Françoise Dellu-Hagedorn

Dimensional Analysis of ADHD Subtypes in Rats

BACKGROUND Attention-deficit/hyperactivity disorder is a heterogeneous disorder that is classified into three subtypes in which the main symptoms, inattention, hyperactivity, and impulsivity, are expressed with various degrees of severity. The nature of the biological dysfunction sustaining each subtype (common or distinct) is unknown, and animal models encompassing different subtypes are needed. METHODS A cluster analysis separated subgroups of rats on the basis of similarities in both impulsivity and attentional scores in the five-choice serial reaction time task. These subgroups were characterized behaviorally and were compared for several aspects of spontaneous hyperactivity in different environmental contexts. The dose effects of two agents used clinically (methylphenidate and atomoxetine) were tested on attention and impulsivity. RESULTS Four distinct subgroups were demonstrated: efficient, middle, inattentive, and inattentive-impulsive. Hyperactivity expressed in a cage, characterized the last subgroup. Subgroups were differentially sensitive to environmental and pharmacologic challenges. Methylphenidate increased impulsivity mainly in the combined subgroup, whereas atomoxetine decreased impulsivity, neither with any effect on the efficient subgroup and on accuracy. CONCLUSIONS This new approach is the first to demonstrate behavioral subtypes in rats that parallel those observed in human beings and is a promising tool to clarify the biological bases of these behavioral subtypes and to explain therapeutic effects.

Risk-Prone Individuals Prefer the Wrong Options on a Rat Version of the Iowa Gambling Task

BACKGROUND Decision making in complex and conflicting situations, as measured in the widely used Iowa Gambling Task (IGT), can be profoundly impaired in psychiatric disorders, such as attention-deficit/hyperactivity disorder, drug addiction, and also in healthy individuals for whom immediate gratification prevails over long-term gain. The cognitive processes underlying these deficits are poorly understood, in part due to a lack of suitable animal models assessing complex decision making with good construct validity. METHODS We developed a rat gambling task analogous to the IGT that tracks, for the first time, the ongoing decision process within a single session in an operant cage. Rats could choose between various options. Disadvantageous options, as opposed to advantageous ones, offered bigger immediate food reward but were followed by longer, unpredictable penalties (time-out). RESULTS The majority of rats can evaluate and deduce favorable options more or less rapidly according to task complexity, whereas others systematically choose disadvantageously. These interindividual differences are stable over time and do not depend on task difficulty or on the level of food restriction. We find that poor decision making does not result from a failure to acquire relevant information but from hypersensitivity to reward and higher risk taking in anxiogenic situations. CONCLUSIONS These results suggest that rats, as well as human poor performers, share similar traits to those observed in decision-making related psychiatric disorders. These traits could constitute risk factors of developing such disorders. The rapid identification of poor decision makers using the rat gambling task should promote the discovery of the specific brain dysfunctions that cause maladapted decision making.

Rodent versions of the iowa gambling task: opportunities and challenges for the understanding of decision-making.

Impaired decision-making is a core problem in several psychiatric disorders including attention-deficit/hyperactivity disorder, schizophrenia, obsessive–compulsive disorder, mania, drug addiction, eating disorders, and substance abuse as well as in chronic pain. To ensure progress in the understanding of the neuropathophysiology of these disorders, animal models with good construct and predictive validity are indispensable. Many human studies aimed at measuring decision-making capacities use the Iowa gambling task (IGT), a task designed to model everyday life choices through a conflict between immediate gratification and long-term outcomes. Recently, new rodent models based on the same principle have been developed to investigate the neurobiological mechanisms underlying IGT-like decision-making on behavioral, neural, and pharmacological levels. The comparative strengths, as well as the similarities and differences between these paradigms are discussed. The contribution of these models to elucidate the neurobehavioral factors that lead to poor decision-making and to the development of better treatments for psychiatric illness is considered, along with important future directions and potential limitations.

