Active Avoidance Learning Research Articles

Active avoidance learning in rats with different audiogenic epilepsy proneness

The success of the formation of the conditioned reflex reaction of two-way avoidance in the shuttle chamber in rats of 3 strains was evaluated. These were rats predisposed to audiogenic epilepsy – the Krushinsky-Molodkina strain rats (KM), "4" strain (selected from a population of F2 hybrids of the KM strain and sound-insensitive Wistars) and rats of "0" strain, selected for the absence of audiogenic epilepsy from the same population (i. e. these strains, diametrically different in audiogenic epilepsy proneness, possessing a similar genetic background). Experiments have shown significantly more successful assimilation of this skill in rats of the "0" strain.

Active Avoidance Learning in Rats with Different Audiogenic Epilepsy Proneness

Active Avoidance Learning in Rats with Different Audiogenic Epilepsy Proneness

Lateralized Active Avoidance Learning and Memory to Ang II and Losartan Microinjected into Amygdala in Rats Depression Model

Depression is a widespread socially significant disease. Studies aiming to reveal the pathogenesis of depression have lasted for decades, but the specific mechanisms remain unclear. Olfactory bulbectomy (OBX) in rats provides a well-validated animal model of depression and Alzheimer's disease. The aim is to evaluate the involvement of Ang II and AT1 receptors in learning and memory after unilateral infusion of Ang II and losartan (specific AT1 antagonist) into CeA (central nucleus of the amygdala) in rats with a model of depression (bilateral olfactory bulbectomy, OBX). The effects of Ang II and losartan infused into CeA on the avoidance performance in OBX rats using the active avoidance (shuttle box) test were investigated. A stereotaxic technique was used for bilateral implantation of guide cannulae into CeA. Fourteen days after OBX, Ang II, or losartan were microinjected unilaterally into CeA of rats with depressive-like behaviour. For the first time it was found that Ang II infused into the left CeA impaired learning and memory, while losartan infused into the left CeA significantly improved these processes and prevented the memory deficits induced by the bulbectomy. The data suggest an involvement of amygdala Ang II and AT1 receptors in learning and memory of rats and a differential distribution of the AT1 receptors in the left and right central nucleus of the amygdala in rats with a model of depression.

Dopamine D2 receptors in WFS1-neurons regulate food-seeking and avoidance behaviors

The selection and optimization of appropriate adaptive responses depends on interoceptive and exteroceptive stimuli as well as on the animal's ability to switch from one behavioral strategy to another. Although growing evidence indicate that dopamine D2R-mediated signaling events ensure the selection of the appropriate strategy for each specific situation, the underlying neural circuits through which they mediate these effects are poorly characterized. Here, we investigated the role of D2R signaling in a mesolimbic neuronal subpopulation expressing the Wolfram syndrome 1 (Wfs1) gene. This subpopulation is located within the nucleus accumbens, the central amygdala, the bed nucleus of the stria terminalis, and the tail of the striatum, all brain regions critical for the regulation of emotions and motivated behaviors. Using a mouse model carrying a temporally controlled deletion of D2R in WFS1-neurons, we demonstrate that intact D2R signaling in this neuronal population is necessary to regulate homeostasis-dependent food-seeking behaviors in both male and female mice. In addition, we found that reduced D2R signaling in WFS1-neurons impaired active avoidance learning and innate escape responses. Collectively, these findings identify a yet undocumented role for D2R signaling in WFS1-neurons as a novel effector through which dopamine optimizes appetitive behaviors and regulates defensive behaviors.

No joy - why bother? Higher anhedonia relates to reduced pleasure from and motivation for threat avoidance

Anhedonia impairs various components of the pleasure cycle, including wanting, liking, and the learning of pleasure-related associations. While successfully controlling threats might be inherently pleasurable, it remains unclear whether anhedonia affects this form of pleasure as well. With aversive pictures as threats, we conducted an online study ( N = 200) to investigate the role of anhedonia during active avoidance learning process. Participants first learned cue-threat associations for different cues (threat vs. safety cues). In a subsequent avoidance learning phase, these cues signaled either avoidable, unavoidable, or no threat; participants could perform avoidance responses to prevent the upcoming threats during those cue presentations. Subjective relief pleasantness was measured after each threat omission. We found that higher trait anticipatory and consummatory anhedonia were both associated with lower relief pleasantness. Higher trait anticipatory anhedonia was also associated with fewer avoidance attempts. Since reduced threat-controlling behavior is reminiscent of a learned-helplessness state, the current results contribute to a better understanding of the connections between anhedonia and learned helplessness that have mostly been studied separately in the context of mood disturbance.

