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In comparison to naturally rewarding behaviors such as feeding and sex, relatively little is known about the neurobiological underpinnings of the positive emotional properties of social behavior. In the period between weaning and sexual maturity (i.e. childhood and adolescence in humans, roughly equivalent to the juvenile and adolescent stages in rodents) substantial changes occur in brain and behavior that are important for behavioral development. In particular, the social repertoire becomes increasingly complex and social interest shifts from the mother towards peers, mostly in the form of social play behavior. Social play behavior serves to facilitate social, physical, emotional and cognitive development. Understanding how social play behavior is generated and which brain areas and neurotransmitter systems modulate this behavior increases our knowledge about normal social behavior. Furthermore, several neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders (DBDs) and autism are characterized by impairments in social (play) behaviors. In addition, drugs of abuse, such alcohol and cocaine are often used in a social setting and this can influence social (play) behavior to a great extent. Furthermore, social disorders such as DBDs and ADHD are an important risk factor for alcohol and drug addiction. Therefore, understanding how drugs of abuse affect social (play) behavior is an important issue. Using operant and place conditioning as well as behavioral analysis of social play behavior in young rats, we aimed to elucidate the neurotransmitter systems and neural substrates underlying the pleasurable, motivational and cognitive aspects of social play behavior. We found that the psychostimulant amphetamine, like methylphenidate, exerts its play suppressant effects via α2-adrenoceptors. In contrast, the psychostimulant cocaine reduces social play by simultaneous increases in dopamine, noradrenaline and serotonin neurotransmission. We subsequently found that prefrontal (anterior cingulate and infralimbic cortex) and limbic subcortical (amygdala and habenula) regions are implicated in the effects of methylphenidate on social play, through noradrenergic neurotransmission. Using place conditioning and operant set-ups, we further elucidate the role of monoamines, opioids and cannabinoids in several aspects of social play behavior. With regard to monoamines, noradrenaline seems to modulate the motivation for social play behavior as well as its expression. For dopamine, clear but opposite roles were found on motivational and pleasurable aspects of social play. We found that the endogenous opioid system is involved in pleasurable and motivational aspects of social play, whereas endocannabinoid neurotransmission does not play a primary role in the motivational and pleasurable aspects of social play behavior. By analyzing the dynamics of social reward-related memories in place conditioning experiments, we found that this type of memories undergoes reconsolidation that depends on β-noradrenergic as well as glucocorticoid receptors, whereas mineralocorticoid, NMDA glutamatergic and CB1 cannabinoid receptors do not seem to be involved. Collectively, the studies in this thesis advance our understanding of the neural mechanisms involved in several aspects of social play behavior in rats. These studies provide important information on the neurobiology of normal, adaptive social behavior and may also give directions for the development of pharmacotherapies for social dysfunctions in psychiatric diseases.

RATIONALE: A bidirectional relationship between alcohol use disorder (AUD) and deficits in impulse control and decision making has been suggested. However, the mechanisms by which neurocognitive impairments predispose to, or result from AUD remain incompletely understood. OBJECTIVES: The aim of this study is to gain more insight in the effects of alcohol exposure on decision making and impulse control. We used two modified versions of the rat gambling task (rGT) that differ in the net gain and the punishment magnitude associated with the different response options. METHODS: In experiment 1, we assessed the effects of acute alcohol treatment (0-0.8 g/kg) on rGT performance. In experiment 2, we determined the effects of alcohol on rGT acquisition (15 sessions, 0.6 g/kg). Next, these animals were challenged with alcohol (0-1.0 g/kg) prior to rGT sessions. RESULTS: Acute alcohol treatment suppressed baseline performance in both rGT versions but only modestly altered decision making. Treatment with alcohol during acquisition increased risky choices in the rGT version that involved larger punishment and blunted the reduction in win-shift behavior during acquisition in both rGT versions. Moreover, rats treated with alcohol during acquisition showed an increase in premature and perseverative responding upon subsequent alcohol challenges (0-1.0 g/kg) and were less sensitive to the behavioral suppressant effects of alcohol. CONCLUSIONS: Our results show that repeated alcohol exposure alters decision making during rGT acquisition and reduces the ability to adjust choice behavior on the basis of feedback. In addition, repeated alcohol exposure unmasks its behavioral disinhibitory effects in the rGT. Impaired responsiveness to choice feedback and behavioral disinhibition may contribute to the development of AUD.

