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PubMed1969

Electroconvulsive shock effects on a reactivated memory trace: further examination.

Rats showed amnesia for conditioned fear training if given an electroconvulsive shock immediately after training. Retention was unimpaired, however, when the electroconvulsive shock treatment was given 1 day after training immediately after the presentation of the stimulus used in the fear conditioning training. These results support the view that electroconvulsive shock disrupts memory trace consolidation but does not disrupt a recently reactivated memory trace.

Animals↗
PubMed2000

Acute exposure to caffeine selectively disrupts context conditioning in rats.

RATIONALE AND OBJECTIVE: Acute caffeine administration has both beneficial and adverse effects on learning and memory; however, the brain regions underlying these effects remain unclear. Several experiments were conducted to examine the effects of acutely administered caffeine on the acquisition and expression of hippocampal-dependent and hippocampal-independent forms of conditioned fear. METHODS: In the first experiment, caffeine (10, 20, or 30 mg/kg; IP) or vehicle was administered to rats 15 min prior to classical fear conditioning, which consisted of ten tone-shock pairings. Freezing to the conditioning context was measured 24 h later, whereas tone-elicited fear was measured 48 h later. A second experiment examined possible state-dependent effects of caffeine by administering caffeine (30 mg/kg) or vehicle 15 min before conditioning and before testing. RESULTS: Pretreatment of acute caffeine severely impaired the acquisition of context conditioning, a hippocampal-dependent task. Tone conditioning, a hippocampal-independent task, was only modestly and non-significantly affected by caffeine (4-21% suppression compared with controls). The disruption of context conditioning was dose-dependent: 10 mg/kg had little effect on context or tone conditioning, whereas doses of 20 and 30 mg/kg caffeine severely disrupted context conditioning (73-87% suppression). In two subsequent experiments, it was found that caffeine's selective disruption of context conditioning could not be attributed to the fact that it is a weaker form of learning than tone conditioning or to state-dependent learning. CONCLUSIONS: Considered together, these results suggest that acute administration of caffeine may preferentially disrupt the acquisition of hippocampal-dependent learning, including context conditioning.

Animals↗
PubMedDate not supplied

Improvements in hippocampal-dependent learning and decremental attention in 5-HT(3) receptor overexpressing mice.

The 5-HT3 receptor for serotonin is expressed within limbic structures and is known to modulate neurotransmitter release, suggesting that this receptor may influence learning and memory. Perturbations in serotonergic neurotransmission lead to changes in the ability to attend, learn, and remember. To examine the role of 5-HT3 receptors in learning, memory, and attention, 5-HT3 receptor overexpressing (5-HT3-OE) transgenic mice and their wild-type littermates (WT) were tested in Pavlovian contextual and cued fear conditioning, fear extinction, and latent inhibition (LI) paradigms. Prepulse inhibition (PPI) was assessed to reveal changes in sensorimotor gating. Additionally, anxious behaviors, shock sensitivity, and reactions to novel stimuli were evaluated. 5-HT3-OE mice displayed enhanced contextual conditioning, whereas cued conditioning remained the same as that of WT mice. 5-HT3-OE mice did not differ from WT in extinction rates to either the context or cue. LI was enhanced for 5-HT3-OE mice compared to WT. PPI remained unchanged. No differences in sensitivity to footshock or startle were found. However, 5-HT3-OE mice demonstrated heightened exploratory behavior in response to novel environmental stimuli and decreased anxiety as measured in the elevated plus-maze. Results indicate that overexpression of the 5-HT3 receptor in mouse forebrain results in enhanced hippocampal-dependent learning and attention. Enhanced inspective behavior in response to novelty may contribute to the observed improvements in learning, memory, and attention due to 5-HT3 receptor overexpression.

Acoustic Stimulation↗
PubMed2006

Opioid receptors regulate retrieval of infant fear memories: effects of naloxone on infantile amnesia.