Divergent encoding of active avoidance behavior in corticostriatal and corticolimbic projections

Active avoidance behavior, in which an animal performs an action to avoid a stressor, is crucial for survival and may provide insight into avoidance behaviors seen in anxiety disorders. Active avoidance requires the dorsomedial prefrontal cortex (dmPFC), which is thought to regulate avoidance via downstream projections to the striatum and amygdala. However, the endogenous activity of dmPFC projections during active avoidance learning has never been recorded. Here we utilized fiber photometry to record from the dmPFC and its axonal projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during active avoidance learning in both male and female mice. We examined neural activity during conditioned stimulus (CS) presentations and during clinically relevant behaviors such as active avoidance or cued freezing. Both prefrontal projections showed learning-related increases in activity during CS onset throughout active avoidance training. The dmPFC as a whole showed increased and decreased patterns of activity during avoidance and cued freezing, respectively. Finally, dmPFC-DMS and dmPFC-BLA projections show divergent encoding of active avoidance behavior, with the dmPFC-DMS projection showing increased activity and the dmPFC-BLA projection showing decreased activity during active avoidance. Our results demonstrate task-relevant encoding of active avoidance in projection-specific dmPFC subpopulations that play distinct but complementary roles in active avoidance learning.

Threat reversal learning and avoidance habits in generalised anxiety disorder

Avoidance and heightened responses to perceived threats are key features of anxiety disorders. These disorders are characterised by inflexibility in dynamically updating behavioural and physiological responses to aversively conditioned cues or environmental contexts which are no longer objectively threatening, often manifesting in perseverative avoidance. However, less is known about how anxiety disorders might differ in adjusting to threat and safety shifts in the environment or how idiosyncratic avoidance responses are learned and persist. Twenty-eight patients with generalised anxiety disorder (GAD), without DSM co-morbidities, and 27 matched healthy controls were administered two previously established paradigms: Pavlovian threat reversal and shock avoidance habits through overtraining (assessed following devaluation with measures of perseverative responding). For both tasks we used subjective report scales and skin conductance responses (SCR). In the Pavlovian threat reversal task, patients with GAD showed a significantly overall higher SCR as well as a reduced differential SCR response compared to controls in the early but not late reversal phase. During the test of habitual avoidance responding, GAD patients did not differ from controls in task performance, habitual active avoidance responses during devaluation, or corresponding SCR during trials, but showed a trend toward more abstract confirmatory subjective justifications for continued avoidance following the task. GAD patients exhibited significantly greater skin conductance responses to signals of threat than controls, but did not exhibit the major deficits in reversal and safety signal learning shown previously by patients with OCD. Moreover, this patient group, again unlike OCD patients, did not show evidence of altered active avoidance learning or enhanced instrumental avoidance habits. Overall, these findings indicate no deficits in instrumental active avoidance or persistent avoidance habits, despite enhanced responses to Pavlovian threat cues in GAD. They suggest that GAD is characterised by passive, and not excessively rigid, avoidance styles.

Influences of Taurine Pharmacodynamics and Sex on Active Avoidance Learning and Memory.

