The effects of sex and neonatal maternal separation on fear-potentiated and light-enhanced startle

This study was based on the higher prevalence of anxiety disorders in women than in men, and on the finding that early adverse experiences are a major risk factor for the development of anxiety disorders later in life. The object of this study was to investigate in rats, the sensitivities of the light-enhanced startle (LES) and fear-potentiated startle (FPS) paradigms to sex differences and to determine the effects of maternal separation (MS) on the baseline startle magnitude and potentiated startle response in these paradigms. Pups in the MS group were separated daily from their mother for 180 min/day from postnatal day 2 (PND2) to PND14. Control litters remained undisturbed. The adult male and female progeny were tested in the FPS and LES. As predicted, females showed a significantly greater potentiation of startle than males in the FPS, and a strong trend towards greater startle potentiation in the LES. Contrary to predictions, MS had no effect on startle potentiation in the FPS and severely disrupted LES in female, but not male rats. The observed sex differences add to the validity of the FPS and LES as animal paradigms of fear and anxiety. The findings indicate that these paradigms can be used to study the biological basis of sex differences in fear and anxiety. In contrast, the effects of MS on startle potentiation argue against the idea that MS provides a robust model for the predicted influences of early adverse effects on these startle potentiation measures of fear and anxiety.     

Light-enhanced and fear-potentiated startle: temporal characteristics and effects of alpha-helical corticotropin-releasing hormone.

BACKGROUND: It has been suggested that the light-enhanced startle paradigm (LES) is an animal model for anxiety, because of the unconditioned and nonspecific cue and the long-term effect. In contrast, the fear-potentiated startle (FPS) is suggested to model fear. In the present study, we assessed in detail the time course of LES and FPS and investigated whether corticotropin-releasing hormone (CRH) is differentially involved in these two models. METHODS: In experiment 1, the amplitude of the startle response was tracked in the presence of the light and after light offset, in both models. In experiment 2, the effects of intracerebroventricular administration of the CRH-receptor antagonist alpha-helical CRH (0, 1, 5, and 25 microg) on LES and FPS were studied. RESULTS: In LES, light onset resulted in a long-lasting potentiation of the startle response and a slow return to baseline after light offset. In FPS, the potentiation of the startle response returned to baseline almost immediately after light offset. Alpha-helical CRH reduced the potentiation in LES at the 5-microg dose but not at 25 microg. In FPS, alpha-helical CRH had no effect. CONCLUSIONS: The results show that the time course of LES is markedly different from that of FPS, which together with the differences in eliciting stimuli suggest that they model anxiety and fear, respectively. Moreover, the results suggest that CRH is involved in LES and not in FPS.     

Cortisol suppression by dexamethasone reduces exaggerated fear responses in posttraumatic stress disorder

PTSD symptoms are associated with heightened fear responses in laboratory fear conditioning paradigms. This study examined the effects of dexamethasone administration on hypothalamic-pituitary-adrenal (HPA) function and fear-potentiated startle (FPS) in trauma-exposed individuals with and without PTSD. We used an established fear discrimination procedure, in which one visual stimulus (CS+, danger cue) was paired with aversive airblasts to the throat (unconditioned stimulus, US), and another stimulus (CS-, safety cue) was presented without airblasts. In addition to FPS, the dexamethasone suppression test (DST) was performed. The study sample (N=100) was recruited from a highly traumatized civilian population in Atlanta, GA. Half of the subjects (n=54, 16 PTSD, 38 controls) underwent conditioning at baseline and the other half (n=46, 17 PTSD, 29 controls) after DST, in a cross-sectional design. We found a significant interaction effect of diagnostic group and dexamethasone treatment. Under baseline conditions, subjects with PTSD showed more than twice as much fear-potentiated startle to the danger cue compared to traumatized controls, F(1,53)=8.08, p=0.006. However, there was no group difference in subjects tested after dexamethasone suppression. Furthermore, there was a significant treatment effect in PTSD subjects but not in controls, with dexamethasone reducing fear-potentiated startle to the CS+, F(1,32)=4.00, p=0.05. There was also a positive correlation between PTSD subjects' FPS and cortisol levels, r=0.46, p=0.01. These results suggest that transient suppression of HPA function via dexamethasone suppression may reduce exaggerated fear in patients with PTSD.     

