Maintenance of conditioned place avoidance induced by gastric malaise requires NMDA activity within the ventral hippocampus

It has been reported that during chemotherapy treatment, some patients can experience nausea before pharmacological administration, suggesting that contextual stimuli are associated with the nauseating effects. There are attempts to reproduce with animal models the conditions under which this phenomenon is observed to provide a useful paradigm for studying contextual aversion learning and the brain structures involved. This manuscript assessed the hippocampus involvement in acquiring and maintaining long-term conditioned place avoidance (CPA) induced by a gastric malaise-inducing agent, LiCl. Our results demonstrate that a reliable induction of CPA is possible after one acquisition trial. However, CPA establishment requires a 20-min confinement in the compartment associated with LiCl administration. Interestingly, both hippocampal regions seem to be necessary for CPA establishment; nonetheless, inactivation of the ventral hippocampus results in a reversion of avoidance and turns it into preference. Moreover, we demonstrate that activation of dorsal/ventral hippocampal NMDA receptors after CS–US association is required for long-term CPA memory maintenance.

Habenula GPR139 is associated with fear learning in the zebrafish

G-protein coupled receptor 139 (GPR139) is an evolutionarily conserved orphan receptor, predominantly expressing in the habenula of vertebrate species. The habenula has recently been implicated in aversive response and its associated learning. Here, we tested the hypothesis that GPR139 signalling in the habenula may play a role in fear learning in the zebrafish. We examined the effect of intraperitoneal injections of a human GPR139-selective agonist (JNJ-63533054) on alarm substance-induced fear learning using conditioned place avoidance paradigm, where an aversive stimulus is paired with one compartment, while its absence is associated with the other compartment of the apparatus. The results indicate that fish treated with 1 µg/g body weight of GPR139 agonist displayed no difference in locomotor activity and alarm substance-induced fear response. However, avoidance to fear-conditioned compartment was diminished, which suggests that the agonist blocks the consolidation of contextual fear memory. On the other hand, fish treated with 0.1 µg/g body weight of GPR139 agonist spent a significantly longer time in the unconditioned neutral compartment as compared to the conditioned (punished and unpunished) compartments. These results suggest that activation of GPR139 signalling in the habenula may be involved in fear learning and the decision-making process in the zebrafish.

Habenula kisspeptin retrieves morphine impaired fear memory in zebrafish

The habenula is an evolutionarily conserved brain structure, which has recently been implicated in fear memory. In the zebrafish, kisspeptin (Kiss1) is predominantly expressed in the habenula, which has been implicated as a modulator of fear response. Hence, in the present study, we questioned whether Kiss1 has a role in fear memory and morphine-induced fear memory impairment using an odorant cue (alarm substances, AS)-induced fear avoidance paradigm in adult zebrafish, whereby the fear-conditioned memory can be assessed by a change of basal place preference (= avoidance) of fish due to AS-induced fear experience. Subsequently, to examine the possible role of Kiss1 neurons-serotonergic pathway, kiss1 mRNA and serotonin levels were measured. AS exposure triggered fear episodes and fear-conditioned place avoidance. Morphine treatment followed by AS exposure, significantly impaired fear memory with increased time-spent in AS-paired compartment. However, fish administered with Kiss1 (10–21 mol/fish) after morphine treatment had significantly lower kiss1 mRNA levels but retained fear memory. In addition, the total brain serotonin levels were significantly increased in AS- and Kiss1-treated groups as compared to control and morphine treated group. These results suggest that habenular Kiss1 might be involved in consolidation or retrieval of fear memory through the serotonin system.

Study of aversive and p38 mapk-inhibitory properties of kappa-agonist with analgesic activity – compound RU-1205

Introduction: The clinical use of kappa-opioid agonists, despite their lack of significant drug potential, is limited by the development of severe sedation, dysphoria, depression, and anhedonia. To this date, there are kappa-opioid receptor agonists lacking these side effects due to the selective activation of intracellular signal transmission pathways without p38-MAPK-kinase activation. Materials and methods: We analyzed assessment of the docking energy of compound RU-1205 to the p38-MAPK active center by the method of similarity to SB203580. The study of possible aversive properties of RU-1205 (0.01–1 mg/kg s.c.) conducted in the tests of the intravenous self-administration and drug differentiation with butorphanol (0.01–0.3 mg/kg). The study of p38 MAPK-inhibitory activity was studied by the ability of RU-1205 to change the aversive properties of U50488 (10 mg/kg i.p.) compared to MAPK-kinase inhibitor SB203580 in the conditioned place avoidance test. Results: The spatial similarity coefficient of the RU-1205 molecule with SB203580 by the molecular conformation method was 1.14 (high similarity), and the docking energy was -8.7 Kcal/mol. RU-1205 did not possess any properties similar to those of butorphanol and did not demonstrate any primary reinforcing aversive properties in the development of intravenous self-administration reaction. Compound RU-1205 did not demonstrate any aversive properties in the conditioned place avoidance test, and reduced the development of aversion caused by U-50488, when they were used together. Discussion: The in silico analysis suggested that, in addition to agonism towards the kappa-opioid receptor, RU-1205 compound exhibits the properties of a p38 MAPK kinase inhibitor, which means it may have a double pharmacological activity. Conclusion: Kappa agonist – compound RU-1205 – is not a trigger of the development of behavioral patterns in animals corresponding to the development of addiction/dysphoria. The mechanism of such an activity may be associated with an inhibitory effect of compound RU-1205 on neuronal p38-MAPK-kinase.