The authors examined the role of the endogenous opioid system in infantile amnesia for contextual fear conditioning. Rats that were 18 days of age received an aversive footshock in a novel context. Rats displayed conditioned fear when tested 1 min after training but not 24 hr after training. Systemic injection of the opioid receptor antagonist naloxone prior to test, but not immediately after training, alleviated infantile amnesia. Naloxone also alleviated infantile amnesia when injected prior to test 7 days after training. These effects of naloxone were due to actions on central rather than peripheral opioid receptors and were not due to any tendency of the drug to produce fear or freezing. These results show that central opioid receptors regulate retrieval of fear memories in infant rats.

Amnesia↗
PubMed1994

Intra-amygdaloid projections of the lateral nucleus in the cat: PHA-L anterograde labeling combined with postembedding GABA and glutamate immunocytochemistry.

Research on the implication of the amygdala in classical fear conditioning suggests that the central amygdaloid nucleus is the output station of the amygdala for conditioned fear responses, while the lateral nucleus acts as the input nucleus, at least for auditory conditioned stimuli. However, the nature and locus of the plastic changes taking place between these two nuclei are unknown partly because the neurotransmitter(s) used by intra-amygdaloid projections of the lateral nucleus has not been identified. To address this issue in cats, anterograde tracing with Phaseolus vulgaris-leucoagglutinin (PHA-L) was combined with postembedding immunocytochemistry for gamma-aminobutyric acid (GABA) and glutamate. Two sectors can be recognized in the lateral nucleus of the cat: a shell located laterally along the external capsule, and a core. Iontophoretic injections of PHA-L in these two sectors revealed that they have nonoverlapping intra-amygdaloid targets with the exception of a common projection to the central lateral nucleus. The core projects mainly to itself and to the basomedial nucleus, whereas the shell contributes a massive projection to the basolateral nucleus. No projection of the lateral nucleus to the central medial nucleus was found. Electron microscopically, PHA-L-labeled axon terminals in the lateral, basomedial, basolateral, and central lateral nuclei as well as in the perirhinal and insular cortices formed asymmetric synapses (100%; n = 289) with dendritic spines (77-100%). Moreover, postembedding immunocytochemistry revealed that PHA-L-labeled axon terminals are immunoreactive for glutamate but not GABA. Since most amygdaloid projections to the brainstem originate in the central medial nucleus, these results suggest that intra-amygdaloid targets of the lateral nucleus are involved in the transmission of auditory conditioned stimuli to the central medial nucleus. Moreover, these findings imply that intra-amygdaloid projections of the lateral nucleus use glutamate but not GABA as a neurotransmitter.

Amygdala↗
PubMed2002

Kainic acid lesions disrupt fear-mediated memory processing.

Previous research has shown that hippocampal lesions impair the expression of fear conditioning. This fear conditioning deficit may be due to memory impairment or a reduction in fear in lesioned animals. To address these possibilities, the authors examined unconditioned and conditioned fear in male Sprague-Dawley rats that had received intracerebroventricular (ICV) infusions of kainic acid (KA) 30 days prior to testing. Animals that had received bilateral ICV infusions of KA (1.0 microl of 0.8 mg/ml solution per side) exhibited cell loss that was primarily confined to the CA3 region of the dorsal hippocampus. Kainic acid lesions impaired contextual and cued fear conditioning but did not affect unconditioned fear in a light:dark test of anxiety. Moreover, animals with KA lesions did not habituate to the light:dark apparatus when tested over a 3-day period. These data suggest that decreases in fear conditioning produced by hippocampal lesions reflect a memory deficit and not a lack of fear.

Animals↗
PubMed1996

Hippocampal-dependent learning and experience-dependent activation of the hippocampus are preferentially disrupted by ethanol.

