised as ‘constant-glut’. Here, we use a mathematical model to demonstrate that obesity-related mortality from poor health in a constant-glut environment should equal the average mortality rate in the ‘pre-modern’ environment when predation risk was more closely linked with foraging. It should therefore not be surprising that animals exposed to abundant food often over-eat to the point of ill-health. Our work suggests that individuals tend to defend a given excessive level of reserves because this level was adaptive when gluts were short-lived. The model predicts that mortality rate in constant-glut conditions can increase as the assumed health cost of being overweight decreases, meaning that any adaptation that reduced such health costs would have counter-intuitively led to an increase in mortality in the modern environment. Taken together, these results imply that efforts to reduce the incidence of obesity that are focussed on altering individual behaviour are likely to be ineffective because modern, constant-glut conditions trigger previously adaptive behavioural responses.