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ABSTRACT: The startle is a relatively simple ubiquitous reflex. Interestingly, it has a "non-zero baseline", i.e., its magnitude can be reduced or enhanced. We reflect here on the translational value of prepulse inhibition and fear-related potentiation as endophenotypes that can be used for the investigation of complex psychiatric diseases such as schizophrenia and anxiety-related disorders. Our main conclusions are that both phenomena of startle modulation are useful tools for basic research in investigating the genetic and/or neurobiological basis of certain aspects of these disorders. Because of their stable and robust nature, however, both biomarkers are of limited use for predicting the occurrence of diseases in high-risk people or for predicting the course of an illness.
Cell and Tissue Research 03/2013; · 3.11 Impact Factor
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ABSTRACT: Fear extinction is defined as the attenuation of a conditioned-fear memory by re-exposing animals to the conditioned stimulus without the aversive stimulus. This process is known to be effectively enhanced via administration of D-cycloserine (DCS), a partial NMDA-receptor agonist. However, other glutamatergic mechanisms, such as interference with metabotropic glutamate receptor (mGluR) subtypes 5 and 7 in the extinction of aversive memories are insufficiently understood. Using the allosteric mGluR5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), and DCS for comparison, we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influenced within- and between-session conditioned-fear extinction training and extinction retention in rats. We show that when injected before extinction training, mGluR7 activation with AMN082 enhanced freezing and thereby attenuated within-session fear extinction, whereas both DCS and the mGluR5 receptor antagonist MPEP had no effect on this process. However, these differential drug effects were not long lasting, as no difference in extinction retention were observed 24 h later. Therefore, we assessed whether the compounds affect 24 h consolidation of extinction training following incomplete extinction training (between-session extinction). Similar to DCS, AMN082- but not MPEP-treated rats showed facilitated extinction retention, as exhibited by decreased freezing. Finally, using fluoxetine, we provide evidence that the effect of AMN082 on between-session extinction retention is most likely not via increasing 5-HT transmission. These findings demonstrate that mGluR7 activation differentially modulates conditioned-fear extinction, in dependence on the protocol employed, and suggests drugs with AMN082-like mechanisms as potential add-on drugs following exposure-based psychotherapy for fear-related human disorders.
Neuropharmacology 11/2011; 62(4):1619-26. · 4.81 Impact Factor
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ABSTRACT: Short-term habituation is a basic form of learning that is analyzed in different species and using different behavioral models. Previous studies on mechanisms of short-term habituation yielded evidence for a potential role of group III metabotropic glutamate receptors (mGluRIIIs). Here we tested the hypothesis that mGluRIII mediate short-term habituation of startle in rats, combining electrophysiological experiments in vitro with behavioral studies in vivo. We applied different mGluRIII agonists and antagonists on rat brainstem slices while recording from startle-mediating neurons in the caudal pontine reticular nucleus (PnC) and monitoring synaptic depression presumably underlying habituation. Furthermore, we injected the mGluRIII antagonist (RS)-alpha-phosphonophenylglycine (MPPG) and the agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) into the PnC of rats in vivo and measured its effect on startle habituation. Our results show that activation of mGluRIIIs in the PnC strongly inhibits startle-mediating giant neurons in vitro. Accordingly, L-AP4 reduced startle responses in vivo. However, synaptic depression in the slice was not disrupted by mGluRIII antagonists or agonists. Correspondingly, the in vivo application of the mGluRIII antagonist MPPG failed to show any effect on short-term habituation of startle responses. We therefore conclude that mGluRs are expressed within the primary startle pathway and that they inhibit startle responses upon activation; however, this inhibition does not play any role in synaptic depression and short-term habituation of startle. This is in contrast to the role of mGluRIIIs in other forms of habituation and supports the notion that there are different mechanisms involved in habituation of sensory-evoked behaviors.