A classical fear conditioning paradigm was used to examine the effect of acute ethanol on the acquisition of context conditioning, a hippocampal-dependent associative task, and tone conditioning, a hippocampal-independent task. Administration of ethanol before the presentation of seven tone-shock pairings severely disrupted the acquisition of context conditioning, but had only a slight effect on tone conditioning, when conditioned fear was measured 48 h later. This effect was dose dependent: a dose of 0.5 g/kg had no effect on either context or tone conditioning, while doses of 1.0 and 1.5 g/kg disrupted context conditioning by 78-86%, and tone conditioning by 9-17%. Subsequent experiments indicated that ethanol's preferential effect on context conditioning could not be attributed to the fact that context conditioning is weaker than tone conditioning, ethanol-induced changes in motivational state or state-dependent learning. The effect of ethanol on stimulus-induced increases in hippocampal and neocortical expression of c-fos mRNA, a marker for changes in metabolic neuronal activity, was also examined. Ethanol completely blocked the induction of hippocampal c-fos mRNA by exposure to the conditioning context alone or seven tone-shock pairings, but only attenuated neocortical responses to these stimuli. Together, these results suggest that ethanol disrupts hippocampal-dependent learning by preferentially impairing stimulus processing at the level of the hippocampus.

Animals↗
PubMed2003

Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning.

Corticotropin-releasing factor (CRF) exerts a key neuroregulatory control on stress responses in various regions of the mammalian brain, including the hippocampus. Using hippocampal slices, extracts, and whole animals, we investigated the effects of human/rat CRF (h/rCRF) on hippocampal neuronal excitability and hippocampus-dependent learning in two mouse inbred strains, BALB/c and C57BL/6N. Intracellular recordings from slices revealed that application of h/rCRF increased the neuronal activity in both mouse inbred strains. Inhibition of protein kinase C (PKC) by bisindolylmaleimide I (BIS-I) prevented the h/rCRF effect only in hippocampal slices from BALB/c mice but not in slices from C57BL/6N mice. Inhibition of cAMP-dependent protein kinase (PKA) by H-89 abolished the h/rCRF effect in slices from C57BL/6N mice, with no effect in slices from BALB/c mice. Accordingly, h/rCRF elevated PKA activity in hippocampal slices from C57BL/6N mice but increased only PKC activity in the hippocampus of BALB/c mice. These differences in h/rCRF signal transduction were also observed in hippocampal membrane suspensions from both mouse strains. In BALB/c mice, hippocampal CRF receptors coupled to G(q/11) during stimulation by h/rCRF, whereas they coupled to G(s), G(q/11), and G(i) in C57BL/6N mice. As expected on the basis of the slice experiments, h/rCRF improved context-dependent fear conditioning of BALB/c mice in behavioral experiments, and BIS-I prevented this effect. However, although h/rCRF increased neuronal spiking in slices from C57BL/6N mice, it did not enhance conditioned fear. These results indicate that the CRF system activates different intracellular signaling pathways in mouse hippocampus and may have distinct effects on associative learning depending on the mouse strain investigated.

Animals↗
PubMed2006

Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behaviour in C57BL6 mice.

The present study tested whether individual differences in anxiety- and fear-related behaviour are associated with between-subjects variation in postmortem brain levels of selected neurotrophic factors. Naïve C57BL6/J mice of both sexes were subjected either to an elevated plus maze test or to a Pavlovian fear conditioning paradigm. Two days after behavioural assays, the mice were sacrificed for postmortem quantification of the protein levels of brain derived neurotrophic factors (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) in the hippocampus and amygdala. Significant correlations between behavioural measures and postmortem regional neurotrophic factor contents were revealed. The magnitude of anxiety-like behaviour in the elevated plus maze was positively related to dorsal hippocampal BDNF levels, but negatively related to NGF levels in dorsal hippocampus and in the amygdala. On the other hand, the expression of conditioned fear is positively related to amygdala BDNF and NGF levels, and to dorsal hippocampal NGF levels. Our results add to existing reports in human as well as in animals of correlation between anxiety trait and gross measures of hippocampal volume or activation levels. Moreover, a distinction between spontaneous and learned (or conditioned) anxiety/fear would be relevant to the identification of neurotrophin signalling mechanisms in the hippocampus and amygdala implicated in anxiety and related psychopathology.

Amygdala↗
PubMed2000

Age-related modifications of contextual information processing in rats: role of emotional reactivity, arousal and testing procedure.