The Role of Central Amygdala Corticotropin-Releasing Factor in Predator Odor Stress-Induced Avoidance Behavior and Escalated Alcohol Drinking in Rats

ABSTRACTPost-traumatic stress disorder (PTSD) is characterized by avoidance of trauma-associated stimuli and amygdala hyperreactivity, and is highly co-morbid with alcohol use disorder (AUD). Our lab uses a predator odor (bobcat urine) stress model that produces conditioned avoidance of an odor-paired context in a subset of rats, mirroring avoidance symptoms that manifest in some but not all humans exposed to trauma. We previously showed that after predator odor stress, Avoiders exhibit escalated alcohol drinking, higher aversion-resistant operant alcohol responding, hyperalgesia, and greater anxiety-like behavior compared to unstressed Controls. We also showed that systemic antagonism of corticotropin-releasing factor-1 receptors (CRFR1) reduced escalation of alcohol drinking in rats not indexed for avoidance, that corticotropin-releasing factor (CRF) infusions into the central amygdala (CeA) produced conditioned place avoidance in stress-naïve rats, and that intra-CeA infusion of a CRFR1 antagonist reduced hyperalgesia in Avoiders. Here, we show that avoidance behavior is persistent after repeated predator odor exposure and is resistant to extinction. In addition, Avoiders showed lower weight gain than Controls after predator odor re-exposure. In the brain, higher avoidance was correlated with higher number of c-Fos+ cells and CRF immunoreactivity in the CeA. Finally, we show that intra-CeA CRFR1 antagonism reversed post-stress escalation of alcohol drinking and reduced avoidance behavior in Avoiders. Collectively, these findings suggest that elucidation of the mechanisms by which CRFR1-gated CeA circuits regulate avoidance behavior and alcohol drinking may lead to better understanding of the neural mechanisms underlying co-morbid PTSD and AUD.

The zebrafish dorsolateral habenula is required for updating learned behaviors

ABSTRACTOperant conditioning requires multiple cognitive processes, such as learning, prediction of potential outcomes and decision making. It is less clear how interactions of these processes lead to the behavioral adaptations that allow animals to cope with a changing environment. We showed that juvenile zebrafish can perform conditioned place avoidance learning, with an improving performance across development. Ablation of the dorsolateral habenula (dlHb), a brain region involved in associative learning and prediction of outcomes, led to an unexpected improvement in performance and delayed memory extinction. Interestingly, while the control animals exhibited rapid adaptation to a changing learning rule, dlHb ablated animals failed to adapt. Altogether, our results show that the dlHb plays a central role in switching animals’ strategies while integrating new evidence with prior experience.

Zebrafish use visual cues and geometric relationships to form a spatial memory

Animals use salient cues to navigate in their environment, but their specific cognitive strategies are largely unknown. We developed a conditioned place avoidance paradigm to discover whether and how zebrafish form spatial memories in a Y-shaped maze. Juvenile zebrafish, older than three weeks, learned to avoid the arm of the maze that was cued with a mild electric shock. We found that the fish required distinct visual patterns to develop a conditioned response. Interestingly, individual fish solve this task in different ways: by staying in the safe center of the maze, by preference for one, or both, of the safe patterns, or by mixed strategies. In experiments in which the learned patterns were swapped, rotated or replaced, the animals could transfer the association of safety to a different arm or to a different pattern using either visual cues or location as the conditioned stimulus. These findings show that juvenile zebrafish exhibit several complementary spatial learning modes and pave the way for neurobiological studies of navigational mechanisms in this model species.

Conditioned place avoidance using encapsulated calcium propionate as an appetite suppressant for broiler breeders Conditioned place avoidance and calcium propionate

Broiler breeders, the parent stock of meat chicks, are feed-restricte throughout rearing to avoid obesity-related problems in their health and reproductive performance. Broiler breeders often show signs of chronic hunger, lack of satiety and feeding frustration, and the development of alternative feeding strategies has investigated the inclusion of calcium propionate (CaP) as an appetite suppressant. However, the mechanisms involved in the reduction of voluntary feed intake are unknown, but are thought to be due to low palatability, gastrointestinal discomfort, or both. The objective of this experiment was to examine the effect of CaP as an appetite suppressant on the experience of a negative affective state, using a conditioned place preference test. Twenty four broiler breeders were trained to associate the consumption of CaP or a placebo pill with a red or blue place, depending on inherent colour preference. Pullets consumed two pills followed by 20 g feed allotment. The CaP pill contained 160 mg of CaP and the placebo pill had 160 mg of feed. Conditioning lasted for 90 min/pullet/day over 8 consecutive days at 7 and 9 weeks of age, and pullets’ choice was tested in a T-maze twice on two consecutive days at both 8 and 10 weeks of age. Data were analysed using a linear mixed regression model, with pen nested in the model and age as a repeated measure. Pullets were less likely to choose the place conditioned with the consumption of CaP (P<0.05) and the preference of the placebo linearly increased with training sessions (P<0.05). These results suggest that calcium propionate as an appetite suppressant can induce a negative affective state, with the lower feed intake resulting from a conditioned response to the negative effect of calcium propionate rather than to satiety.