Background: Pathological forms of impulsivity are manifest in a number of psychiatric disorders listed in DSM-5, including attentiondeficit/ hyperactivity disorder and substance use disorder. However, the molecular and cellular substrates of impulsivity are poorly understood. Here, we investigated a specific form of motor impulsivity in rats, namely premature responding, on a five-choice serial reaction time task. Methods: We used in vivo voxel-based magnetic resonance imaging and ex vivo Western blot analyses to investigate putative structural, neuronal, and glial protein markers in low-impulsive (LI) and high-impulsive rats. We also investigated whether messenger RNA interference targeting glutamate decarboxylase 65/67 (GAD65/67) gene expression in the nucleus accumbens core (NAcbC) is sufficient to increase impulsivity in LI rats. Results: We identified structural and molecular abnormalities in the NAcbC associated with motor impulsivity in rats. We report a reduction in gray matter density in the left NAcbC of high-impulsive rats, with corresponding reductions in this region of glutamate decarboxylase (GAD65/67) and markers of dendritic spines and microtubules. We further demonstrate that the experimental reduction of de novo of GAD65/67 expression bilaterally in the NAcbC is sufficient to increase impulsivity in LI rats. Conclusions: These results reveal a novel mechanism of impulsivity in rats involving gamma aminobutyric acidergic and structural abnormalities in the NAcbC with potential relevance to the etiology and treatment of attention-deficit/hyperactivity disorder and related disorders.

Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, which are mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this article, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive, and addictive disorders and indicate new directions for research.

Continued seeking and drinking of alcohol despite adverse legal, health, economic, and societal consequences is a central hallmark of human alcohol use disorders. This compulsive drive for alcohol, defined by resistance to adverse and deleterious consequences, represents a major challenge when attempting to treat alcoholism clinically. Thus, there has long been interest in developing pre-clinical rodent models for the compulsive drug use that characterizes drug addiction. Here, we review recent studies that have attempted to model compulsive aspects of alcohol and cocaine intake in rodents, and consider technical and conceptual issues that need to be addressed when trying to recapitulate compulsive aspects of human addiction. Aversion-resistant alcohol intake has been examined by pairing intake or seeking with the bitter tastant quinine or with footshock, and exciting recent work has used these models to identify neuroadaptations in the amygdala, cortex, and striatal regions that promote compulsive intake. Thus, rodent models do seem to reflect important aspects of compulsive drives that sustain human addiction, and will likely provide critical insights into the molecular and circuit underpinnings of aversion-resistant intake as well as novel therapeutic interventions for compulsive aspects of addiction.

Social play behavior is the most vigorous and characteristic form of social interaction displayed by developing mammals. The laboratory rat is an ideal species to study this behavior, since it shows ample social play that can be easily recognized and quantified. In this chapter, we will first briefly describe the structure of social play behavior in rats. Next, we will discuss studies that used social isolation rearing during the period in life when social play is most abundant to investigate the developmental functions of social play behavior in rats, focusing on the consequences of play deprivation on social, cognitive, emotional, and sensorimotor development. Last, we will discuss the neural substrates of social play behavior in rats, with emphasis on the limbic corticostriatal circuits that underlie emotions and their influence on behavior.

Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction.The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats.Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration.Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose-response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation.Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.