Hyperactivity in the rat is associated with spontaneous low level of n-3 polyunsaturated fatty acids in the frontal cortex

Inattention, hyperactivity and impulsiveness are the main symptoms of the heterogeneous attention-deficit/hyperactivity disorder (ADHD). It has been suggested that ADHD is associated with an imbalance in polyunsaturated fatty acid (PUFA) composition, with abnormal low levels of the main n-3 PUFA, DHA (22: 6n-3). DHA is highly accumulated in nervous tissue membranes and is implicated in neural function. Animal studies have shown that diet-induced lack of DHA in the brain leads to alterations in cognitive processes, but the relationship between DHA and hyperactivity is unclear. We examined the membrane phospholipid fatty acid profile in frontal cortex of rats characterized for attention, impulsiveness and motricity in various environmental contexts to determine the relationship between brain PUFA composition and the symptoms of ADHD. The amounts of n-3 PUFA in the PE were significantly correlated with nocturnal locomotor activity and the locomotor response to novelty: hyperactive individuals had less n-3 PUFA than hypoactive ones. We conclude that spontaneous hyperactivity in rats is the symptom of ADHD that best predicts the n-3 PUFA content of the frontal cortex. This differential model in rats should help to better understand the role of PUFA in several psychopathologies in which PUFA composition is modified.

Inter-individual decision-making differences in the effects of cingulate, orbitofrontal, and prelimbic cortex lesions in a rat gambling task.

Deficits in decision-making is a hallmark of several neuropsychiatric pathologies but is also observed in some healthy individuals that could be at risk to develop these pathologies. Poor decision-making can be revealed experimentally in humans using the Iowa gambling task, through the inability to select options that ensure long term gains over larger immediate gratification. We devised an analogous task in the rat, based on uncertainty and conflicting choices, the rat gambling task (RGT). It similarly reveals good and poor performers within a single session. Using this task, we investigated the role of three prefrontal cortical areas, the orbitofrontal, prelimbic, and cingulate cortices on decision-making, taking into account inter-individual variability in behavioral performances. Here, we show that these three distinct subregions are differentially engaged to solve the RGT. Cingulate cortex lesion mainly delayed good decision-making whereas prelimbic and orbitofrontal cortices induced different patterns of inadapted behaviors in the task, indicating varying degree of functional specialization of these three areas. Their contribution largely depended on the level of adaptability demonstrated by each individual to the constraint of the task. The inter-individual differences in the effect of prefrontal cortex area lesions on decision-making revealed in this study open new perspectives in the search for vulnerability markers to develop disorders related to executive dysfunctioning.

Relationship between impulsivity, hyperactivity and working memory: a differential analysis in the rat

BackgroundImpulsivity is a behavioural trait that comprises several distinct processes. It is a key feature of many psychopathologies such as mania, addictive disorders or attention deficit-hyperactivity disorders. To date, the aspects of impulsiveness involved in these pathologies have not yet been explicitly defined. In these disorders, sensation or drug seeking and cognitive deficits are closely related, but the nature of these relationships remains largely unknown. A new animal model of impulsiveness based on spontaneous inter-individual differences is proposed here to help clarify the relationship between characteristic aspects of impulsive-related pathologies.MethodsRats were divided into sub-groups according to their scores in three operant tasks with varying degrees of behavioural inhibition, timing and motor vs. cognitive impulsivity demands. These tasks included a fixed consecutive number schedule (ability to complete an action to receive a reinforcer), a multiple fixed-interval/extinction schedule of reinforcement (high level of responding), and a delayed reward task (delay discounting). In addition, measurements of locomotor responses to novelty and to amphetamine in a circular corridor, and working memory in an 8-arm radial maze were obtained.ResultsSubstantial behavioural inter-individual differences were observed in each task, whereas few inter-task relationships were found. Impulsive rats, as defined in a task requiring inhibition of premature responses, presented a higher increase in amphetamine-induced locomotion. Reduced working memory performance was only observed in hyperactive rats in an extinction schedule.ConclusionThis novel approach shows that distinct aspects of impulsiveness and hyperactivity can be expressed based on large inter-individual differences that vary from poorly to highly adapted behaviours ones in a normal population of rats. Inhibitory deficit was related to a higher response to psychostimulants a characteristic of rats predisposed to amphetamine self-administration and related to higher limbic dopaminergic activity, whereas working memory capacity was only related to hyperactivity. This approach allows for the identification of particular individuals presenting distinct behavioural characteristics of impulsive-related psychopathologies. These individuals may be of great interest in the modelling of these disorders and the exploration of their neurobiological bases.