Two experiments were conducted to examine contextual information processing in adult (7 months) and aged (22 months) Wistar rats. In Experiment 1, rats were tested for contextual fear conditioning when exposed to six series, one per day, of ten pairings of a tone (CS) with a foot-shock (US) delivered in one of a two-compartment apparatus. Conditioned fear was estimated by recording: (1) the amount of freezing in the shock compartment; and (2) the time spent avoiding the shock compartment. Results show that, after only one series of ten CS-US pairings, all rats showed freezing in the shock compartment, with aged rats exhibiting the stronger response. Adult rats also avoided the shock compartment during place preference tests in contrast to aged rats, that spent an equivalent time - with an intense freezing reaction - in both the shock and the safe compartments. After 60 CS-US pairings, contextual freezing in the shock compartment decreased in both groups, but, contrary to adults, aged rats were still not avoiding that compartment. In Experiment 2, radial maze performance was studied under distinct quantitative extra-maze cueing conditions (poor versus rich) and successive context shifts. Compared to adults, aged rats were impaired when trained initially under poor cueing conditions. No group difference was evident when rats were transferred to a context involving more cues (rich cueing conditions), but age-related impairments re-emerged when rats were returned to the original poor cueing conditions. Thus, the fact that performance deficits in a given task were restricted to certain testing procedures suggests that aging affects more the utilization than the processing of contextual information.

Aging↗
PubMed2001

Conditioned antinociception and freezing using electrical stimulation of the dorsal periaqueductal gray or inferior colliculus as unconditioned stimulus are differentially regulated by 5-HT2A receptors in rats.

RATIONALE: Electrical stimulation of the dorsal periaqueductal gray matter (dPAG) and the inferior colliculus (IC) has been used as an aversive unconditioned stimulus. However, studies on the behavioral, sensorial and autonomic components of the conditioned fear elaborated in the midbrain tectum are lacking. OBJECTIVES: This study was undertaken to investigate the nature of the aversiveness of stimulation of the dPAG and IC as well as the modulation by 5-HT mechanisms of the fear conditioned responses to these stimulations. METHODS: Animals chronically implanted with an electrode glued to a guide cannula into the dPAG or the IC were submitted to one, two or three sessions of conditioning. Each session consisted of ten pairings of the light in a distinctive chamber (CS) with the electrical stimulation of one of these regions at the escape threshold determined previously. Control groups were submitted to the same procedure, except for the conditioning sessions in which the conditioned stimuli were presented alone in one case and performed in a different context in the other. On the next day, each animal was exposed only to the CS (testing) and the duration of freezing, number of rearings, grooming, bouts of micturition and fecal boli were recorded for 5 min. Before and after the testing session, the animals were submitted to the tail-flick test. RESULTS: The data showed that the conditioning with electrical stimulation of the dPAG and the IC caused significant increases in the time of freezing, defecation and micturition, and significant reductions in the number of rearings and grooming. On the other hand, only the conditioning with electrical stimulation of the dPAG produced significant conditioned antinociception. Microinjections of methysergide, a non-specific antagonist of 5-HT receptors, or ketanserin, an antagonist of 5-HT2A receptors, into the dPAG before testing significantly inhibited the antinociception without affecting any of the behavioral or autonomic conditioned responses. CONCLUSIONS: 1) Conditioned freezing may be produced using the electrical stimulation of the dPAG or IC as unconditioned stimuli, 2) only the pairing of CS plus dPAG but not with IC stimulation, produces significant conditioned antinociception, 3) blockade of 5-HT2A receptors inhibits conditioned antinociception but not the conditioned defensive behavior using the electrical stimulation of the dPAG as unconditioned stimulus.

Animals↗
PubMed2003

A robust animal model of state anxiety: fear-potentiated behaviour in the elevated plus-maze.

Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.

Animals↗
PubMed2005

Functional correction of CNS phenotypes in a lysosomal storage disease model using adeno-associated virus type 4 vectors.