How external stimuli prevent the onset of sleep has been little studied. This is usually considered to be a non-specific type of phenomenon. However, the hypnotic drug dexmedetomidine, an agonist at a2 adrenergic receptors, has unusual properties that make it useful for investigating this question. Dexmedetomidine is considered to produce an ‘arousable’ sleep-like state, so that patients or animals given dexmedetomidine become alert following modest stimulation. We hypothesized that it might be more difficult to make mice unconscious with dexmedetomidine if there was a sufficient external stimulus. Employing a motorized rotating cylinder, which provided a continuous and controlled arousal stimulus, we quantitatively measured the ability of such a stimulus to prevent dexmedetomidine loss of righting reflex in two inbred strains of mice (C57BL/6 and 129X1). We found that whereas the C57BL/6 strain required a strong stimulus to prevent dexmedetomidine-induced hypnosis, the 129X1 strain stayed awake even with minimal stimuli. Remarkably, this could be calibrated as a simple threshold trait, i.e. a binary ‘yes–no’ response, which after crossing the two mouse strains behaved as a dominant-like trait. We carried out a genome-wide linkage analysis on the F2 progeny to determine if the ability of a stimulus to prevent dexmedetomidine hypnosis could be mapped to one or more chromosomal regions. We identified a locus on chromosome 4 with an associated Logarithm of Odds score exceeding the pre-established threshold level. These results show that complex traits, such as the ability of a stimulus to reverse drug-induced hypnosis, may have precise genetic determinants.

Objective: Neuropeptide Y (NPY), given centrally augments food intake and the motivation to work for palatable food. Here, the brain regions were identified through which NPY increases food intake and motivation. Methods: NPY was infused into three brain regions implicated in food intake and motivation: the lateral hypothalamus (LH), nucleus accumbens shell (NAc), and ventral tegmental area (VTA). Motivation for sucrose was assessed using a progressive-ratio schedule of reinforcement in which the effort to obtain successive rewards increased incrementally. To disentangle the effects of NPY on motivation for palatable food from food consumption, free-feeding experiments were performed in which animals had ad libitum access to sucrose pellets. Results: Infusion of NPY into either VTA or NAc increased the motivation to respond for sucrose, whereas infusion of NPY in either NAc or LH increased sucrose consumption. In addition, the effect of intra-VTA NPY on motivation for food was attenuated after pretreatment with the dopamine receptor antagonist alpha-flupenthixol. Conclusions: Specific limbic substrates through which NPY influences consumption of and motivation for palatable food were identified by these data. The motivational effects of NPY are exerted through the VTA, its consummatory effects through the LH, and the NAc is involved in both.

Much consideration of animal welfare issues, as well as the bulk of welfare legislation, is closely related to context, with clear distinction between defined responsibilities towards farm-, laboratory-, companion- and wild animals. It has however been recognised that such distinction leads to inconsistencies, in that it might lead to different welfare management practices for the same rat (for example) as a pet, laboratory animal or pest. We suggest that if legal provisions recognize animals as having moral status, then that implies certain responsibilities towards the animal that cannot be context-dependent. Although we argue the moral responsibility to consider an animal’s welfare is context-independent, we suggest that the requirement to take action (and the form of that action) may alter with context. From a biological perspective, we argue that there exists an obligation to take action to address potential welfare problems only when a challenge exceeds the animal’s adaptive capacity, such that it cannot adequately respond by changes of its behaviour. The obligation to intervene further depends on whether or not there are practical (and economically feasible) options available for mitigation. Beyond this, additional constraints may be posed by anthropocentric aims or objectives, where any suffering may be adjudged avoidable (in theory), but necessary (because of specific human interests). Finally, whatever may be determined necessary or unavoidable by the actual manager or agent himself/herself, such judgement is inevitably subjective and possibly subject to self-interest. Thus any decision must be further evaluated within the context of what is considered by a wider society to be (morally) acceptable or unacceptable.

Mens en dier delen dezelfde ziektes. Daarom werken dierenartsen en mensendokters wereldwijd steeds meer samen. Beide specialisten kunnen veel van elkaar leren.