Tools for translational neuroscience: PTSD is associated with heightened fear responses using acoustic startle but not skin conductance measures

Background: Posttraumatic stress disorder (PTSD) patients show heightened fear responses to trauma reminders and an inability to inhibit fear in the presence of safety reminders. Brain imaging studies suggest that this is in part due to amygdala over‐reactivity as well as deficient top‐down cortical inhibition of the amygdala. Consistent with these findings, previous studies, using fear‐potentiated startle (FPS), have shown exaggerated startle and deficits in fear inhibition in PTSD participants. However, many PTSD studies using the skin conductance response (SCR) report no group differences in fear acquisition. Method: The study included 41 participants with PTSD and 70 without PTSD. The fear conditioning session included a reinforced conditioned stimulus (CS+, danger cue) paired with an aversive airblast, and a nonreinforced conditioned stimulus (CS?, safety cue). Acoustic startle responses and SCR were acquired during the presentation of each CS. Results: The results showed that fear conditioned responses were captured in both the FPS and SCR measures. Furthermore, PTSD participants had higher FPS to the danger cue and safety cue compared to trauma controls. However, SCR did not differ between groups. Finally, we found that FPS to the danger cue predicted re‐experiencing symptoms, whereas FPS to the safety cue predicted hyper‐arousal symptoms. However, SCR did not contribute to PTSD symptom variance. Conclusions: Replicating earlier studies, we showed increased FPS in PTSD participants. However, although SCR was a good measure of differential conditioning, it did not differentiate between PTSD groups. These data suggest that FPS may be a useful tool for translational research. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc.     

Fear conditioning in virtual reality contexts: a new tool for the study of anxiety.

BACKGROUND: Context conditioning has been suggested to model clinical anxiety, but context, as manipulated in animal models, has not been translated to human studies. A virtual environment might prove to be the ideal tool for innovative experimental paradigms to study explicitly cued fear and contextual anxiety in humans. METHODS: Subjects were guided through a virtual environment that consisted of two rooms connected by a street scene. In each of the rooms, a blue and a yellow panel on a wall served as explicit conditioned stimuli (CS). The panels were displayed several times. One of the panels (CS+) was associated with a shock in one of the rooms (shock room). No shock was administered in the other room (safe room). Acoustic startle stimuli were administered in the presence and in the absence of the panels to assess explicit cued conditioning to the CS and context conditioning to the rooms, respectively. RESULTS: Startle was potentiated by the CS+ in both rooms, which suggests generalization of fear across contexts. After acquisition, startle was potentiated in the shock room, compared with the safe room, in the absence of the CS+. CONCLUSIONS: These results support the future use of virtual reality to design new conditioning experiments to study both fear and anxiety.     

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.     

Differential regulation of the expression of contextual freezing and fear-potentiated startle by 5-HT mechanisms of the median raphe nucleus

It has previously been shown that the median raphe nucleus (MR) is one of the main sources of projections to the septum and hippocampus. 5-HT projections from this nucleus to the hippocampus are implicated in the acquisition and expression of contextual fear (background stimuli), as assessed by freezing. It has also been reported that amygdala is involved in the acquisition of conditioned fear to foreground cues such as light, used as CS. As the MR projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to contextual and classical fear conditioning remains to be elucidated. The present study examined the involvement of the MR serotonergic mechanisms in the expression of two distinct types of conditioned fear responses: contextual freezing and fear conditioning to explicit cue (light) measured in a fear-potentiated startle (FPS) procedure. Animals received MR electrolytic lesions of or microinjections of 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino tetralin) (1 microg/0.2 microl) into the MR, 1 or 7 days after two consecutive training sessions in which they received 10 pairings of the CS (light, 4 s)-US (foot-shocks 0.6 mA, 1s) and were tested in a contextual fear paradigm and in a FPS procedure. The startle was clearly potentiated in the presence of light-CS in animals bearing lesions of or microinjected with 8-OH-DPAT into MR at 1 or 7 days post-training. However, animals bearing MR electrolytic lesions or microinjections of 8-OH-DPAT into the MR at 1 day, but not at 7 days post-training, showed a significant decrease in time spent in freezing than control ones. Thus, the memory for contextual conditioned fear seems to be formed during a time-window shorter than 1 week. As FPS may be produced in lesioned rats unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, the production of contextual freezing and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN.     