Lysosomal storage diseases (LSDs) represent a significant portion of inborn metabolic disorders. More than 60% of LSDs have CNS involvement. LSD therapies for systemic diseases have been developed, but efficacy does not extend to the CNS. In this study, we tested whether adeno-associated virus type 4 (AAV4) vectors could mediate global functional and pathological improvements in a murine model of mucopolysaccharidosis type VII (MPS VII) caused by beta-glucuronidase deficiency. Recombinant AAV4 vectors encoding beta-glucuronidase were injected unilaterally into the lateral ventricle of MPS VII mice with established disease. Transduced ependyma expressed high levels of recombinant enzyme, with secreted enzyme penetrating cerebral and cerebellar structures, as well as the brainstem. Immunohistochemical studies revealed close association of recombinant enzyme and brain microvasculature, indicating that beta-glucuronidase reached brain parenchyma via the perivascular spaces lining blood vessels. Aversive associative learning was tested by context fear conditioning. Compared with age-matched heterozygous controls, affected mice showed impaired conditioned fear response and context discrimination. This behavioral deficit was reversed 6 weeks after gene transfer in AAV4 beta-glucuronidase-treated MPS VII mice. Our data show that ependymal cells can serve as a source of enzyme secretion into the surrounding brain parenchyma and CSF. Secreted enzymes subsequently spread via various routes to reach structures throughout the brain and mediated pathological and functional disease correction. Together, our proof-of-principal experiments suggest a unique and efficient manner for treating the global CNS deficits in LSD patients.

Animals↗
PubMed2006

Neurotoxic lesions of the dorsal and ventral hippocampus impair acquisition and expression of trace-conditioned fear-potentiated startle in rats.

Pavlovian delay conditioning, in which a conditioned stimulus (CS) and unconditioned stimulus (US) co-terminate, is thought to reflect non-declarative memory. In contrast, trace conditioning, in which the CS and US are temporally separate, is thought to reflect declarative memory. Hippocampal lesions impair acquisition and expression of trace conditioning measured by the conditioned freezing and eyeblink responses, while having little effect on the acquisition of delay conditioning. Recent evidence suggests that lesions of the ventral hippocampus (VH) impair conditioned fear under conditions in which dorsal hippocampal (DH) lesions have little effect. In the present study, we examined the time-course of fear expression after delay and trace conditioning using the fear-potentiated startle (FPS) reflex, and the effects of pre- and post-training lesions to the VH and DH on trace-conditioned FPS. We found that both delay- and trace-conditioned rats displayed significant FPS near the end of the CS relative to the unpaired control group. In contrast, trace-conditioned rats displayed significant FPS throughout the duration of the trace interval, whereas FPS decayed rapidly to baseline after CS offset in delay-conditioned rats. In experiment 2, both DH and VH lesions were found to significantly reduce the overall magnitude of FPS compared to the control group, however, no differences were found between the DH and VH groups. These findings support a role for both the DH and VH in trace fear conditioning, and suggest that the greater effect of VH lesions on conditioned fear might be specific to certain measures of fear.

Animals↗
PubMed1992

Involvement of pertussis toxin sensitive G-proteins in conditioned fear-potentiated startle: possible involvement of the amygdala.

The present study evaluated the effects of intraventricular or intracerebral administration of pertussis toxin on fear-potentiated startle (a measure of conditioned fear) and shock sensitization (a measure of unconditioned fear). In Experiment 1 all animals were unilaterally implanted with cannulae into the lateral ventricle 1 week prior to 2 days of fear conditioning (ten light-shock pairings on each of 2 days). Five days later, animals were infused with either 1 microgram pertussis toxin or saline and tested for fear-potentiated startle 24 h after infusion and tested for shock sensitization 26 or 50 h after infusion. Pertussis toxin blocked the ability of a light conditioned stimulus to facilitate startle but did not alter the ability of acute footshock to increase startle amplitude in the same animals. In Experiment 2 bilateral infusion of 1 microgram pertussis toxin into the basolateral nuclei of the amygdala, but not the interpositus nuclei of the cerebellum, also blocked fear-potentiated startle when animals were tested 6 h after infusion. These findings suggest a role for pertussis toxin sensitive G-proteins, perhaps within the amygdala, in the expression of conditioned but not unconditioned fear.

Acoustic Stimulation↗
PubMed1998

Conditioned fear-induced tachycardia in the rat: vagal involvement.

