Avoidance Behavior In Rats Research Articles

Investigation of changed conditional stimulus parameters on memory formation during avoidance behaviour in rats

Investigation of changed conditional stimulus parameters on memory formation during avoidance behaviour in rats

Central Amygdala Projections to Lateral Hypothalamus Mediate Avoidance Behavior in Rats.

Persistent avoidance of stress-related stimuli following acute stress exposure predicts negative outcomes such as substance abuse and traumatic stress disorders. Previous work using a rat model showed that the central amygdala (CeA) plays an important role in avoidance of a predator odor stress-paired context. Here, we show that CeA projections to the lateral hypothalamus (LH) are preferentially activated in male rats that show avoidance of a predator odor-paired context (termed Avoider rats), that chemogenetic inhibition of CeA-LH projections attenuates avoidance in male Avoider rats, that chemogenetic stimulation of the CeA-LH circuit produces conditioned place avoidance (CPA) in otherwise naive male rats, and that avoidance behavior is associated with intrinsic properties of LH-projecting CeA cells. Collectively, these data show that CeA-LH projections are important for persistent avoidance of stress-related stimuli following acute stress exposure.SIGNIFICANCE STATEMENT This study in rats shows that a specific circuit in the brain [i.e., neurons that project from the central amygdala (CeA) to the lateral hypothalamus (LH)] mediates avoidance of stress-associated stimuli. In addition, this study shows that intrinsic physiological properties of cells in this brain circuit are associated with avoidance of stress-associated stimuli. Further characterization of the CeA-LH circuit may improve our understanding of the neural mechanisms underlying specific aspects of stress-related disorders in humans.

The effects of lateral habenula lesions on foraging and avoidance behavior in rats living in a naturalistic, risky foraging environment

The effects of lateral habenula lesions on foraging and avoidance behavior in rats living in a naturalistic, risky foraging environment

Phencyclidine Discoordinates Hippocampal Network Activity But Not Place Fields.

We used the psychotomimetic phencyclidine (PCP) to investigate the relationships among cognitive behavior, coordinated neural network function, and information processing within the hippocampus place cell system. We report in rats that PCP (5 mg/kg, i.p.) impairs a well learned, hippocampus-dependent place avoidance behavior in rats that requires cognitive control even when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium-freguency gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive impairment caused by systemic PCP administration. PCP discoordinates theta-modulated medium-frequency and slow gamma oscillations in CA1 LFPs such that medium-frequency gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell firing fields are preserved under PCP, but the drug discoordinates the subsecond temporal organization of discharge among place cells. This discoordination causes place cell ensemble representations of a familiar space to cease resembling pre-PCP representations despite preserved place fields. These findings point to the cognitive impairments caused by PCP arising from neural discoordination. PCP disrupts the timing of discharge with respect to the subsecond timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as the root of PCP-induced cognitive impairment.SIGNIFICANCE STATEMENT Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma oscillations in the LFP and the discharge of a subset of pyramidal neurons called "place cells" is spatially organized such that discharge is restricted to locations called a cell's "place field." Because this temporal coordination and spatial discharge organization is thought to represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt cognitive behavior and assess the importance of neural coordination and place fields for spatial cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal discharge without disrupting firing fields. These findings dissociate place fields from spatial cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial cognition.

Preclinical evaluation of the antipsychotic potential of the mGlu2-positive allosteric modulator JNJ-40411813.

JNJ-40411813/ADX71149 (1-butyl-3-chloro-4-(4-phenylpiperidin-1-yl) pyridin-2(1H)-one) is a positive allosteric modulator (PAM) of the mGlu2 receptor, which also displays 5-Hydroxytryptamine (5HT2A) antagonism after administration in rodents due to a rodent-specific metabolite. JNJ-40411813 was compared with the orthosteric mGlu2/3 agonist LY404039 (4-amino-2-thiabicyclo [3.1.0] hexane-4,6-dicarboxylic acid 2,2-dioxide), the selective mGlu2 PAM JNJ-42153605 (3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine) and the 5HT2A antagonist ritanserin in rodent models for antipsychotic activity and potential side effects, attempting to differentiate between the various compounds and mechanisms of action. In mice, JNJ-40411813, JNJ-42153605, and LY404039 inhibited spontaneous locomotion and phencyclidine- and scopolamine-induced but not d-amphetamine-induced hyperlocomotion; the 5HT2A antagonist ritanserin inhibited only spontaneous locomotion and phencyclidine-induced hyperlocomotion. As measured by 2-deoxyglucose uptake, all compounds reversed memantine-induced brain activation in mice. The two mGlu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mGlu2 ligands antagonized 2,5-dimethoxy-4-methylamphetamine-induced head twitches in rats. LY404039 but not the mGlu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT2A antagonism has effect in some models, mGlu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mGlu2 PAMs mimicked the in vivo pharmacodynamic effects observed with LY404039 except for effects on the rotarod and acoustic startle, suggesting that they produce a primary activity profile similar to that of the mGlu2/3 receptor agonist while they can be differentiated based on their secondary activity profile. The results are discussed in light of clinical data available for some of these molecules, in particular JNJ-40411813.