Pain is described as a subjective unpleasant sensory and emotional experience, which is generated in the brain. In both humans and animals, pain is frequently undertreated. The primary barrier to an effective pain treatment is the incomplete knowledge about underlying central mechanisms. In animals, the recognition and effective treatment of pain is furthermore hampered by a lack of reliable and quantifiable read-out parameters of pain. This necessitates the generation of more fundamental knowledge about animal pain (patho)physiology. When investigating and treating pain, it is important to acknowledge and address the multidimensional character of pain, i.e. affirm the relevance of both the sensory and emotional component. The sensory component relates to the recognition and determination of the type of stimulus, location, intensity, temporal pattern and duration of the pain experience. The emotional component relates to the affective-motivational aspect (e.g. pain unpleasantness). It is the latter component which determines the 'painfulness' or 'hurtfulness' in the subject’s experience. One promising tool to investigate pain is the somatosensory-evoked potential (SEP), which potentially quantifies and differentiates between the sensory and emotional component. SEPs are used in humans and animals to study the central processing of pain. Previous research, using anaesthetic interventions, supports the SEP as a valid method to objectively quantify central pain processing in animals. The studies described in this thesis focus on refinement of the technique to measure the SEP in rats and the subsequent validation of the SEP as a method to study central pain processing. The principal conclusion of the studies described in this thesis is that the SEP as such is to be considered a highly suitable tool to assess alterations in central pain processing caused by non-pharmacological interventions. Effects of an altered emotional state and differences in innate pain sensitivity on central pain processing are reflected in the cortically-derived SEP, further supporting the SEP as a valid and valuable read-out parameter in pain research. However, to investigate and differentially determine the underlying mechanisms of the sensory and emotional component of pain, the SEP's measurement technology applied needs to be refined further. More detailed and differential knowledge about the underlying central mechanisms of pain will ultimately contribute to the adequate treatment of animal pain.

In this study, we investigated the effect of antenatal allopurinol (ALLO) treatment on levels and expression of plasticity markers in the dorsal hippocampus of low (LBW) and normal (NBW) birth weight piglets. ALLO treatment given daily in the last trimester to pregnant sows had a protective effect on neuronal plasticity markers in their piglets. ALLO increases protein levels of BDNF and the postsynaptic marker PSD95 in LBW and NBW piglets. ALLO treatment increases the pCREB/CREB ratio in LBW piglets to a similar level as that found in untreated NBW piglets. In conclusion, antioxidant treatment administered in the last trimester might be a promising treatment for LBW neonates.

This thesis aimed at developing a better understanding on how mice perceive their own emotional state. Next to extending on previous research on the adaptive capacities laboratory mice, we aimed at approaching the emotional perceptions of mice by establishing a behavioural test for the assessment of judgement bias. Adaptive behaviour translates into the waning of a behavioural response over time (i.e. behavioural habituation). Evaluation of behavioural habituation therefore offers a valuable “behavioural tool” to investigate changes in emotional assessments of a given stimulus in animals. The results of this thesis show that mice differ significantly regarding their ability to adapt to challenging conditions. Further, to better understand whether such behaviour might reflect the animals’ perception of its own emotional state we aimed at developing a judgement bias test for mice. A judgement bias results from an either more positive or more negative interpretation of an ambiguous stimulus (a stimulus with uncertain value).Negative emotional states induce a more negative interpretation while positive emotional states induce a more positive interpretation of the same stimulus: the glass is either half full or half empty. This thesis supports the idea that odour conditioning tests can be useful in investigating judgement bias in mice, although some methodological issues remain to be solved in future experiments. In addition to behavioural observations, different physiological and central nervous parameters were investigated in order to get a first indication of the underlying mechanisms that may regulate emotional perception in mice. From both the findings on mouse behaviour and at the central nervous level in the present thesis and previous work it can be concluded that a lack of behavioural habituation might be the result of an impaired cognitive control of emotional processes. Such a characteristic seems to have a clear genetic component since environmental challenges alone did not result in a persistent impairment of habituation in mice. From that it can be concluded that impaired habituation might be indicative of exceeded adaptive capacities and might be a valuable “behavioural tool” to investigate emotional dysfunctions in animals. In addition, brain area’s related to emotion and cognition seem to be involved in the expression of judgement biases as well, supporting the notion that the measurement of judgement biases in mice might provide more information on the animals’ perception of its own emotional state and, thus, first steps have been taken in establishing methods for gaining a better understanding of the (dys)regulation of emotions in mice and, hence in the management of their welfare.

