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Stimuli that are either presented directly after or explicitly unpaired to an aversive event can be associated with the relief or absence of the aversive event. Such stimuli then become conditioned stimuli (CS) for relief or safety, respectively, and are able to induce appetitive-like behavioral responses, e.g. startle attenuation. Of note, the aversive event is not only associated with the stimuli but also with the context in which the aversive event occurs. However, it is poorly understood whether this context affects the expression of conditioned relief or safety. Using laboratory rats, we demonstrated that the individual effects of a safety CS, but not of a relief CS, is strongly correlated with the fear-inducing properties of the experimental context. This suggest that the expression of conditioned safety is more sensitive to contextual fear than conditioned relief. Our findings are in line with the idea that a safety CS works as a conditioned inhibitor (here: of contextual fear). As safety learning is affected in anxiety disorders, the context-sensitivity of safety CS could be considered in the therapy of anxiety disorder patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Predator odours induce defensive behaviour in prey animals such as rats. The present study investigated (1) whether laboratory rats exposed to predator odours emit 22-kHz calls which may have an alarming function and (2) whether playback of such calls induces behavioural changes in conspecifics. For this, Sprague-Dawley rats were exposed to samples of fox and lion urine, as well as to the synthetic predator odour TMT. Despite that all odours induced defensive behaviour, only predator urine samples but not TMT were able to induce 22-kHz calls in a few rats. In a second experiment, naive rats were exposed to playback presentations of the 22-kHz calls recorded in the first experiment, as well as to phase-scrambled and frequency-shifted control stimuli. Low intensity playback presentations led to a reduction of locomotor activity during the presentation of the 22-kHz calls but not of the control stimuli. This effect was less specific under high intensity conditions. Taken together the present findings show that natural predator odours are able to induce emission of 22-kHz calls in rats and support the hypothesis that these calls have an alarming function.

Background and Purpose: Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning., Experimental Approach: The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested., Key Results: Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections., Conclusion and Implication: The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory., (© 2015 The British Pharmacological Society.)

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 (2.6 nmol/0.3 μl) 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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The metabotropic glutamate receptor subtype 7 (mGlu7) is an important presynaptic regulator of neurotransmission in the mammalian CNS. mGlu7 function has been linked to autism, drug abuse, anxiety, and depression. Despite this, it has been difficult to develop specific blockers of native mGlu7 signaling in relevant brain areas such as amygdala and limbic cortex. Here, we present the mGlu7-selective antagonist 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), which inhibits lateral amygdala long term potentiation (LTP) in brain slices from wild type mice with a half-maximal blockade at 88 nm. There was no effect of XAP044 on LTP of mGlu7-deficient mice, indicating that this pharmacological effect is mGlu7-dependent. Unexpectedly and in contrast to all previous mGlu7-selective drugs, XAP044 does not act via the seven-transmembrane region but rather via a binding pocket localized in mGlu7's extracellular Venus flytrap domain, a region generally known for orthosteric agonist binding. This was shown by chimeric receptor studies in recombinant cell line assays. XAP044 demonstrates good brain exposure and wide spectrum anti-stress and antidepressant- and anxiolytic-like efficacy in rodent behavioral paradigms. XAP044 reduces freezing during acquisition of Pavlovian fear and reduces innate anxiety, which is consistent with the phenotypes of mGlu7-deficient mice, the results of mGlu7 siRNA knockdown studies, and the inhibition of amygdala LTP by XAP044. Thus, we present an mGlu7 antagonist with a novel molecular mode of pharmacological action, providing significant application potential in psychiatry. Modeling the selective interaction between XAP044 and mGlu7's Venus flytrap domain, whose three-dimensional structure is already known, will facilitate future drug development supported by computer-assisted drug design.

Orexin-deficient mice express narcoleptic episodes which mirror some of the main symptoms of human narcolepsy. Therefore, they are often used in narcolepsy research. However, little is known about some behavioral characteristics of narcoleptic episodes, e.g. about episode types, duration, and variability. In the present study, 351 narcoleptic episodes of orexin-deficient mice were behaviorally characterized. Based on this data, we describe different onset and progression episodes types. These episode types affected episode duration, i.e. abrupt onsets and 'shaking'-like movements increased episode duration. Our data suggests that promoting motor activity enhances the frequency of narcoleptic episode. Inter-individual variability of episode frequency and duration was large; however, the intra-individual frequency was relatively stable. Based on these findings we suggest the following to increase the statistical power of experiments in orexin-deficient mice: Using a pre-screen and selecting the mice with decent episode frequency, using an enriched environment as well as using repeated-measure designs.

Background: Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species, but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown., Results: Here, we identify a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication. Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice, but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout., Conclusions: TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Calls of avian predators potentially predict danger for murine rodents. Indeed, exposure of field-experienced rodents to owl calls induces defensive behavior suggesting that recognition of vocalizations of avian predators is innate. To address this hypothesis, we investigated whether laboratory-reared and predator-naive rodents (mice, gerbils, rats) express defensive behavior in response to calls of different avian predators but we observed no such defensive behavior. We then asked whether the calls of avian predators are faster or better learned as a danger-predicting cue than the calls of avian non-predators. All calls could be learned as danger-predicting cues, but we found no differences in the speed or strength of the learning. Taken together, our results suggest that there is no innate recognition of the calls of avian predators in murine rodents and that the recognition of the calls of avian predators observed in field-experienced rodents is acquired by learning.