Journal of Neuroscience 08/2010; 30(31):10422-30. · 7.11 Impact Factor
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ABSTRACT: The prefrontal cortex and the nucleus accumbens are two brain sites which are known to be involved in the modulation of the acoustic startle response. In particular, the release of monoaminergic transmitters within these brain sites plays an important role in prepulse inhibition of the startle response which serves as an operational measure of sensorimotor gating. Like for dopamine, it is well established that serotonin transmission plays an important role in prepulse inhibition. However, there are only few studies investigating the effects of local manipulation of serotonin transmission on prepulse inhibition. The aim of the present study was to test whether prepulse inhibition or the startle response itself was affected by serotonergic depletion of either the prefrontal cortex or the nucleus accumbens. Serotonergic depletion was induced by local injections of 5,7-dihydroxytryptamine and verified by ex vivo analysis of transmitter levels by high pressure liquid chromatography. In our behavioural tests, we found that 5,7-dihydroxytryptamine into the prefrontal cortex decreased prepulse inhibition, whereas injections into the nucleus accumbens facilitated prepulse inhibition. The time course of these behavioural effects, as well as the transmitter level changes within the different brain sites was very different. Most interestingly, 5,7-dihydroxytryptamine injections into the nucleus accumbens affect serotonin and dopamine levels in both, nucleus accumbens and prefrontal cortex. Taken together, the present study supports an important role of serotonin in the modulation of prepulse inhibition and baseline startle magnitude. However, the observed changes cannot be attributed to a specific brain site since our data clearly show that local 5,7-dihydroxytryptamine injections also affect transmitter levels in brain sites away from the injection site.
Behavioural brain research 09/2009; 202(1):58-63. · 3.22 Impact Factor
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ABSTRACT: 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.
Journal of Experimental Biology 09/2009; 212(Pt 15):2324-7. · 3.00 Impact Factor
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ABSTRACT: 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.
Journal of Experimental Biology 03/2009; 212(Pt 4):506-13. · 3.00 Impact Factor
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ABSTRACT: The metabotropic glutamate receptor subtype 7 (mGluR7) is presynaptically located and modulates transmitter release. An earlier study from our group demonstrated that systemic administration of N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), a selective allosteric mGluR7 agonist, attenuates the acquisition of conditioned fear measured by fear-potentiated startle. Aim of this study was to explore whether this effect is mediated by the basolateral amygdala, a crucial brain structure for acquisition of conditioned fear. Therefore, AMN082 was locally injected into the basolateral amygdala of rats and the effects of these injections on the acquisition of conditioned fear was measured. Our data clearly show that intra-amygdala injection of AMN082 impairs fear acquisition. This finding demonstrates that amygdaloid mGluR7 controls the learning of conditioned fear.
Neuroreport 08/2008; 19(11):1147-50. · 1.66 Impact Factor
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ABSTRACT: 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.
Neuroscience & Biobehavioral Reviews 06/2008; 32(7):1259-66. · 8.65 Impact Factor
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ABSTRACT: 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.
Neuroreport 05/2008; 19(6):667-70. · 1.66 Impact Factor
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ABSTRACT: Alarm calls are widely used in mammals. Their biological function is to deter predators and warn relatives of danger. Despite this important function of alarm calls, the development of alarm call recognition is poorly understood. Using laboratory rats, the present study investigated in a first experiment whether alarm calls are recognized innately. In experimentally naive animals, we found significantly increased freezing if stimuli in the 22 kHz range were presented but this response was not specific to conspecific 22 kHz calls. Therefore, a second experiment addressed the hypothesis whether recognition of conspecific 22 kHz calls can be learned and whether this learning is facilitated by a preparedness to acquire defensive responses to alarm calls. Our data show that rats learned quickly to associate the 22 kHz calls with aversive stimuli. Interestingly, the animals were more reluctant to extinguish this memory, and this information retained longer in memory than in the case of other types of calls and ultrasonic stimuli. We, therefore, conclude that rats are predisposed to acquire adaptive defensive behaviour in response to alarm calls. In particular, our data indicate that better encoding of such learning in rats leads to a stable memory which better resists extinction.