Researchers have begun to direct their research to focus on the use of taurine as a psychopharmacotherapeutic compound to treat a wide range of health- related conditions as well as neuropathological diseases. Moreover, taurine has been shown to improve emotional and cognitive declines associated with senescence in neurotypical animal models. However, despite these advances in the field of taurine therapeutics, much less is known regarding the effects of sex and taurine on neurotypical animal models that are then manipulated, modified, and/or mutated to study human diseases. The present study sought to investigate this matter in a Long Evans Hooded rat model of mature age (i.e., postnatal day 60-90) in an active avoidance test (AAT). Rats were trained for 20 trials, given a 1h. test break, retrained for another 20 trials, and then tested at 24h, 48h, and 1week for learning and memory retention. An N=63 rats were randomly assigned to three groups: (1) Control (n=22), (2) Taurine Pre-Train (n=19), and (3) Taurine Post-Train (n=20). The aim of the present study was to determine the effects of taurine given 15 min before training when compared to being given after training but 15 min before testing at 24h on learning and memory consolidation of the AAT. The results showed in Control rats that females had shorter latencies to cross in the shuttle box, increased rates of correct learning by the % Avoids/Escapes, and decreased rates of learning errors by the % Shocks. In Taurine Post-Train male rats, taurine treatment decreased their latency to cross in the shuttle box and their rate of learning errors by the % Shocks at 24h and 48h Testing, but it had no effect on their rate of correct learning by the % Avoids/Escapes when compared to Control and Taurine Pre-Train male rats. In contrast, Taurine Post-Train female rats increased their latency to cross in the shuttle box during Training, 24h and 48h Testing, when compared to the Control and Taurine Pre-Train female rats. Further, Taurine Post-Train female rats decreased their rate of learning % Avoids/Escapes and increased the rate of learning errors % Shocks when compared to Control female rats during Training and 24h Testing but decreased their rate of learning % Avoids/Escapes and increased the rate of learning errors % Shocks when compared to Taurine Pre-Train female rats across all test conditions. These findings suggest that neurotypical female rats may be more sensitive to the aversive stimuli (i.e., foot shocks) used in the AAT as a motivating factor for learning that may cause paradoxical behavioral learning and memory patterns. This phenomenon raises an important concern for researchers to consider when studying learning and behavioral tests in rodents that use aversive and non-aversive stimuli or a combination of both such as in the AAT. Taurine, albeit neuroprotective, may not have as much benefit in a neurotypical animal model and may increase the susceptibility for anxiogenic behaviors and interfere with cognitive learning and memory behaviors. Therefore, the mechanistic way(s) in which taurine can treat, recovery, ameliorate, and forestall other neuropathological diseases in animal models may have different psychopharmacodynamics and psychopharmacokinetics in a neurotypical animal model and should be studied with caution. This does not preclude the continued investigation of taurine psychopharmacotherapies for neuropathological diseases but encourages the careful investigation of taurine supplementation and treatment in neurotypical animals as paradoxical behavioral and cognitive outcomes have been observed herein.

Imaging of Functional Brain Circuits during Acquisition and Memory Retrieval in an Aversive Feedback Learning Task: Single Photon Emission Computed Tomography of Regional Cerebral Blood Flow in Freely Behaving Rats.

Active avoidance learning is a complex form of aversive feedback learning that in humans and other animals is essential for actively coping with unpleasant, aversive, or dangerous situations. Since the functional circuits involved in two-way avoidance (TWA) learning have not yet been entirely identified, the aim of this study was to obtain an overall picture of the brain circuits that are involved in active avoidance learning. In order to obtain a longitudinal assessment of activation patterns in the brain of freely behaving rats during different stages of learning, we applied single-photon emission computed tomography (SPECT). We were able to identify distinct prefrontal cortical, sensory, and limbic circuits that were specifically recruited during the acquisition and retrieval phases of the two-way avoidance learning task.

State Transitions During Discrimination Learning in the Gerbil Auditory Cortex Analyzed by Network Causality Metrics.

This work studies the evolution of cortical networks during the transition from escape strategy to avoidance strategy in auditory discrimination learning in Mongolian gerbils trained by the well-established two-way active avoidance learning paradigm. The animals were implanted with electrode arrays centered on the surface of the primary auditory cortex and electrocorticogram (ECoG) recordings were made during performance of an auditory Go/NoGo discrimination task. Our experiments confirm previous results on a sudden behavioral change from the initial naïve state to an avoidance strategy as learning progresses. We employed two causality metrics using Granger Causality (GC) and New Causality (NC) to quantify changes in the causality flow between ECoG channels as the animals switched to avoidance strategy. We found that the number of channel pairs with inverse causal interaction significantly increased after the animal acquired successful discrimination, which indicates structural changes in the cortical networks as a result of learning. A suitable graph-theoretical model is developed to interpret the findings in terms of cortical networks evolving during cognitive state transitions. Structural changes lead to changes in the dynamics of neural populations, which are described as phase transitions in the network graph model with small-world connections. Overall, our findings underscore the importance of functional reorganization in sensory cortical areas as a possible neural contributor to behavioral changes.