The effects of conditioned fear on gross activity, heart rate, PQ interval, noradrenaline and adrenaline were studied in freely moving rats. Subcutaneous (s.c.) injections of atropine methyl nitrate (0.5 mg/kg) during rest resulted in a significant shortening of the PQ interval, indicating that the PQ interval can be used as a measure of vagal activity. Conditioned fear was induced by 10-min forced exposure to a cage in which the rat had previously experienced footshocks (5 x 0.5 mA x 3 s). In non-shocked controls, an increase in gross activity was found and a pronounced tachycardia, without changes in PQ interval. Conditioned fear rats showed immobility behaviour, associated with a less pronounced tachycardia and an increase in PQ interval. Noradrenaline was similarly increased in both groups, whereas adrenaline was increased in conditioned fear rats only. To further evaluate the role of the vagus, rats were exposed to conditioned fear after pre-treatment with atropine methyl nitrate (0.5 mg/kg, s.c.). Again, immobility was observed with a concomitant tachycardia, but without an increase in PQ interval. These results indicate that the autonomic nervous system is differentially involved in heart rate regulation in conditioned fear rats and in non-shocked controls: in non-shocked controls a predominant sympathetic nervous system activation results in an increase in heart rate, whereas in conditioned fear rats the tachycardiac response is attenuated by a simultaneous activation of sympathetic nervous system and parasympathetic nervous system.

Animals↗
PubMed2002

Clonidine injections into the lateral nucleus of the amygdala block acquisition and expression of fear-potentiated startle.

Numerous studies of aversive learning with different animal models have shown that the noradrenergic system has an important role in the acquisition, consolidation and expression of aversive learning. We used intracerebral clonidine injections to investigate the role of the noradrenergic amygdaloid system in the fear-potentiated startle paradigm. Clonidine is a noradrenergic alpha2-receptor agonist which can decrease noradrenergic transmission by stimulating presynaptic alpha2-receptors. Rats received injections of 0, 2.5, 5 and 10 nmol clonidine into the lateral amygdala (i) before fear-conditioning, (ii) immediately after fear-conditioning, (iii) before testing and (iv) before both fear-conditioning and the testing of conditioned fear. Clonidine injections blocked the acquisition and expression of conditioned fear. The effect on acquisition was not caused by state-dependency or possible side-effects of clonidine on consolidation. Given that clonidine decreases amygdaloid noradrenaline release, these results show a crucial role of noradrenergic transmission within the amygdala in classical fear-conditioning. Surprisingly, both the acquisition and the expression of conditioned fear were blocked after amygdaloid injections of clonidine, suggesting that amygdaloid noradrenaline is necessary to induce both unconditioned and conditioned fear.

Acoustic Stimulation↗
PubMed2006

A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear.

The pathomechanisms of posttraumatic stress disorder (PTSD) are still unknown, but both fear conditioning and stress sensitisation are supposed to play a crucial role. Hence, valid animal models that model both associative and non-associative components of fear will facilitate elucidation of the biological substrates of the illness, and to develop novel and specific approaches for its prevention and therapy. Here we applied a single electric footshock to C57BL/6N (B6N) and C57BL/6JOla (B6JOla) mice and recorded the conditioned response to contextual trauma reminders (associative fear), the sensitised reaction to a neutral tone in a novel environment (non-associative fear, hyperarousal), social interaction and various emotional behaviours using Modified Holeboard, Test for Novelty-Induced Suppression of Feeding and Forced Swimming Test, after different incubation times (1, 14, 28 days). Freezing generally increased as a function of shock intensity. In B6N mice, sensitised fear was maximal 28 days after trauma and was accompanied by signs of emotional blunting and social withdrawal. B6JOla mice, in contrast, were less susceptible to develop PTSD-like symptoms. The phenotype of B6N exhibited high behavioural variance, allowing distinction between vulnerable and resilient individuals. Only in vulnerable B6N mice, chronic fluoxetine treatment - initiated after an incubation period of 28 days - ameliorated sensitised fear. This new mouse model fulfils common criteria for face and predictive validity and can be used to investigate the biological correlates of individual fear susceptibility, as well as the impact and interrelationship of associative and non-associative fear components in the development and maintenance of PTSD.

Administration, Oral↗