Cross-species approaches to pathological gambling: A review targeting sex differences, adolescent vulnerability and ecological validity of research tools

Decision-making plays a pivotal role in daily life as impairments in processes underlying decision-making often lead to an inability to make profitable long-term decisions. As a case in point, pathological gamblers continue gambling despite the fact that this disrupts their personal, professional or financial life. The prevalence of pathological gambling will likely increase in the coming years due to expanding possibilities of on-line gambling through the Internet and increasing liberal attitudes towards gambling. It therefore represents a growing concern for society. Both human and animal studies rapidly advance our knowledge on brain-behaviour processes relevant for understanding normal and pathological gambling behaviour. Here, we review in humans and animals three features of pathological gambling which hitherto have received relatively little attention: (1) sex differences in (the development of) pathological gambling, (2) adolescence as a (putative) sensitive period for (developing) pathological gambling and (3) avenues for improving ecological validity of research tools. Based on these issues we also discuss how research in humans and animals may be brought in line to maximize translational research opportunities.

Impulsivity in youth predicts early age-related cognitive deficits in rats

Impulsivity is a feature of psychiatric disorders such as mania, addictive behaviors or attention deficit-hyperactivity disorder (ADHD), which has recently been related to complaints of forgetfulness in adults. We investigated whether impulsiveness exerts a long-term influence on cognitive function in rats in a longitudinal study. Impulsivity, assessed by the ability to complete a sequence of presses to obtain food (conditioning box), spatial working memory (8-arm radial maze) assessed with varying degree of attentional load and recognition memory (Y-maze) were tested at different ages. Marked individual differences in impulsivity were observed at youth and remained stable at middle-age despite a general decline in the trait. Working memory scores of impulsive and non-impulsive rats did not differ in youth, whereas by middle-age the impulsive group had impaired working memory and was more sensitive to a higher attentional demand. Thus, impulsiveness in youth predicts cognitive performance in middle-age. These findings may help refine the search for early biological substrates of successful aging and for preventive follow-up of subjects at risk of impaired cognitive aging.

Monoamines tissue content analysis reveals restricted and site-specific correlations in brain regions involved in cognition.

The dopamine (DA), noradrenalin (NA) and serotonin (5-HT) monoaminergic systems are deeply involved in cognitive processes via their influence on cortical and subcortical regions. The widespread distribution of these monoaminergic networks is one of the main difficulties in analyzing their functions and interactions. To address this complexity, we assessed whether inter-individual differences in monoamine tissue contents of various brain areas could provide information about their functional relationships. We used a sensitive biochemical approach to map endogenous monoamine tissue content in 20 rat brain areas involved in cognition, including 10 cortical areas and examined correlations within and between the monoaminergic systems. Whereas DA content and its respective metabolite largely varied across brain regions, the NA and 5-HT contents were relatively homogenous. As expected, the tissue content varied among individuals. Our analyses revealed a few specific relationships (10%) between the tissue content of each monoamine in paired brain regions and even between monoamines in paired brain regions. The tissue contents of NA, 5-HT and DA were inter-correlated with a high incidence when looking at a specific brain region. Most correlations found between cortical areas were positive while some cortico-subcortical relationships regarding the DA, NA and 5-HT tissue contents were negative, in particular for DA content. In conclusion, this work provides a useful database of the monoamine tissue content in numerous brain regions. It suggests that the regulation of these neuromodulatory systems is achieved mainly at the terminals, and that each of these systems contributes to the regulation of the other two.

Elucidating Poor Decision-Making in a Rat Gambling Task

Although poor decision-making is a hallmark of psychiatric conditions such as attention deficit/hyperactivity disorder, pathological gambling or substance abuse, a fraction of healthy individuals exhibit similar poor decision-making performances in everyday life and specific laboratory tasks such as the Iowa Gambling Task. These particular individuals may provide information on risk factors or common endophenotypes of these mental disorders. In a rodent version of the Iowa gambling task – the Rat Gambling Task (RGT), we identified a population of poor decision makers, and assessed how these rats scored for several behavioral traits relevant to executive disorders: risk taking, reward seeking, behavioral inflexibility, and several aspects of impulsivity. First, we found that poor decision-making could not be well predicted by single behavioral and cognitive characteristics when considered separately. By contrast, a combination of independent traits in the same individual, namely risk taking, reward seeking, behavioral inflexibility, as well as motor impulsivity, was highly predictive of poor decision-making. Second, using a reinforcement-learning model of the RGT, we confirmed that only the combination of extreme scores on these traits could induce maladaptive decision-making. Third, the model suggested that a combination of these behavioral traits results in an inaccurate representation of rewards and penalties and inefficient learning of the environment. Poor decision-making appears as a consequence of the over-valuation of high-reward-high-risk options in the task. Such a specific psychological profile could greatly impair clinically healthy individuals in decision-making tasks and may predispose to mental disorders with similar symptoms.