Fox urine exposure induces avoidance behavior in rats and activates the amygdalar olfactory cortex

Predator odors represent a group of biologically-relevant chemosignals called kairomones. Kairomones enable prey animals to recognize potential predatory threats in their environment and to initiate appropriate defensive responses. Although the behavioral repertoire of anti-predatory responses (e.g. avoidance, freezing, risk assessment) has been investigated extensively, our knowledge about the neural network mediating these innate fear responses is rather limited. In the present study, the GABAA agonist muscimol was bilaterally injected (2.6nmol/0.3μl) into the amygdalar olfactory cortex (AOC), a brain area that receives massive olfactory input from both olfactory systems and is strongly interconnected with the medial hypothalamic defense circuit. Temporary inactivation of the AOC substantially disrupted avoidance behavior of rats to fox urine that is strongly avoided under control conditions (saline injections). Taken together, these results demonstrate that the AOC is critically involved in fox urine-induced fear behavior. This suggests that the AOC is part of a brain fear circuit that mediates innate fear responses toward predatory odors.

MGlu2 receptor-mediated modulation of conditioned avoidance behavior in rats

Inhibition of conditioned avoidance behavior in rats is generally considered predictive for antipsychotic activity in man. The present study investigated the mGlu2-mediated modulation of conditioned avoidance and compared mGlu2 agonists with available antipsychotics for their relative effects on conditioned avoidance behavior and locomotion. The mGlu2/3 orthosteric agonist 4-amino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide (LY-404039) and mGlu2 positive allosteric modulator (PAM) 3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605) inhibited avoidance and blocked escape behavior. The mGlu2/3 negative allosteric modulators (NAMs) 7-(dimethylamino)-4-(3-pyridin-3-ylphenyl)-8-(trifluoromethyl)-1,3-dihydro-2 H-1,5-benzodiazepin-2-one (JNJ-42112265) and 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-(trifluoromethyl)-1,3-dihydro-2H-1,5-benzodiazepin-2-one (RO-4491533) reversed the LY-404039-induced impairment of avoidance and escape. JNJ-42112265 also reversed the impairment of avoidance and escape induced by the mGlu2-specific PAM JNJ-42153605, suggesting that the effects on conditioned avoidance are specifically mGlu2-mediated. The mGlu2/3 antagonist (2-(2-carboxycyclopropyl)-3-(9H-xanthen-9-yl)-d-alanine (LY-341495; s.c.) reversed the LY-404039-induced escape impairment but failed to restore avoidance, suggesting interfering side effects. Like the tested antipsychotics, mGlu2/3 orthosteric and allosteric agonists inhibited avoidance behavior and locomotion at similar doses. Hence no clear-cut differences between mGlu2 modulators and currently available antipsychotics in the way they interfere with avoidance behavior in relation to inhibition of locomotion could be established.

Quantitative Analysis of Formation of Active Avoidance Behavior in the Hippocampus Coagulated and Intact White Albino Rats

Unsupervised cluster analysis is proposed for analysis of active avoidance formation in three groups of albino rats: 1) intact; 2) with electrolytic lesions of neocortex over the dorsal hippocampus; and 3) with electrolytic lesions of dorsal hippocampus. The term “behavior vector” has been introduced to assess quantitatively the behavior of rats while learning. The proposed approach enables to assess active avoidance behavior in rats simultaneously by all the test parameters: 1) reaction to the light; 2) reaction to the electric irritation; and 3) inter-trial spontaneous behavior. The animals were grouped by their behavioral resemblance through the learning process. The proposed method facilitates the assessment of learning capacities in animals and paves way for getting additional information concerning correlative relationships between their learning skills and other neuroethological and neurobiological parameters.