Behavioural Brain Research 01/2008; 185(2):69-75. · 3.42 Impact Factor
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ABSTRACT: One operational measure of sensorimotor gating that is deficient in many psychiatric disorders is prepulse inhibition (PPI) of the startle response. To investigate the role of dopamine D1 and D2 receptors within the nucleus accumbens (NAC) in sensorimotor gating in mice, we infused dopamine D1 and D2 receptor agonists (dihydrexidine and quinpirole respectively) directly into the NAC and measured the effects on PPI and on prepulse facilitation. Quinpirole infusions increased PPI and attenuated prepulse facilitation, whereas dihydrexidine had no effects. These results stand in contrast to data after systemic injections in mice and rats and intra-accumbal infusions in rats, suggesting that the role of dopamine D2 receptors within the NAC in mice differs from their role in rats.
Neuroreport 10/2007; 18(14):1493-7. · 1.66 Impact Factor
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ABSTRACT: Contextual fear conditioning is the learning of a fear response in a specific context in response to repeated application of aversive stimuli (e.g., foot shocks) or danger-related stimuli (predator odors) within that context. Cat odor, a danger-related stimulus common in laboratory studies of fear in the past, has often been replaced recently with trimethylthiazoline (TMT), a component of fox feces. No contextual fear conditioning in response to TMT has been reported so far, whereas cat odor has often been shown to induce such fear conditioning in rats. Using TMT in both a 1-compartment and a 2-compartment setup, the authors found conditioned fear behavior (expressed as avoidance behavior) in the 2-compartment setup but not--as reported by others--in the 1-compartment setup. Detailed analysis revealed 2 different coping strategies in the 2-compartment setup: Half of the rats showed pronounced avoidance behavior, whereas the other half showed intense risk assessment behavior. These results indicate that expression of conditioned fear behavior in response to a TMT-paired context is dependent on the experimental setup used, as well as the strategy of the individual rat.
Behavioral Neuroscience 07/2007; 121(3):594-601. · 2.62 Impact Factor
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Markus Fendt
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ABSTRACT: Predator odors induce defensive behavior in many prey species. For various reasons, studies carried out up to now have been unable to establish whether predator odor recognition is innate or not. Mostly, only particular odors or wild-living (i.e., experienced) test animals have been used in these studies, restricting the conclusiveness of the observations. In the present study, the behavioral effects of exposure to different predator odors on predator odor-naive laboratory male rats were compared with the effects of different nonpredator odors and of a no-odor control stimulus. Results show that exposure to urine of canids and felids, but not of herbivores or conspecifics, induce defensive behaviors. Taken together, the study provides support for the hypothesis that there is an innate recognition of predator odors in laboratory rats.
Journal of Chemical Ecology 01/2007; 32(12):2617-27. · 2.66 Impact Factor
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ABSTRACT: In rats, different types of vocalization can be observed. High frequency vocalizations (so called 50 kHz calls) are believed to indicate an appetitive state of the emitting animal. This is supported by studies demonstrating that infusions of the dopamine agonist amphetamine into the nucleus accumbens (NAC), a key structure for appetitive behaviors, induce 50 kHz calls. Several studies during the last years demonstrated that not only infusions of dopamine agonists such amphetamine but also infusions of acetylcholine receptor agonists into the NAC stimulate the appetitive system. In present study, we tested whether infusions of the unspecific cholinergic agonist carbachol into the NAC are able to induce 50 kHz calls. Indeed, we observed a high number of 50 kHz calls after intra-NAC infusions of carbachol. The main frequency of the these calls was between 40 and 70 kHz, and the duration was mainly between 10 and 50 ms. We hypothesize that acetylcholine transmission within the NAC plays an important role in the induction of those ultrasonic calls indicating an appetitive state.