In this thesis the cognitive performance of piglets with low birth weight (LBW) caused by intra-uterine growth restriction (IUGR), and the effects of a possible therapy to prevent IUGR-related brain damage and associated cognitive impairments were studied. To achieve these goals, several conditions had to be fulfilled. First, an appropriate cognitive task had to be selected and validated. Then, the effects of IUGR in this task had to be investigated using the most suitable task. In addition, basic pharmacokinetic data of the putative therapeutic drug were collected in sows and piglets. Finally, the effects of the therapeutic drug on IUGR piglets were assessed. A test for visual discrimination and a test for spatial cognition were developed and applied. Based on the behavioural performance of the pigs in both tasks, the latter was found most suitable as it allows for species-specific behaviour, and matches the capabilities and motivation of the pig the best. This spatial test, ‘the cognitive pig holeboard’ was therefore further developed and automated. To improve validity of this cognitive test, a study with biperiden (a muscarinic M1 receptor blocker, inducing temporary cognitive impairments) was performed with both conventional pigs and Göttingen minipigs. During the training phase, both groups were able to reach nearly errorless performance.Biperiden had only a minor effect on holeboard performance overall, and mainly on reference memory performance. Furthermore, LBW piglets were trained in the cognitive pig holeboard test. Both LBW and their normal birth weight littermates were able to learn the task. After presenting them a reversal (rewards hidden in different places than before), the LBW piglets showed a transiently retarded acquisition of this task supporting the hypothesis that LBW is related to (mild) subsequent cognitive impairments. These results were not replicated in the next experiment in which allopurinol was tested as a possible therapy to prevent brain damage in IUGR neonates. The differences in the set-up of training could have caused these different findings. In this experiment, piglets were, via the sow, chronically treated with allopurinol during the last trimester of pregnancy. No detrimental effects of treatment were found but a beneficial effect on holeboard performance could not be demonstrated in both LBW and normal birth weight piglets. Though, on brain level long-lasting increased mBDNF and PSD95 protein levels in the dorsal hippocampus of allopurinol treated pigs were found. This could be seen as a promising indicator for the efficacy of chronic prenatal allopurinol treatment. Both proteins are part of the BDNF mediated neuronal plasticity pathway that is involved in spatial memory performance. To conclude with, the LBW piglet model is considered to be suitable for further development and practical application. Enhanced postnatal care of the piglets could increase translatability of the model. The cognitive pig holeboard is found to be a reliable behavioural task for measuring several components of spatial learning and memory of various pig breeds from the age of weaning onwards. Therefore this test can be applied when testing the LBW piglet and possible preventive therapeutics.

The reinforcing and addictive properties of cocaine are thought to rely on the dopaminergic innervation of the striatum. The ventromedial [i.e. nucleus accumbens shell (NAcc) shell] and dorsolateral [dorsolateral striatum (DLS)] regions of the striatum are serially connected, and it is thought that slowly developing neuroadaptations are responsible for the recruitment of the DLS in mediating habitual drug use after extended drug experience. Remarkably, we have recently shown that the DLS is also involved in cocaine self-administration after limited use, to modulate the reinforcing properties of the drug, a function usually ascribed to the NAcc shell. Here, we investigated whether the involvement of the DLS in cocaine reinforcement requires dopaminergic activity within the NAcc shell, by performing a pharmacological disconnection study. We infused the dopamine receptor antagonist α-flupenthixol unilaterally into the NAcc shell and infused this same antagonist into the contralateral DLS, thereby disrupting dopaminergic interconnectivity within the striatum. We show that this disconnection results in increased responding for cocaine under a fixed ratio-1 schedule of reinforcement in rats with limited cocaine experience. These data suggest that a functional dopaminergic interaction between the NAcc shell and the DLS mediates cocaine reinforcement during the early stages of drug use.