Spatial Memory Using Active Allothetic Place Avoidance in Adult Rats After Isoflurane Anesthesia

We described a paradigm of active allothetic place avoidance (AAPA) as a measure of spatial memory in adult rats. We hypothesized that, pending successful AAPA training, treatment with isoflurane would trigger spatial memory deficits. Fifteen of 20 adult rats were successfully trained and randomly allocated to control and isoflurane treatment groups. An additional 7 animals were used to demonstrate hemodynamic stability during general anesthesia. After training, experimental animals received a 2-hour isoflurane anesthetic. General endotracheal anesthesia was maintained at an isoflurane concentration of 1.8% to 2%. After intervention, retention of training was tested on postanesthesia days 1, 3, and 7. Animals treated with isoflurane displayed selected spatial memory changes up to postanesthesia day 7. There were 2 findings of decreased active avoidance behavior in rats receiving isoflurane: a significant (P=0.029) reduction in maximum path of avoidance in the isoflurane-treated rats compared with controls, and a significant (P=0.038) increase in total path length in the controls. No other measured AAPA parameters achieved statistical significance. Control animals demonstrated increased active avoidance behavior in the AAPA task compared with isoflurane-treated animals. Animals exposed to 2-hour isoflurane general anesthetic had a reduction in the maximum path of avoidance measure up to 7 days postanesthesia, whereas gross spatial parameters such as number of entrances into the shock zone were not significantly different between groups. The AAPA model may prove useful in ascertaining the learning and memory deficits of postoperative cognitive dysfunction.

Different types of avoidance behavior in rats produce dissociable post-training changes in sleep

Avoidance learning affects post-training sleep, and post-training sleep deprivation impairs performance. However, not all rats learn to make avoidance responses, and some rats fail to escape; a definitive behavior of learned helplessness, a model of depression. This study investigated the changes in sleep associated with different behaviors adopted following avoidance training. Rats (n=53) were trained for 100 trials over 2 days (50 trials/day), followed by 23-24 h of post-training polysomnography, then re-tested (25 trials). At re-test, rats were categorized into: 1) Active Avoiders (AA; n=22), 2), Non-learning (NL; n=21), or 3) Escape Failures (EF; n=10). AA rats increased avoidances over days, whereas the NL and EF groups did not. EF rats increased escape failures over days, whereas the NL and AA rats did not. EF rats had increased rapid eye movement (REM) sleep in the first 4h on training day 1. They also had increased non-REM sleep in the first 4h and last 4h on both training days. AA rats had increased REM sleep 13-20 h post-training. The type of behavioral strategy adopted throughout training is associated with a unique pattern of changes in post-training sleep. Training-dependent changes in post-acquisition sleep may reflect distinct processes involved in the consolidation of these different memory traces.

Social Transmission of Avoidance Behavior under Situational Change in Learned and Unlearned Rats

BackgroundRats receive information from other conspecifics by observation or other types of social interaction. Such social interaction may contribute to the effective adaptation to changes of environment such as situational switching. Learning to avoid dangerous places or objects rapidly occurs with even a single conditioning session, and the conditioned memory tends to be sustained over long periods. The avoidance is important for adaptation, but the details of the conditions under which the social transmission of avoidance is formed are unknown. We demonstrate that the previous experience of avoidance learning is important for the formation of behaviors for social transmission of avoidance and that the experienced rats adapt to a change of situation determined by the presence or absence of aversive stimuli. We systematically investigated social influence on avoidance behavior using a passive avoidance test in a light/dark two-compartment apparatus.Methodology/Principal FindingsRats were divided into two groups, one receiving foot shocks and another with no aversive experience in a dark compartment. Experienced and inexperienced rats were further divided into subjects and partners. In Experiment 1, each subject experienced (1) interaction with an experienced partner, (2) interaction with an inexperienced partner, or (3) no interaction. In Experiment 2, each subject experienced interaction with a partner that received a shock. The entering latency to a light compartment was measured. The avoidance behavior of experienced rats was inhibited by interaction with inexperienced or experienced partners in a safely-changed situation. The avoidance of experienced rats was reinstated in a dangerously-changed situation by interaction with shocked rats. In contrast, the inexperienced rats were not affected by any social circumstances.Conclusions/SignificanceThese results suggest that transmitted information among rats can be updated under a situational change and that the previous experience is crucial for social enhancement and inhibition of avoidance behavior in rats.