During recent years, an increasing number of studies have used 2,3,5-trimethyl-3-thiazoline (TMT), a component of fox feces, as a stimulus to induce fear in predator naive rodents. The use of TMT is controversially discussed: There are some clear advantages of TMT against natural predator odors (e.g. stimulus intensity can be better controlled) but also still some open questions and objections regarding TMT. The aim of the present article is to discuss four often mentioned objections against TMT: (1) In some cases, TMT failed to produce fear behavior, (2) TMT is rather a noxious than a fear-inducing stimulus, (3) TMT does not support fear conditioning, and (4) there are different neural pathways processing natural predator odors and TMT. We summarize data showing different sensitivity to TMT in different rat strains. Then, new data are presented showing that TMT concentrations which are not avoided by rats induce fear behavior, and that concentrations of TMT and of the control odor butyric acid, which are similarly avoided, are totally different in their ability to induce fear behavior. Furthermore, we summarize and discuss data showing that fear conditioning to a TMT-paired context is possible and that there is an overlap between the neural basis for TMT- and cat odor-induced fear behavior. In conclusion, the recent data do not support the idea that TMT is simply a noxious stimulus which non-specifically induces fear behavior. Therefore, TMT is still a viable alternative stimulus to natural predator odors to investigate effects of predator odors on behavior.

Introduction: As a consequence of obstetric complications hypoxia has been discussed as a possible factor in the pathophysiology of schizophrenia. The present study investigated the effects of weak chronic neonatal hypoxia in rats on different behavioural animal models of schizophrenia., Methods: (1) After neonatal hypoxia, half of the pups were fostered by normally treated nurse animals to control for possible maternal effects. (2) The animals were tested on postnatal days (PD) 36, 86, 120 and 150 by applying three different behavioural tests: prepulse inhibition (PPI), social interaction and recognition, and motor activity in an open field. (3) Before the PD 150 test, half of the animals had been chronically treated with the antipsychotic drug clozapine (45 mg/kg/day)., Results: Rats exposed to hypoxia as neonates exhibited a deficit in locomotor activity on PD 86, 120, and 150, as well as a PPI deficit on PD 120 and 150 but not before. Chronic treatment with clozapine reverses the hypoxia induced PPI deficit, but not the decreased locomotor activity. In a second experiment, clozapine was chronically administered before PD 120 and blocked the development of the PPI deficit in the animals exposed to hypoxia., Discussion: The time course of the hypoxia-induced PPI deficit and reversibility by clozapine supports the validity of our animal model and the hypothesis that hypoxia as an obstetric complication is an important factor in the pathophysiology of schizophrenia.

A number of lesion studies have shown that the lateral septum plays an important role in the modulation of innate fear. Furthermore, an increased c-fos expression in the lateral septum was demonstrated after exposure to natural predator odors and 2,3,5,-trimethyl-3-thiazoline (TMT), a component of fox odor. This study investigates, on a behavioral level, whether the lateral septum plays a role in TMT-induced fear. Temporary inactivation of the lateral septum by local muscimol injections clearly blocked TMT-induced fear behavior but had no effect on behavior in a controlled condition. This indicates that the lateral septum is important for the processing of TMT-induced fear and suggests that the lateral septum is also involved in fear behavior induced by natural predator odors.

Trimethylthiazoline (TMT) is a component of fox feces and is thought to be a stimulus with innate fear-eliciting properties for rodents. Naive laboratory rats that are exposed to TMT display freezing behavior, a known behavioral sign of fear and anxiety. Early studies examining the neural basis of TMT-induced fear showed that the bed nucleus of the stria terminalis is important for this behavior. In contrast, the central and lateral nuclei of the amygdala does not seem to participate in the neural processing of TMT-induced fear. However, a study investigating c-fos expression in response to TMT-exposure revealed a strong activation of the medial as well as a weak activation of the basolateral amygdala. Therefore, the present study examined the effects of temporary inactivation of the medial and basolateral amygdala on TMT-induced freezing. Temporary inactivation was accomplished by local injections of the GABA(A) receptor agonist muscimol into the areas of interest. TMT-induced freezing was completely blocked by temporary inactivation of the medial amygdala. Temporary inactivation of the basolateral amygdala resulted in a delay of the onset of the freezing response to TMT. These results clearly demonstrate that the medial amygdala is crucial for TMT-induced freezing, whereas the basolateral amygdala seems to play a modulatory role in this type of fear behavior. Since the medial amygdala is also involved in the processing of cat odor-induced fear, the finding of the present study points towards a general role of the medial amygdala in the processing of predator odor-induced fear.

Trimethylthiazoline (TMT), a component of fox feces, has been used in various studies as a natural predator stimulus to induce autonomic and behavioral signs of fear (e.g., higher levels of stress hormones, freezing, and risk assessment). The present study investigated whether 2 further behavioral signs of fear are induced in rats by TMT exposure: potentiation of the acoustic startle response and inhibition of appetitive behavior. In addition, the authors tested the rats for dose dependency of TMT-induced freezing behavior. The study confirmed that behavioral changes observed during TMT exposure are caused by TMT-induced fear and are dose dependent., ((c) 2005 APA)

One of the main interests in the field of neuroscience is the investigation of the neural basis of fear. During recent years, an increasing number of studies have used trimethylthiazoline (TMT), a component of red fox feces, as a stimulus to induce fear in predator naive rats, mice, and voles. The aim of the present review is to summarize these studies. We present an overview to the autonomic and behavioral changes that are induced by TMT exposure. Then, we summarize the small number of studies that have examined the neural processing of the TMT stimulus. Finally, we compare these studies with those using a natural predator or predator odor to induce fear and discuss the possible use of TMT exposure in rodents as an animal model of unconditioned fear in humans.