Active avoidance learning in WAG/Rij rats with genetic predisposition to absence epilepsy

Neurological disorders are often accompanied by impairment of memory, attention deficit that cause learning difficulties. Better understanding of learning problems in neurological patients might help to improve the quality of their life. Here we studied the character of fear-based associative learning using the standard active avoidance test in WAG/Rij rats with genetic predisposition to absence epilepsy. Electroencephalographic properties of spike-wave seizures (i.e., hallmarks of absence epilepsy) were examined at the age of 5 and 7 m. Around 24 % of rats did not express epileptic activity despite genetic predisposition. In the active avoidance test, 6 m old rats with the epileptic phenotype needed more trails to obtain the first avoidance than non-epileptic rats, but showed the same number of avoidances to reach the learning criterion. The total time of spike-wave activity positively correlated with the outcomes of avoidance performance only in subjects with severe epilepsy, but not in subjects with mild epilepsy.In order to evaluate early sensory (epigenetic) factors governing cognitive comorbidities in adult WAG/Rij rats, we performed bilateral whisker trimming during PN1-8 and PN9-16. This led to a quicker development of SWD, but did not influence cognitive abilities at the age of 6 m.In summary, epileptic WAG/Rij rats had difficulties with executive functions before the first avoidance of adverse stimulus, rather than impairment of memory after the first avoidance. Our data assume that cognitive comorbidities in epileptic WAG/Rij rats primarily may relate to executive deficit during the initial stage of avoidance test and secondary - to impairment of short-term memory. This fits well to outcomes of clinical studies in patients with generalized epilepsy.

Subchronic use of rivastigmine increases procognitive flexibility across multimodal behavioral tasks in healthy male rats

Rivastigmine (RVT) is a reversible inhibitor of cholinesterase approved worldwide for the treatment of cognitive dysfunctions, especially in Alzheimer’s disease. Most previous pre-clinical studies have examined the effects of RVT treatment in a wide variety of pathological research models. Nonetheless, the effects of this drug on sensorimotor gating, memory, and learning tasks in healthy subjects remains unclear. In this study, we investigate the procognitive effects of RVT treatment in healthy rats through sensorimotor gating evaluations (measured as prepulse inhibition of the acoustic startle reflex), active avoidance learning, and spatial memory learning in a radial maze. There is an increase in the amplitude of the startle reflex in RVT-treated rats compared to the control groups, whereas the latency remained constant. Sensorimotor gating values were also incremented compared to those values from controls. In active avoidance, rats treated with RVT learned faster to successfully perform the task compared to controls, but afterwards all groups exhibited virtually identical results. During the sessions in the radial maze, RVT-treated rats committed fewer errors in both the working and reference memory compared to controls. All in all, our results support the hypothesis that RVT treatment may entail procognitive effects in healthy subjects.

Pattern of dopamine signaling during aversive events predicts active avoidance learning

Learning to avoid aversive outcomes is an adaptive strategy to limit one's future exposure to stressful events. However, there is considerable variance in active avoidance learning across a population. The mesolimbic dopamine system contributes to behaviors elicited by aversive stimuli, although it is unclear if the heterogeneity in active avoidance learning is explained by differences in dopamine transmission. Furthermore, it is not known how dopamine signals evolve throughout active avoidance learning. To address these questions, we performed voltammetry recordings of dopamine release in the ventral medial striatum throughout training on inescapable footshock and signaled active avoidance tasks. This approach revealed differences in the pattern of dopamine signaling during the aversive cue and the safety period that corresponded to subsequent task performance. Dopamine transmission throughout the footshock bout did not predict performance but rather was modulated by the prior stress exposure. Additionally, we demonstrate that dopamine encodes a safety prediction error signal, which illustrates that ventral medial striatal dopamine release conveys a learning signal during both appetitive and aversive conditions.