Aversion- vs fear-inducing properties of 2,4,5-trimethyl-3-thiazoline, a component of fox odor, in comparison with those of butyric acid

2,4,5-trimethyl-3-thiazoline (TMT), a component of fox feces, is a widely used odorant to induce innate fear behavior in rats and mice. However, based on the slight acrid smell it was argued that the observed behavioral effects are a result of the aversive and not of the fear-inducing properties of TMT. In the present study, we tried to directly compare the aversive and fear-inducing properties of TMT with those of the aversive control odor butyric acid. We first identified concentrations of butyric acid and TMT that induce similar amounts of avoidance behavior in rats, indicating that these concentrations have similar aversive properties. In a second experiment, these two concentrations were then tested for their ability to induce freezing, a species-specific defensive response. Only TMT but not butyric acid induced freezing in the rats. This supports the hypothesis that TMT indeed has specific fear-inducing properties and that the observed behavioral effects could not simply be reduced to the aversive properties of TMT.

Serotoninergic mechanisms of the effects of neurotensin on passive avoidance behavior in rats

The aim of the present work was to identify the features of the actions of neurotensin on administration into the substantia nigra or dorsal cervical nucleus on the reproduction of passive avoidance reactions in rats. The results showed that the action of neurotensin administered into the substantia nigra was accompanied by sharp reductions in passive avoidance reactions, while administration into the dorsal cervical nucleus, conversely, led to increases in these reactions and slowing of their extinction. The effects of microinjections of the serotonin 5-HT(1A) receptor agonist 8-hydroxydipropylaminotetraline (8-OH-DPAT) into these brain structures were analogous to the effects of neurotensin. The different behavioral effects of administration of neurotensin corresponded to identifiable changes in the levels of serotonin and its metabolite 5-hydroxyindoleacetic acid in the caudate nuclei of the brain. These data led to the conclusion that the effects of neurotensin on passive avoidance behavior are associated with the regulation of the emotional state of the animals via actions on the functions of brain serotoninergic structures.

Experimental dissociation of neural circuits underlying conditioned avoidance and hypophagic responses to lithium chloride

We previously reported that noradrenergic (NA) neurons in the nucleus of the solitary tract (NST) are necessary for exogenous CCK octapeptide to inhibit food intake in rats. To determine whether NST NA neurons also are necessary for lithium chloride (LiCl) to inhibit food intake and/or to support conditioned avoidance behavior, saporin toxin conjugated to an antibody against dopamine beta hydroxylase (DSAP) was microinjected bilaterally into the NST to ablate resident NA neurons. DSAP and sham control rats subsequently were tested for the ability of LiCl (0.15M, 2% body wt) to inhibit food intake and to support conditioned flavor avoidance (CFA). LiCl-induced hypophagia was significantly blunted in DSAP rats, and those with the most extensive loss of NST NA neurons demonstrated the most attenuated LiCl-induced hypophagia. Conversely, LiCl supported a robust CFA that was of similar magnitude in sham control and DSAP rats, including rats with the most extensive NA lesions. A terminal c-Fos study revealed intact LiCl-induced c-Fos expression in the lateral parabrachial nucleus and central amygdala in DSAP rats, despite significant loss of NST NA neurons and attenuated c-Fos activation of corticotropin-releasing hormone-positive neurons in the paraventricular nucleus of the hypothalamus (PVN). Thus, NST NA neurons contribute significantly to LiCl-induced hypophagia and recruitment of stress-responsive PVN neurons but appear to be unnecessary for CFA learning and expression. These findings support the view that distinct central nervous system circuits underlie LiCl-induced inhibition of food intake and conditioned avoidance behavior in rats.

Approaches to extrapolating animal toxicity data on organic solvents to public health

Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific endpoints measured in laboratory animals seldom translate into effects of concern in humans; and (3) the mode of action of the chemical is rarely understood. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function).

Lobeline produces conditioned taste avoidance in rats

Previous results indicate that pretreatment with lobeline attenuates methamphetamine (METH) self-administration in rats, but not by acting as a substitute reinforcer. Given these findings, it has been suggested that lobeline may serve as a useful pharmacotherapy for psychostimulant abuse. However, because lobeline produces emesis and nausea in humans, the present study examined whether lobeline has direct effects on taste avoidance behavior in rats within the same dose range shown previously to decrease METH self-administration. Two experiments utilized a Pavlovian conditioning procedure to determine if lobeline produces conditioned taste avoidance (CTA) in rats. In Experiments 1 and 2, rats consumed either novel milk or salt solutions, respectively, and within 10 min, were injected with lobeline (0.3–3.0 mg/kg) or METH (0.3–3.0 mg/kg). A single-bottle test conducted 48 h after flavor–drug pairings indicated that the dose of lobeline that reduced METH self-administration in a previous study (i.e., 3.0 mg/kg) also produced reliable CTA for milk and salt solution. These findings suggest a need to develop lobeline analogs that reduce METH self-administration, but do not produce CTA following the consumption of a novel solution.