The inability to make profitable long-term decisions has been implicated in several psychiatric disorders. There is emerging evidence to support a role for dopamine (DA) in decision making, but our understanding of the role of noradrenaline (NA) and serotonin (5-HT) in decision making, and of possible interactions between the three monoamines, is limited. Moreover, impulsivity has been associated with aberrant decision making, but the underlying mechanisms are incompletely understood.The purpose of this study is to improve our understanding of the neuropharmacological mechanisms of decision making and impulse control.We investigated the effects of amphetamine (0.25-1.0 mg/kg) and selective reuptake inhibitors of DA (GBR12909; 2.5-10 mg/kg), NA (atomoxetine; 0.3-3.0 mg/kg), and 5-HT (citalopram; 0.3-3.0 mg/kg) in a rat gambling task (rGT). Since the rGT allows for detection of impulsive action, i.e., premature responding, we also assessed the relationship between decision making and impulsivity.In the rGT, rats developed an optimal choice strategy from the first session onwards. Elevation of endogenous DA or NA levels increased and decreased impulsivity, respectively, but did not alter decision making. However, simultaneous blockade of DA and NA disrupted decision making, reflected by a relative decrease in choice for the advantageous choice options. Increasing 5-HT neurotransmission did not affect decision making or impulsivity.These data suggest important but complementary or redundant roles of DA and NA neurotransmission in decision-making processes based on reward probability and punishment. Moreover, impulse control and decision making in the rGT rely on dissociable mechanisms.

Feather pecking and cannibalism in farm-kept laying hens are damaging behaviors both in terms of animal welfare and economic loss, and a major challenge in modern poultry farming. Both rearing with a foster hen and genetic selection have been demonstrated to reduce feather pecking in laying hens. We examined the effects of rearing with a foster hen, genetic selection for low mortality from cannibalism, and interactions between both, using cellular morphology and levels of the rate-limiting enzyme in dopamine production, tyrosine hydroxylase, in the hippocampus and nidopallium caudolaterale (NCL) as a potential measure for laying hen welfare. Hens from the second generation of a sib-selection scheme line derived from a pure-bred White Leghorn line, selected for low mortality and for production characteristics, or their control line (CL) selected only for production characteristics, were housed with or without a foster Silky hen for the first 7 wk of life. Aside from the presence or absence of a foster Silky hen during the first 7 wk of life, housing conditions were identical for all hens. The hens were then sacrificed and brains were removed at 52 wk of age. Brains were sectioned and stained using a Nissl staining to reveal cell soma morphology, or using immunocytochemistry for tyrosine hydroxlase. A greater degree of lateralization in the hippocampus was observed in hens reared without a foster hen, as measured by absolute difference in cell soma size between hemispheres (P

Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.

This review discusses neurobiological studies of oppositional defiant disorder and conduct disorder within the conceptual framework of three interrelated mental domains: punishment processing, reward processing, and cognitive control. First, impaired fear conditioning, reduced cortisol reactivity to stress, amygdala hyporeactivity to negative stimuli, and altered serotonin and noradrenaline neurotransmission suggest low punishment sensitivity, which may compromise the ability of children and adolescents to make associations between inappropriate behaviors and forthcoming punishments. Second, sympathetic nervous system hyporeactivity to incentives, low basal heart rate associated with sensation seeking, orbitofrontal cortex hyporeactiviy to reward, and altered dopamine functioning suggest a hyposensitivity to reward. The associated unpleasant emotional state may make children and adolescents prone to sensation-seeking behavior such as rule breaking, delinquency, and substance abuse. Third, impairments in executive functions, especially when motivational factors are involved, as well as structural deficits and impaired functioning of the paralimbic system encompassing the orbitofrontal and cingulate cortex, suggest impaired cognitive control over emotional behavior. In the discussion we argue that more insight into the neurobiology of oppositional defiance disorder and conduct disorder may be obtained by studying these disorders separately and by paying attention to the heterogeneity of symptoms within each disorder.

