Sequential behaviour in the Rat: Design and applications of a Serial Reaction Time Task

The study of sequential behaviour which relies among others on dopamine mechanisms and basal ganglia networks, is particularly relevant in Parkinsonian patients. Sequential behaviour can be ex- tensively studied through the use of a standard test known as the Serial Reaction Time Task (SRTT) in humans and non-human pri- mates. Although a rodent model of such a test would be very useful to investigate the underlying brain mechanisms of this type of learn- ing, there is no standardised rodent test. The aim of the three studies presented in this work was to characterise sequential behaviour in the intact rat as an analogy to the human standard test. The aim of the first study was to implement a rat model of the hu- man standard SRTT. The designed task required the rats to poke fast with their nose (motor answer) into lit holes (visual stimulus, one of four locations) and to perform a series of such nosepokes in order to get a food-reward, according to a fixed ratio schedule of reinforce- ment (FR). The location of the light was displayed in either random or sequential order and sequential learning was inferred from the dif- ference in performance between the two conditions within-session. We found that the rats performed better in the sequential condition, in terms of speed, accuracy and number of rewards earned. Details of the test were improved in the course of the studies to ensure that the better performance in sequential condition could only be attributed to the learning of the serial order information and no other general skill. Rats were finally tested on a repeated sequence of twelve ordered locations under a FR13. The length of the FR13 series was intention- ally longer than the length of the repeated sequence to dissociate the sequence locations from the FR schedule positions. The sequence structure was cautiously generated according to statistical rules (e.g. locations frequency, transitions frequency). These features provided a level of sequence difficulty comparable to the human one. This test was used in the second study to investigate the role of dopamine in this task in general and in the sequential performance of well-trained rats in particular. As this SRTT was planned to be applied in dopamine-depleted rats, the effects of the blockade of the dopaminergic transmission were first studied. A D1 and a D2 se- lective antagonists were used and injected systemically. We found that both antagonists produced dramatic disruption of responding, decreased response rate and increased the number of omissions. Only the D1 antagonist increased accuracy to a small extent. These effects were independent of the condition and dose-dependent. The D1 antagonist specifically impaired initial reaction times (within the first halves) of the series, whereas the D2 antagonist affected the whole pattern. Under D1 antagonist treatment, reaction times did not improve in sequential condition compared to random condition, which would reflect a specific effect of the D1 receptor in sequential performance. The third study aimed at investigating to which extent well-trained rats in the SRTT developed a habit. Rats were trained in sequential con- dition and were then confronted during a test with randomly inserted unique sequence violations. A detailed analysis of the performance yielded that rats showed indices of habit but also that attention was still playing a role. At the position of the violation, either the rats dis- played lengthened reaction times for correct pokes or poked fast into the hole where the light should have appeared according to the se- quential order (“expected” light location). This fast answer was how- ever now incorrect because of the sequence violation. Repetition of this test in a bigger group of rats proved the reliability of these results. In this repeated experiment, the apparatus and details of the task (but not of the sequence) were modified to suit application in dopamine- depleted animals for which motor requirements for example, have to be minimized. The rat SRTT with food-reinforcement described here shows high face-validity with the standard human SRTT. It has been effective for the biopsychological characterisation in intact rats of sequential performance, which in many aspects resembled the human one. The designed SRTT with food-reinforcement will probably be of value as a rodent model for the study of sequential behaviour in dopamine- depleted animals as a model for Parkinson disease

Social Behavior and Ultrasonic Vocalizations in a Genetic Rat Model Haploinsufficient for the Cross-Disorder Risk Gene Cacna1c

The top-ranked cross-disorder risk gene CACNA1C is strongly associated with multiple neuropsychiatric dysfunctions. In a recent series of studies, we applied a genomically informed approach and contributed extensively to the behavioral characterization of a genetic rat model haploinsufficient for the cross-disorder risk gene Cacna1c. Because deficits in processing social signals are associated with reduced social functioning as commonly seen in neuropsychiatric disorders, we focused on socio-affective communication through 22-kHz and 50-kHz ultrasonic vocalizations (USV). Specifically, we applied a reciprocal approach for studying socio-affective communication in sender and receiver by including rough-and-tumble play and playback of 22-kHz and 50-kHz USV. Here, we review the findings obtained in this recent series of studies and link them to the key features of 50-kHz USV emission during rough-and-tumble play and social approach behavior evoked by playback of 22-kHz and 50-kHz USV. We conclude that Cacna1c haploinsufficiency in rats leads to robust deficits in socio-affective communication through 22-kHz and 50-kHz USV and associated alterations in social behavior, such as rough-and-tumble play behavior

Pro-social 50-kHz ultrasonic communication in rats: Post-weaning but not post-adolescent social isolation leads to social impairments – phenotypic rescue by re-socialization

Rats are highly social animals and social play during adolescence has an important role for social development, hence post-weaning social isolation is widely used to study the adverse effects of juvenile social deprivation and to induce behavioral phenotypes relevant to neuropsychiatric disorders, like schizophrenia. Communication is an important component of the rat’s social behavior repertoire, with ultrasonic vocalizations (USV) serving as situation-dependent affective signals. High-frequency 50-kHz USV occur in appetitive situations and induce approach behavior, supporting the notion that they serve as social contact calls; however, post-weaning isolation effects on the behavioral changes displayed by the receiver in response to USV have yet to be studied. We therefore investigated the impact of post-weaning isolation on socio-affective information processing as assessed by means of our established 50-kHz USV radial maze playback paradigm. We showed that post-weaning social isolation specifically affected the behavioral response to playback of pro-social 50-kHz but not alarm 22-kHz USV. While group-housed rats showed the expected preference, i.e. approach, towards 50-kHz USV, the response was even stronger in short-term isolated rats (i.e. 1 day), possibly due to a higher level of social motivation. In contrast, no approach was observed in long-term isolated rats (i.e. 4 weeks). Importantly, deficits in approach were reversed by peer-mediated re-socialization and could not be observed after post-adolescent social isolation, indicating a critical period for social development during adolescence. Together, these results highlight the importance of social experience for affiliative behavior, suggesting a critical involvement of play behavior on socio-affective information processing in rats

Effects of amphetamine on pro-social ultrasonic communication in juvenile rats: Implications for mania models

Deutsche Forschungsgemeinschaft https://doi.org/10.13039/50110000165

Fear Extinction and Predictive Trait-Like Inter-Individual Differences in Rats Lacking the Serotonin Transporter

Anxiety disorders are associated with a failure to sufficiently extinguish fear memories. The serotonergic system (5-hydroxytryptamine, 5-HT) with the 5-HT transporter (5-HTT, SERT) is strongly implicated in the regulation of anxiety and fear. In the present study, we examined the effects of SERT deficiency on fear extinction in a differential fear conditioning paradigm in male and female rats. Fear-related behavior displayed during acquisition, extinction, and recovery, was measured through quantification of immobility and alarm 22-kHz ultrasonic vocalizations (USV). Trait-like inter-individual differences in novelty-seeking, anxiety-related behavior, habituation learning, cognitive performance, and pain sensitivity were examined for their predictive value in forecasting fear extinction. Our results show that SERT deficiency strongly affected the emission of 22-kHz USV during differential fear conditioning. During acquisition, extinction, and recovery, SERT deficiency consistently led to a reduction in 22-kHz USV emission. While SERT deficiency did not affect immobility during acquisition, genotype differences started to emerge during extinction, and during recovery rats lacking SERT showed higher levels of immobility than wildtype littermate controls. Recovery was reflected in increased levels of immobility but not 22-kHz USV emission. Prominent sex differences were evident. Among several measures for trait-like inter-individual differences, anxiety-related behavior had the best predictive quality

Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 subunit CACNB2

Bipolar disorder (BD) is a chronic mood disorder characterized by manic and depressive episodes. Dysregulation of neuroplasticity and calcium homeostasis are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that miR-499-5p regulates dendritogenesis and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients, as well as in the hippocampus of rats which underwent juvenile social isolation. In rat hippocampal neurons, miR-499-5p impairs dendritogenesis and reduces surface expression and activity of the L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory beta-subunit of Cav1.2, as a direct functional target of miR-499-5p in neurons. miR-499-5p overexpression in the hippocampus in vivo induces short-term memory impairments selectively in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. In humans, miR-499-5p expression is negatively associated with gray matter volumes of the left superior temporal gyrus, a region implicated in auditory and emotional processing. We propose that stress-induced miR-499-5p overexpression contributes to dendritic impairments, deregulated calcium homeostasis, and neurocognitive dysfunction in BD.ISSN:1469-221XISSN:1469-317

Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study

Advanced paternal age (APA) is a risk factor for several neurodevelopmental disorders, including autism and schizophrenia. The potential mechanisms conferring this risk are poorly understood. Here, we show that the personality traits schizotypy and neuroticism correlated with paternal age in healthy subjects (N = 677). Paternal age was further positively associated with gray matter volume (VBM, N = 342) in the right prefrontal and the right medial temporal cortex. The integrity of fiber tracts (DTI, N = 222) connecting these two areas correlated positively with paternal age. Genome-wide methylation analysis in humans showed differential methylation in APA individuals, linking APA to epigenetic mechanisms. A corresponding phenotype was obtained in our rat model. APA rats displayed social-communication deficits and emitted fewer pro-social ultrasonic vocalizations compared to controls. They further showed repetitive and stereotyped patterns of behavior, together with higher anxiety during early development. At the neurobiological level, microRNAs miR-132 and miR-134 were both differentially regulated in rats and humans depending on APA. This study demonstrates associations between APA and social behaviors across species. They might be driven by changes in the expression of microRNAs and/or epigenetic changes regulating neuronal plasticity, leading to brain morphological changes and fronto-hippocampal connectivity, a network which has been implicated in social interaction