Neuroscience Letters 07/2006; 401(1-2):10-5. · 2.11 Impact Factor
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ABSTRACT: The medial prefrontal cortex is known to be crucially involved in the memory for fear extinction. It has been shown that the dopamine D4 receptor is abundantly localized in the medial prefrontal cortex of rodents and that this receptor subtype is involved in the mediation of fear-related behaviour. In the present study, we tested whether dopamine D4 receptors within the medial prefrontal cortex are involved in the learning and encoding of fear extinction. Infusions of the specific dopamine D4 receptor antagonist L-741,741 into the medial prefrontal cortex immediately before fear extinction did not affect fear extinction learning but attenuated the memory on fear extinction on the following day. These results suggest that medial prefrontal cortex dopamine D4 receptors are involved in the consolidation of fear extinction memory.
Neuroreport 06/2006; 17(8):847-50. · 1.66 Impact Factor
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ABSTRACT: The lateral amygdala plays an important role in emotional learning. Previous studies found that amygdaloid plasticity processes involve the activation of metabotropic glutamate receptors. In the present study we examined the effect of the highly specific mGluR8 agonist (S)-3,4-DCPG on conditioned fear in vivo measuring fear-potentiated startle. Both, acquisition and expression of conditioned fear were dose-dependently inhibited by (S)-3,4-DCPG injections into the amygdala. Since synaptic long-term potentiation in the lateral amygdala has been correlated with the acquisition of conditioned fear in rats, the effect of (S)-3,4-DCPG in vitro on synaptic transmission, short- and long-term plasticity in the lateral amygdala was evaluated in parallel. Patch clamp recordings in rat brain slices revealed that (S)-3,4-DCPG strongly attenuated synaptic transmission from sensory afferents. The lack of detectable effects on postsynaptic neurons and altered short-term plasticity indicate that (S)-3,4-DCPG acts at presynaptic sites. Long-term potentiation of thalamic afferent fiber synapses induced by a pairing protocol was slightly attenuated in the presence of (S)-3,4-DCPG, but long-term potentiation by tetanic afferent stimulation was inhibited. We conclude that mGluR8 activation is not specifically involved in long-term plasticity processes but that it rather provides a powerful inhibitory control of synaptic transmission within the lateral amygdala, with the ability to reduce activity in such a way that the expression and the acquisition of learned fear become strongly impaired in vivo.
Neuropharmacology 03/2006; 50(2):154-64. · 4.81 Impact Factor
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ABSTRACT: 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.
Behavioural Brain Research 03/2006; 167(1):57-62. · 3.42 Impact Factor
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ABSTRACT: The present study investigated whether the rostral perirhinal cortex is involved in aversive information processing, particularly in unconditioned fear (anxiety). We temporarily inactivated the rostral perirhinal cortex by local injections of the GABA(A) agonist muscimol (0.0, 1.1, and 4.4 nmol/0.5 microl) and tested whether these injections affected the behavior of rats in the elevated plus-maze and in the yohimbine-enhanced startle test. Temporary inactivation of the rostral perirhinal cortex increased the number of open arm entries and the open arm ratio in the elevated plus-maze. In addition, startle response enhancement caused by the anxiogenic drug yohimbine was reduced by perirhinal cortex inactivation. Taken together, these data clearly show that the rostral perirhinal cortex is involved in the processing of emotional stimuli and is critical for the expression of unconditioned fear (anxiety).
Behavioural Brain Research 10/2005; 163(2):168-73. · 3.42 Impact Factor
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ABSTRACT: 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.
Behavioral Neuroscience 09/2005; 119(4):1004-10. · 2.62 Impact Factor
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ABSTRACT: Several studies show that the hippocampus is critical for the memories mediating trace and contextual fear conditioning. This study investigates whether N-methyl-D-aspartate-induced lesions of the dorsal hippocampus made prior to training affect context fear conditioning and trace fear conditioning measured with the fear-potentiated startle. Pretraining excitotoxic lesions of the dorsal hippocampus blocked acquisition of trace fear conditioning to a tone stimulus but did not affect context fear conditioning. These data indicate that without a dorsal hippocampus rats are unable to acquire trace conditioning but can acquire contextual fear when fear is measured by potentiation of the startle response.
Behavioral Neuroscience 07/2005; 119(3):834-8. · 2.62 Impact Factor
