Peter Karel

Elevated microRNA-181c and microRNA-30d levels in the enlarged amygdala of the valproic acid rat model of autism ☆

Autism spectrum disorders are severe neurodevelopmental disorders, marked by impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. Accumulating evidence suggests that dysfunction of the amygdala may be partially responsible for the impairment of social behavior that is a hallmark feature of ASD. Our studies suggest that a valproic acid (VPA) rat model of ASD exhibits an enlargement of the amygdala as compared to controls rats, similar to that observed in adolescent ASD individuals. Since recent research suggests that altered neuronal development and morphology, as seen in ASD, may result from a common post-transcriptional process that is under tight regulation by microRNAs (miRs), we examined genome-wide transcriptomics expression in the amygdala of rats prenatally exposed to VPA, and detected elevated miR-181c and miR-30d expression levels as well as dysregulated expression of their cognate mRNA targets encoding proteins involved in neuronal system development. Furthermore, selective suppression of miR-181c function attenuates neurite outgrowth and branching, and results in reduced synaptic density in primary amygdalar neurons in vitro. Collectively, these results implicate the small non-coding miR-181c in neuronal morphology, and provide a framework of understanding how dysregulation of a neurodevelopmentally relevant miR in the amygdala may contribute to the pathophysiology of ASD.

Individual differences in cocaine addiction: maladaptive behavioural traits

Cocaine use leads to addiction in only a subset of individuals. Understanding the mechanisms underlying these individual differences in the transition from cocaine use to cocaine abuse is important to develop treatment strategies. There is agreement that specific behavioural traits increase the risk for addiction. As such, both high impulsivity and high anxiety have been reported to predict (compulsive) cocaine self‐administration behaviour. Here, we set out a new view explaining how these two behavioural traits may affect addictive behaviour. According to psychological and psychiatric evolutionary views, organisms flourish well when they fit (match) their environment by trait and genotype. However, under non‐fit conditions, the need to compensate the failure to deal with this environment increases, and, as a consequence, the functional use of rewarding drugs like cocaine may also increase. It suggests that neither impulsivity nor anxiety are bad per se, but that the increased risk to develop cocaine addiction is dependent on whether behavioural traits are adaptive or maladaptive in the environment to which the animals are exposed. This ‘behavioural (mal)adaptation view’ on individual differences in vulnerability to cocaine addiction may help to improve therapies for addiction.

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model­

ABSTRACT Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction. Summary: Rats with a novel dopamine D1 receptor mutation, which causes reduced membrane Drd1 expression, display impaired social cognition, although their exploratory and anxiety-like behaviours are unaffected.

Reduced cocaine-induced serotonin, but not dopamine and noradrenaline, release in rats with a genetic deletion of serotonin transporters

It has recently been proposed that the increased reinforcing properties of cocaine and ecstasy observed in rats with a genetic deletion of serotonin transporters are the result of a reduction in the psychostimulant-induced release of serotonin. Here we provide the neurochemical evidence in favor of this hypothesis and show that changes in synaptic levels of dopamine or noradrenaline are not very likely to play an important role in the previously reported enhanced psychostimulant intake of these serotonin transporter knockout rats. The results may very well explain why human subjects displaying a reduced expression of serotonin transporters have an increased risk to develop addiction.

D-Cycloserine enhanced extinction of cocaine-induced conditioned place preference is attenuated in serotonin transporter knockout rats

d‐Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug‐related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5‐HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5‐HTT−/− compared with 5‐HTT+/+ rats. Based on this finding, we hypothesized a lower sensitivity to DCS in the 5‐HTT−/− rats. To test this, rats were trained in a cocaine‐induced conditioned place preference (CPP) paradigm. A significant extinction of CPP was observed in 5‐HTT+/+ rats receiving 1 mg/kg i.v. DCS, while a similar effect was found in the 5‐HTT−/− rats only after 5 mg/kg. Following CPP, we tested if DCS were able to reduce FosB/∆FosB protein expression, a molecular switch for cocaine‐seeking behaviour. We observed an overall lower number of FosB/∆FosB positive cells in 5‐HTT−/− ventromedial prefrontal cortex and amygdala and an overall effect of DCS treatment on the number of positive cells in the nucleus accumbens. In conclusion, in this study, we show that the dosing of DCS to facilitate the extinction of cocaine‐seeking behaviour is, at least partially, determined by 5‐HTT genotype.

Median and dorsal raphe serotonergic neurons control moderate versus compulsive cocaine intake

BACKGROUND Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes. METHODS We used virally mediated RNA interference to locally downregulate SERT expression and compared the results with those of constitutive SERT knockout. Rats were allowed either short access (ShA) (1 hour) or long access (LgA) (6 hours) to cocaine self-administration to model moderate versus compulsive-like cocaine taking. RESULTS SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions and, like ShA cocaine self-administration, reduced corticotropin-releasing factor (CRF) immunodensity in the paraventricular nucleus of the hypothalamus. In contrast, SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions and, like LgA cocaine self-administration, reduced CRF immunodensity in the central nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior, as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific SERT knockdown. CONCLUSIONS Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine.

Aversive Counterconditioning Attenuates Reward Signaling in the Ventral Striatum

Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula.

Appetitive to aversive counter-conditioning as intervention to reduce reinstatement of reward-seeking behavior: the role of the serotonin transporter: 5-HTT in counter-conditioning

Counter‐conditioning can be a valid strategy to reduce reinstatement of reward‐seeking behavior. However, this has not been tested in laboratory animals with extended cocaine‐taking backgrounds nor is it well understood, which individual differences may contribute to its effects. Here, we set out to investigate the influence of serotonin transporter (5‐HTT) genotype on the effectiveness of counter‐conditioning after extended access to cocaine self‐administration. To this end, 5‐HTT+/+ and 5‐HTT−/− rats underwent a touch screen‐based approach to test if reward‐induced reinstatement of responding to a previously counter‐conditioned cue is reduced, compared with a non‐counter‐conditioned cue, in a within‐subject manner. We observed an overall extinction deficit of cocaine‐seeking behavior in 5‐HTT−/− rats and a resistance to punishment during the counter‐conditioning session. Furthermore, we observed a significant decrease in reinstatement to cocaine and sucrose associated cues after counter‐conditioning but only in 5‐HTT+/+ rats. In short, we conclude that the paradigm we used was able to produce effects of counter‐conditioning of sucrose seeking behavior in line with what is described in literature, and we demonstrate that it can be effective even after long‐term exposure to cocaine, in a genotype‐dependent manner.

Corrigendum to “Serotonin transporter genotype × construction stress interaction in rats” [Behav. Brain Res. 223 (2011) 169–175]

orrigendum orrigendum to “Serotonin transporter genotype × construction stress nteraction in rats” [Behav. Brain Res. 223 (2011) 169–175] ieter Schippera,b, Lourens J.P. Nonkesb, Peter Karelb, Amanda J. Kiliaana,b, Judith R. Hombergb,∗ Department of Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands