Johanneke E. van der Harst

Standard housed rats are more sensitive to rewards than enriched housed rats as reflected by their anticipatory behaviour.

The present study was designed to investigate the effects of potentially stressful standard housing conditions for laboratory rats on the sensitivity to rewards as reflected by their anticipatory behaviour for sucrose. This anticipatory response is evoked in a conditioning paradigm in which a sucrose reward is repeatedly announced by a stimulus. The underlying neurocircuitry of this anticipatory response in expectation of a reward involves mesolimbic dopaminergic systems of which it is known that they can be sensitised by stressors. The results show that the anticipatory response for the sucrose reward is stronger in the standard housed animals which indicates that these animals are more sensitive to the reward than the enriched animals. From this, it is concluded that standard housed rats are stressed which is likely to be caused by deprivation of the ability to satisfy behavioural needs in these impoverished housing conditions.

Toward a rodent model of the Iowa gambling task

The Iowa gambling task in humans is, in principle, suited for the study of the long-term efficiency of behavior in a biologically relevant context. Key features of this task are uncertainty of outcomes and a conflict between the immediate and the long-term payoff options. Animal models allow us to study the underlying neurobiology of decision-making processes and the long-term efficiency of behavior in more detail and at a greater depth than is possible in humans. Therefore, we set out to develop a model of this task in rodents, using the task’s key features. In this article, we describe the results of the first series of experiments with rats and mice. The data thus far suggest that mice and rats behave in a way similar to humans; that is, they tend to choose the option with the best long-term payoff more often as the test progresses.

Rats assess costs and benefits according to an internal standard

Variation in effort to obtain rewards is a fact of mammalian everyday life. In this study, we assess how rats scale variable costs and benefits. Different groups of rats were trained in a T-maze to discriminate a high (three or five sugar pellets) from a low reward (one sugar pellet) arm. Subsequently barriers were introduced at the high and low reward side such that the overall long-term pay-off of the high reward arm finally became lower than that of the low reward arm. The data show that under different regimes of costs (climbing barriers) and benefits (number of rewards) of the two arms rats appear to shift their behaviour towards the better side according to a constant relative cost-benefit ratio between the arms. Such a ratio allows them to deal with variation in the (physical appearance of) costs and benefits and choose the best long-term option.

Announced rewards counteract the impairment of anticipatory behaviour in socially stressed rats.

It is known that stress can influence the sensitivity to rewarding stimuli. Previous observations revealed that socially stressed rats do not display an appetitive behavioural response in anticipation of a reward. A previous study showed that this insensitivity to rewards (anhedonia) could be restored by chronic administration of an antidepressant. Several lines of evidence exist for the role of dopamine in the mechanism of action of antidepressant treatments concerning their therapeutic effect on anhedonia. Therefore, it was hypothesized that regular activation of the reward system, that involves mesolimbic dopaminergic systems, could counteract the effect of social stress on reward-sensitivity. For this, it was investigated whether a treatment of regular reward announcements could prevent the development of anhedonia. This was confirmed by the result that socially stressed rats that received this treatment were able to display anticipatory behaviour which is characterized by increased activity after presentation of a stimulus that was previously associated with a sucrose reward. Surprisingly, a non-treated socially stressed group, that did not show an anticipatory response for sucrose, did display anticipatory behaviour for another type of reward (enriched cage). It seems that, although one might assume the existence of an anhedonic state based upon the absence of anticipatory activity towards a sucrose reward, this assumption cannot be generalised to other types of reward. It will be discussed whether this might be caused by the highly rewarding properties of the enriched cage which probably has a therapeutical efficacy of its own.

A sustained depressive state promotes a guanfacine reversible susceptibility to alcohol seeking in rats.

High rates of comorbidity between alcohol use disorder (AUD) and major depressive disorder (MDD) are reported. Preclinical models examining effects of primary depression on secondary AUD are currently absent, preventing adequate testing of drug treatment. Here, we combined social defeat-induced persistent stress (SDPS) and operant alcohol self-administration (SA) paradigms to assess causality between these two neuropsychiatric disorders. We then exploited guanfacine, an FDA-approved adrenergic agent reported to reduce drug craving in humans, against SDPS-induced modulation of operant alcohol SA. Wistar rats were socially defeated and isolated for a period of ⩾9 weeks, during which depression-like symptomatology (cognitive and social behavioral symptoms) was assessed. Subsequently, animals were subjected to a 5-month operant alcohol SA paradigm, examining acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking. The effects of guanfacine on motivation and relapse were measured at >6 months following defeat. SDPS rats exhibited significant disruption of social and cognitive behavior, including short-term spatial and long-term social memory, several months following defeat. Notably, SDPS increased motivation to obtain alcohol, and cue-induced relapse vulnerability. Guanfacine reversed the SDPS-induced effects on motivation and relapse. Together, our model mimics core symptomatology of a sustained depressive-like state and a subsequent vulnerability to alcohol abuse. We show that SDPS is strongly associated with an enhanced motivation for alcohol intake and relapse. Finally, we show that the clinically employed drug guanfacine has potential as a novel treatment option in comorbid patients, as it effectively reduced the enhanced sensitivity to alcohol and alcohol-associated stimuli.

On the relationship between anticipatory behaviour in a Pavlovian paradigm and Pavlovian-to-instrumental transfer in rats (Rattus norvegicus)

The present rat study assessed the relationship between, and the sensitivity of, two different tests for appetitive conditioned responding to differences in the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), and to differences in US magnitude. The first test used a Pavlovian-to-Instrumental Transfer (PIT) paradigm, assessing the capacity of the CS to enhance instrumental responding for food. The second test employed a Pavlovian conditioning paradigm with an extended CS-US interval, and total number of behavioural elements in this interval as a dependent measure. The PIT test proved to be sensitive to contingency but not reward magnitude differences, whereas the reverse was true for the Pavlovian test. Although there was a significant correlation between tests in the magnitude of the CS-induced increase of food-magazine entries, the main dependent measure from PIT (number of lever presses) and that from the Pavlovian test (total number of behavioural elements) did not correlate. It is suggested that in the PIT procedure, the CS induces a chain of behavioural responses of which lever pressing is just a single element and that the Pavlovian test, in principle, is more sensitive.

Announced reward counteracts the effects of chronic social stress on anticipatory behavior and hippocampal synaptic plasticity in rats.

Chronic stress causes insensitivity to rewards (anhedonia) in rats, reflected by the absence of anticipatory behavior for a sucrose-reward, which can be reversed by antidepressant treatment or repeated announced transfer to an enriched cage. It was, however, not clear whether the highly rewarding properties of the enriched cage alone caused this reversal or whether the anticipation of this reward as such had an additional effect. Therefore, the present study compared the consequences of the announcement of a reward to the mere effect of a reward alone with respect to their efficacy to counteract the consequences of chronic stress. Two forms of synaptic plasticity, long-term potentiation and long-term depression were investigated in area CA1 of the hippocampus. This was done in socially stressed rats (induced by defeat and subsequent long-term individual housing), socially stressed rats that received a reward (short-term enriched housing) and socially stressed rats to which this reward was announced by means of a stimulus that was repeatedly paired to the reward. The results were compared to corresponding control rats. We show that announcement of enriched housing appeared to have had an additional effect compared to the enriched housing per se as indicated by a significant higher amount of LTP. In conclusion, announced short-term enriched housing has a high and long-lasting counteracting efficacy on stress-induced alterations of hippocampal synaptic plasticity. This information is important for counteracting the consequences of chronic stress in both human and captive rats.

Automated quantitative analysis to assess motor function in different rat models of impaired coordination and ataxia

BACKGROUND An objective and automated method for assessing alterations in gait and motor coordination in different animal models is important for proper gait analysis. The CatWalk system has been used in pain research, ischemia, arthritis, spinal cord injury and some animal models for neurodegenerative diseases. NEW METHOD Our goals were to obtain a comprehensive gait analysis of three different rat models and to identify which motor coordination parameters are affected and are the most suitable and sensitive to describe and detect ataxia with a secondary focus on possible training effects. RESULTS Both static and dynamic parameters showed significant differences in all three models: enriched housed rats show higher walking and swing speed and longer stride length, ethanol-induced ataxia affects mainly the hind part of the body, and the SCA17 rats show coordination disturbances. Coordination changes were revealed only in the case of the ethanol-induced ataxia and the SCA17 rat model. Although training affected some gait parameters, it did not obscure group differences when those were present. COMPARISON WITH EXISTING METHODS To our knowledge, a comparative gait assessment in rats with enriched housing conditions, ethanol-induced ataxia and SCA17 has not been presented before. CONCLUSIONS There is no gold standard for the use of CatWalk. Dependent on the specific effects expected, the protocol can be adjusted. By including all sessions in the analysis, any training effect should be detectable and the development of the performance over the sessions can provide insight in effects attributed to intervention, treatment or injury.

Short- and long-term behavioral analysis of social interaction, ultrasonic vocalizations and social motivation in a chronic phencyclidine model

HighlightsShort and long term effects of chronic PCP were examined.On short term, social interaction behavior was negatively affected by PCP.PCP could not induce a permanent decrease in social behavior.But, distinct effects on social motivation were observed.In lights of these results, the validity of the PCP model is questionable. Abstract Phencyclidine (PCP) has been suggested to induce symptoms of schizophrenia. However, animal models using PCP administration have produced ambiguous results thus far. It seems that acute effects are similar to symptoms of schizophrenia, however, it is not clear if PCP can induce permanent behavioral changes that reflect schizophrenic‐like symptoms. Therefore, we assessed the ability of chronic PCP administration (3 mg/kg, 14 days) to induce short or long lasting behavioral changes in rats. Social behavior, including ultrasonic vocalizations and motivation for social contact were investigated at different time points, up to 29–36 days, after cessation of PCP treatment. During a social separation test, performed at 5 and 36 days, PCP treated rats spent less time near the divider that separates them from their familiar cage mate compared with saline (SAL) treated rats. Further, at short term, PCP was able to induce a decrease in social behavior. In contrast, at long‐term, PCP treated animals spent more time in contact when exposed to an unfamiliar partner as compared to SAL treated rats. But, this difference was not observed when exposed to a familiar partner. We did not find any difference in ultrasonic vocalizations at all time points. The results of our study indicate that PCP is unable to induce overt long term deficits in social interaction behavior. Rather, it seems that PCP diminishes motivation for social contact. The long‐term consequences of chronic PCP administration on social behavior in rodent models remain complex, and future studies addressing this are still needed.

Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats

Alterations in the hippocampal extracellular matrix contribute to cognitive deficits in rats exhibiting a chronic depressive-like state after exposure to social defeat–induced persistent stress. Netting a new understanding of hippocampal function A common feature of major depression is cognitive impairment, including difficulties in memory recall. The underlying mechanisms of these symptoms are unclear. In a new study, Riga and colleagues used social defeat–induced persistent stress to induce a depressive-like state in rats and then examined molecular changes in the hippocampus related to cognitive deficits associated with this state. They found increased expression of extracellular matrix proteins and decreased plasticity potential and inhibitory neurotransmission in the dorsal hippocampus in this rat model. Treatment with an antidepressant drug or a single injection into the hippocampus of an enzyme that breaks down the extracellular matrix resulted in improved hippocampal function and rescue of memory recall in this preclinical rat model. Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat–induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.