In various animal species, a correlation has been found between the individual's response to ‘stressing’ stimuli (coping style) in behaviour tests and the susceptibility to develop behavioural disorders. Based on analogies with feather pecking in laying hens, a similar correlation might be present in parrots with feather damaging behaviour. To investigate whether this correlation is present in parrots, 22 Grey parrots (Psittacus erithacus erithacus) with and without feather damaging behaviour were subjected to (1) a manual restraint test, (2) novel object test and (3) open field test. All tests were performed in a standardized setting, with a one-week interval between the tests. Recordings were made of the parrots’ responses, which were subsequently analysed to determine latency times, intensity, frequency and/or duration of specific behaviours. In addition, blood was collected to assess the birds’ neurophysiologic responses (corticosterone, norepinephrine) during manual restraint. Significant differences were found between the groups of birds with and without feather damaging behaviour with regard to the birds’ reactions in all the behaviour tests. Particularly the response during the open field test was found to correlate well with the presence of feather damaging behaviour: birds with feather damaging behaviour showed higher open field activity indicative of a proactive coping style. Additionally, feather damaging birds displayed proactive behaviour in the novel object test, as expressed by their initial reaction to a novel object. A manual restraint test did not reveal distinct differences in the amount of resistance displayed by the parrots with and without feather damaging behaviour. Struggling frequencies and neurophysiologic responses, however, tended to be different, with a higher number of struggling attempts and a more prominent rise in plasma corticosterone concentrations in birds without feather damaging behaviour. Aforementioned results suggest that parrots with feather damaging behaviour display a proactive coping style, which is similar to the findings in feather pecking laying hens. These findings provide further insight into the aetiology of feather damaging behaviour, and suggest a potential role for behavioural testing in establishing whether a parrot is at risk for developing this behavioural disorder. Further (prospective) studies with larger groups of parrots are, however, needed to confirm a correlation between coping style and the display of feather damaging behaviour throughout the parrot population and to determine whether and which behaviour tests have (the highest) predictive value.

It is increasingly recognized that studying drug taking in laboratory animals does not equate to studying genuine addiction, characterized by loss of control over drug use. This has inspired recent work aimed at capturing genuine addiction-like behavior in animals. In this work, we summarize empirical evidence for the occurrence of several DSM-IV-like symptoms of addiction in animals after extended drug use. These symptoms include escalation of drug use, neurocognitive deficits, resistance to extinction, increased motivation for drugs, preference for drugs over nondrug rewards, and resistance to punishment. The fact that addiction-like behavior can occur and be studied in animals gives us the exciting opportunity to investigate the neural and genetic background of drug addiction, which we hope will ultimately lead to the development of more effective treatments for this devastating disorder.

The worldwide obesity epidemic poses an enormous and growing threat to public health. However, the neurobehavioral mechanisms of overeating and obesity are incompletely understood. It has been proposed that addiction-like processes may underlie certain forms of obesity, in particular those associated with binge eating disorder. To investigate the role of addiction-like processes in obesity, we adapted a model of cocaine addiction-like behavior in rats responding for highly palatable food. Here, we tested whether rats responding for highly palatable chocolate Ensure would come to show three criteria of addiction-like behavior, i.e., high motivation, continued seeking despite signaled non-availability and persistence of seeking despite aversive consequences. We also investigated whether exposure to a binge model (a diet consisting of alternating periods of limited food access and access to highly palatable food), promotes the appearance of food addiction-like behavior. Our data show substantial individual differences in control over palatable food seeking and taking, but no distinct subgroup of animals showing addiction-like behavior could be identified. Instead, we observed a wide range extending from low to very high control over palatable food intake. Exposure to the binge model did not affect control over palatable food seeking and taking, however. Animals that showed low control over palatable food intake (i.e., scored high on the three criteria for addiction-like behavior) were less sensitive to devaluation of the food reward and more prone to food-induced reinstatement of extinguished responding, indicating that control over palatable food intake is associated with habitual food intake and vulnerability to relapse. In conclusion, we present an animal model to assess control over food seeking and taking. Since diminished control over food intake is a major factor in the development of obesity, understanding its behavioral and neural underpinnings may facilitate improved management of the obesity epidemic.