Increases in avoidance responding produced by REM sleep deprivation or serotonin depletion are reversed by administration of 5-hydroxytryptophan

Our objective was to directly compare the effects of rapid eye movement (REM) sleep deprivation (REMSD) and serotonin 5-hydroxytryptamine (5-HT) depletion on free-operant avoidance behavior in rats. These experiments were designed to determine if declining 5-HT levels observed during REMSD might mediate the increases in avoidance responding observed in REM sleep deprived rats. Rats were trained on a free-operant avoidance task. Following training, the animals were assigned to one of three sleep conditions (REMSD, tank control, or cage control). Animals in each sleep condition were exposed to four 5-HT manipulations: (a) saline plus saline; (b) p-chlorophenylalanine (PCPA) plus saline; (c) saline plus 5-hydroxytryptophan (5-HTP) and (d) PCPA plus 5-HTP. Both REMSD and 5-HT depletion via PCPA resulted in an increase in avoidance responding that was reversed by administration of 5-HTP. REMSD and 5-HT depletion via PCPA resulted in increased avoidance efficiency and were reversed by 5-HTP administration, but only changes following PCPA injection were statistically significant. Decreases in 5-HT levels that occur during REMSD likely mediate increases in avoidance responding.

Repeated administration of the neurotensin analogue NT69L induces tolerance to its suppressant effect on conditioned avoidance behaviour

Although acute neurotensin receptor stimulation exerts diverse behavioural effects that resemble those seen after administration of antipsychotic drugs, data on effects after repeated exposure to neurotensin receptor agonism is relatively sparse. Here, we demonstrate that repeated administration of the novel neurotensin-(8–13) analogue NT69L [( N-methyl-Arg), Lys, Pro, l- neo-Trp, tert-Leu, Leu] induce tolerance to its suppressant effect on conditioned avoidance behaviour in rats, a predictive assay for antipsychotic activity. In contrast, the inhibitory effect of haloperidol on this behaviour was sustained despite repeated administration of this classical antipsychotic drug. These findings indicate that repeated exposure to neurotensin receptor stimulation induces tolerance to the antipsychotic-like effects of neurotensin receptor agonists.

Changes in the Concentration of NCAM in the Blood Serum after Amnesia of Passive Avoidance Behavior in Rats

Changes in the Concentration of NCAM in the Blood Serum after Amnesia of Passive Avoidance Behavior in Rats

Role of corticotropin-releasing factor, vasopressin and the autonomic nervous system in learning and memory

Learning and memory are essential requirements for every living organism in order to cope with environmental demands, which enables it to adapt to changes in the conditions of life. Research on the effects of hormones on memory has focused on hormones such as adrenocorticotropic hormone (ACTH), glucocorticoids, vasopressin, oxytocin, epinephrine, corticotropin-releasing factor (CRF) that are released into the blood and brain following arousing or stressful experiences. Most of the information have been derived from studies on conditioned behavior, in particular, avoidance behavior in rats. In these tasks, an aversive situation was used as a stimulus for learning. Aversive stimuli are associated with the release of stress hormones and neuropeptides. Many factors play a role in different aspects of learning and memory processes. Neuropeptides not only affect attention, motivation, concentration and arousal or vigilance, but also anxiety and fear. In this way, they participate in learning and memory processes. Furthermore, neuropeptides such as CRF and vasopressin modulate the release of stress hormones such as epinephrine. In turn, systemic catecholamines enhance memory consolidation. CRF and vasopressin are colocalized in neurons from the nucleus paraventricularis, which project to nuclei in the brainstem involved in autonomic regulation. The objective of this paper is to discuss the role of CRF, vasopressin, and the autonomic nervous system (ANS) in learning and memory processes. Both CRF and vasopressin have effects in the same direction on behavior, learning and memory processes and stress responses (release of catecholamines and ACTH). These neuropeptides may act synergistically or in a concerted action aimed to learn to adapt to environmental demands.