Effects of a methanol extract of Ficus platyphylla stem bark on a two-way active avoidance task and on body core temperature

Preparations of Ficus platyphylla are used in Nigeria’s folk medicine to manage a variety of diseases, including insomnia, psychoses, depression, epilepsy, pain, and inflammation. In this study, we examined the effects of the standardised methanol extract of F. platyphylla stem bark (FP) on two-way active avoidance learning and body core temperature to complement earlier studies on the neuroleptic potential of this medicinal plant, which is already in common use. The extract did not interfere with the acquisition and consolidation of the conditioned avoidance reaction (CAR), but did diminish the retrieval of CAR. The extract dose-dependently reduced body core temperature; this was significantly ameliorated by the use of amphetamine. The results confirmed the neuroleptic-like efficacy of FP, probably via the modulation of dopaminergic neurons.

Active avoidance learning differentially activates ERK phosphorylation in the primary auditory and visual cortices of Roman high- and low-avoidance rats

Understanding the mechanisms underlying conditioned avoidance is a critical step toward the development of novel treatments of anxiety. In this context, the two-way active avoidance (2WAA) task is a validated paradigm to investigate uncontrolled avoidance, a hallmark of anxiety disorders. The outbred Roman high- (RHA) and low-avoidance (RLA) rat lines are selected for respectively rapid vs. poor acquisition of active avoidant behavior, and emotional reactivity appears to be the most prominent behavioral difference between the two lines, with RLA rats being more fearful/anxious than their RHA counterparts. This study was aimed at assessing the relationship between the different performance of RHA and RLA rats in the 2WAA task and the number of phosphorylated ERK positive (pERK+) neurons in the primary auditory and visual cortices, in three sub-nuclei of the amygdala, as well as in the nucleus accumbens, and the prefrontal cortex. The results indicate that: (1) RHA rats, but not their RLA counterparts, learn very rapidly to avoid mild electric foot-shocks by crossing to the opposite compartment of the shuttle-box during the presentation of the conditioned stimulus and (2) the different behavior of the Roman lines during active avoidance training is associated with differential changes in the number of pERK+ neurons in the primary auditory and visual cortices (where the proactive coping of RHA rats is associated with increased ERK phosphorylation), but not in the other brain areas examined. These results are consistent with the hypothesis that the activation of the ERK signaling cascade in the auditory and visual cortices may be involved in the acquisition of aversive learning in RHA rats.

Social isolation impairs active avoidance performance and decreases neurogenesis in the dorsomedial telencephalon of rainbow trout

Alterations in the social environment, such as isolating an individual that would normally live in a social group, can generate physiological responses that compromise an individual's capacity to learn. To investigate this, we tested whether social isolation impairs learning skills in the rainbow trout. We show that rainbow trout can achieve an active avoidance (AA) learning program with inter-individual variability. Moreover, c-Fos expression in dorsomedial telencephalon (Dm) correlates with the AA performance, indicating that this structure is involved in this cognitive task. Given that Dm participates in AA learning and this region is under plastic remodelling by addition of new-born neurons, we tested whether social isolation impinges on adult neurogenesis and, consequently, on the Dm cognitive outcome. Trout were reared for four weeks in control or isolated conditions. We found that social isolation diminished the percentage of adult-born neurons that are being incorporated into Dm network. Interestingly, the same isolation treatment also induced a severe deficit in the AA performance. Our results demonstrate a structure-to-function relationship between the Dm and the learning ability in an AA task, indicate that social isolation reduces the incorporation of adult-born neurons into Dm, and show that social isolation impairs the Dm-related cognitive function.

Cognitive function is preserved in aged mice following long-term β-hydroxy β-methylbutyrate supplementation