Alcoholism is a devastating brain disorder that affects millions of people worldwide. The development of alcoholism is caused by alcohol-induced maladaptive changes in neural circuits involved in emotions, motivation, and decision-making. Because of its involvement in these processes, the amygdala is thought to be a key neural structure involved in alcohol addiction. However, the molecular mechanisms that govern the development of alcoholism are incompletely understood. We have previously shown that in a limited access choice paradigm, C57BL/6J mice progressively escalate their alcohol intake and display important behavioral characteristic of alcohol addiction, in that they become insensitive to quinine-induced adulteration of alcohol. This study used the limited access choice paradigm to study gene expression changes in the amygdala during the escalation to high alcohol consumption in C57BL/6J mice. Microarray analysis revealed that changes in gene expression occurred predominantly after one week, i.e. during the initial escalation of alcohol intake. One gene that stood out from our analysis was the adapter protein 14-3-3ζ, which was up-regulated during the transition from low to high alcohol intake. Independent qPCR analysis confirmed the up-regulation of amygdala 14-3-3ζ during the escalation of alcohol intake. Subsequently, we found that local knockdown of 14-3-3ζ in the amygdala, using RNA interference, dramatically augmented alcohol intake. In addition, knockdown of amygdala 14-3-3ζ promoted the development of inflexible alcohol drinking, as apparent from insensitivity to quinine adulteration of alcohol. This study identifies amygdala 14-3-3ζ as a novel key modulator that is engaged during escalation of alcohol use.

During spoken language interpretation, listeners rapidly relate the meaning of each individual word to what has been said before. However, spoken words often contain spurious other words, like 'day' in 'daisy', or 'dean' in 'sardine'. Do listeners also relate the meaning of such unintended, spurious words to the prior context? We used ERPs to look for transient meaning-based N400 effects in sentences that were completely plausible at the level of words intended by the speaker, but contained an embedded word whose meaning clashed with the context. Although carrier words with an initial embedding ('day' in 'daisy') did not elicit an embedding-related N400 effect relative to matched control words without embedding, carrier words with a final embedding ('dean' in 'sardine') did elicit such an effect. Together with prior work from our lab and the results of a Shortlist B simulation, our findings suggest that listeners do semantically interpret embedded words, albeit not under all conditions. We explain the latter by assuming that the sense-making system adjusts its hypothesis for how to interpret the external input at every new syllable, in line with recent ideas of active sampling in perception.

Onderzoek naar taal en communicatie heeft zich in het verleden veel te veel gericht op taal als systeem om berichten te coderen, een soort TCP/IP (netwerkprotocol voor communicatie tussen computers). Dat moet maar eens veranderen, stelde prof. dr. Jos van Berkum, hoogleraar Discourse, Cognitie en Communicatie, in zijn oratie die hij op 30 september hield aan de Universiteit Utrecht. Hij pleit voor meer onderzoek naar de sterke verwevenheid van taal en gevoel. Wat hebben taal en gevoel met elkaar te maken? Op het eerste gezicht wellicht niet zo veel. Natuurlijk kunnen we taal gebruiken om iemand te vertellen hoe we ons voelen, of te beschrijven hoe anderen zich voelen. Maar is dat alles? Zo ja, dan hebben taal en gevoel ongeveer net zo veel met elkaar te maken als taal en vakantie: je kan er over praten. Van Berkum laat zien dat taal en gevoel in ons brein veel sterker met elkaar verweven zijn dan dit. In een wereld zonder vakanties is taal nog steeds prima denkbaar. Maar in een wereld zonder gevoelens blijft er van taal niet veel over.