β-hydroxy β-methylbutyrate (HMB) is a nutritional supplement purported to enhance skeletal muscle mass and strength, as well as cognitive function in older adults. The purpose of this study was to determine the potential for long-term HMB supplementation to preserve muscle function and cognition in aged mice, as well as provide evidence of a link between vessel-associated pericyte function and outcomes. Four- (Adult/Ad) and 17 month-old (Aged/Ag) C57BL/6J mice consumed chow containing 600 mg/kg BW/day of either Ca-HMB (Ad, n=16; Ag, n=17) or Ca-Lactate (Ad, n=16; Ag, n=17) for 6 months. HMB did not prevent age-related reductions in muscle mass, strength and coordination (Age main effect, P<0.05). The rate of muscle protein synthesis decreased within the mitochondrial fraction (age main effect, P<0.05), and this decline was not prevented with HMB. Despite no change in muscle mass or function, an age-dependent reduction in active avoidance learning was attenuated with HMB (Age and HMB main effects, P<0.05). Age detrimentally impacted muscle-resident pericyte gene expression with no recovery observed with HMB, whereas no changes in brain-resident pericyte quantity or function were observed with age or HMB. The findings from this study suggest that prolonged HMB supplementation starting in adulthood may preserve cognition with age.

Phasic Dopamine Signals in the Nucleus Accumbens that Cause Active Avoidance Require Endocannabinoid Mobilization in the Midbrain

Phasic dopamine (DA) release accompanies approach toward appetitive cues. However, a role for DA in the active avoidance of negative events remains undetermined. Warning signals informing footshock avoidance are associated with accumbal DA release, whereas depression of DA is observed with unavoidable footshock. Here, we reveal a causal role of phasic DA in active avoidance learning; specifically, optogenetic activation of DA neurons facilitates avoidance, whereas optical inhibition of these cells attenuates it.Furthermore, stimulation of DA neurons during presentation of a fear-conditioned cue accelerates the extinction of a passive defensive behavior (i.e.,freezing). Dopaminergic control of avoidance requires endocannabinoids (eCBs), as perturbing eCB signaling in the midbrain disrupts avoidance, which is rescued by optical stimulation of DA neurons. Interestingly, once the avoidance task is learned, neither DA nor eCB manipulations affect performance, suggesting that once acquisition occurs, expression of this behavior is subserved by other anatomical frameworks. Our findings establish an instrumental role for DA release in learning active responses to aversive stimuli and its control by eCB signaling.

Effects of regulatory BC1 RNA deletion on synaptic plasticity, learning, and memory.

Nonprotein coding dendritic BC1 RNA regulates translation of mRNAs in neurons. We examined two lines of BC1 knockout mice and report that loss of BC1 RNA exaggerates group I mGluR-stimulated LTD of the Schaffer collateral synapse, with one of the lines showing a much more enhanced DHPG-induced LTD than the other. When the animals were given the hippocampus-synaptic plasticity-dependent active place avoidance task, learning and memory were impaired in the BC1-KO line with the more severely altered DHPG-induced LTD. These findings indicate a role for BC1 RNA control of mGluR-dependent synaptic function in hippocampus and associated cognitive ability.

Activation of β-adrenoceptor facilitates active avoidance learning through enhancement of glutamate levels in the hippocampal dentate gyrus.

Long-term potentiation (LTP) is widely accepted as the best studied model for neurophysiological mechanisms that could underlie learning and memory formation. Despite a number of studies indicating that β-adrenoceptors in the hippocampal dentate gyrus (DG) is involved in the modulation of learning and memory as well as LTP, few studies have used glutamate release as a visual indicator in awake animals to explore the role of β-adrenoceptors in learning-dependent LTP. Therefore, in the present study, the effects of propranolol (an antagonist of β-adrenoceptor) and isoproterenol (an agonist of β-adrenoceptor) on extracellular concentrations of glutamate and amplitudes of field excitatory postsynaptic potential were measured in the DG region during active avoidance learning in freely moving conscious rats. In the control group, the glutamate level in the DG was significantly increased during the acquisition of active avoidance behavior and returned to basal level following extinction training. In propranolol group, antagonism of β-adrenoceptors in the DG significantly reduced the change in glutamate level, and the acquisition of the active avoidance behavior was significantly inhibited. In contrast, the change in glutamate level was significantly enhanced by isoproterenol, and the acquisition of the active avoidance behavior was significantly accelerated. Furthermore, in all groups, the changes in glutamate level were accompanied by corresponding changes in field excitatory postsynaptic potential amplitude and active avoidance behavior. Our results suggest that activation of β-adrenoceptors in the hippocampal DG facilitates active avoidance learning by modulations of glutamate level and synaptic efficiency in rats.