Influence of age on reactivity to diverse emotional challenges in low- and high-anxiety rats

Studies have revealed that the extent of reactivity of high-anxiety rats to diverse challenges is different than low-anxiety rats and have provided important insights into the psychopathology of anxiety. Various factors intervene to allow defensive mechanisms to react to diverse threatening challenges, including ontogeny and the nature of the emotional challenge (e.g., conditioned vs. unconditioned). The present study investigated the extent to which a particular type of fear extrapolates to other emotional responses to diverse threatening challenges. Groups of 30- and 60-day-old rats were assigned to low freezing behavior (LFB) and high freezing behavior (HFB) groups using the contextual fear conditioning paradigm and subjected to either the fear-potentiated startle (FPS) test, novelty-induced ultrasound vocalizations (USVs) or elevated plus-maze (EPM) tests. At 30 days of age, HFB rats exhibited greater FPS than LFB rats. In contrast, prior selection of HFB and LFB did not affect the performance of 30-day-old animals in the EPM and novelty-induced USVs. Sixty-day-old animals exhibited a performance deficit in all three tests. These data suggest that the performance of young rats in animal models of anxiety parallels their selection as LFB and HFB in the contextual fear conditioning paradigm. However, the increased fear-like behavior exhibited by the 60-day-old HFB rats may elicit performance deficits in conditioned and unconditioned fear tests. These results suggest that the interaction between hyperanxiety and age may cause a performance deficit despite the animals’ increased fear-like behavior when facing emotional challenges, thus resembling psychiatric patients in many respects.     

Anxiogenic treatments do not increase fear-potentiated startle in mice.

BACKGROUND: In rodents, the fear-potentiated startle paradigm (FPS; exaggerated startle as a measure of the conditioned fear response to cues associated with footshock) has demonstrated predictive validity for anxiolytic drugs. The predictive validity of the model for anxiogenic drugs, however, remains unclear. Therefore, we evaluated the bi-directionality of the FPS model for anxiety-modulating compounds in mice. METHODS: The clinical anxiogenics FG-7142 (1-20 mg/kg), yohimbine (.1-10 mg/kg), and m-Chlorophenylpiperazine (mCPP; .3-3 mg/kg), and the putative anxiogenics atipamezole (.3-3 mg/kg) and corticotropin-releasing factor (h/r-CRF; .03-1 microg) were tested in DBA/1J mice trained for FPS. RESULTS: Contrary to predictions, FG-7142 (10 and 20 mg/kg) and yohimbine (10 mg/kg) reduced FPS in mice without affecting baseline startle. Atipamezole (3 mg/kg), mCPP (3 mg/kg), and h/r-CRF (.3, 1 microg) did not affect FPS, but increased startle independently from the presence of the cue. FG-7142 and h/r-CRF had similar effects in 129SvEv mice. CONCLUSIONS: Murine FPS is not bi-directionally predictive for anxiety-modulating compounds, although murine baseline startle may have some utility as a bi-directional model of anxiety. These data corroborate the recent hypothesis that systems mediating FPS are independent from systems mediating increased startle from unconditioned and putatively anxiogenic stimuli.     

Strain differences in anxiety-like behavior: association with corticotropin-releasing factor

The purpose of the current study was to relate basal corticotropin-releasing factor (CRF) mRNA level in the central nucleus of the amygdala (CeA) with anxiety-like behavior using three strains of rat reported to exhibit a range of behavioral and neuroendocrine responses to stress. Anxiety-like behavior was determined for Fischer (F344), Wistar, and Wistar-Kyoto (WKY) rats with an elevated plus-maze and CRF mRNA level was measured using in situ hybridization. WKY rats exhibited more anxiety-like behavior on the elevated plus-maze than both F344 (p's < 0.01) and Wistar rats (p's < 0.05). WKY rats had higher basal levels of CRF mRNA in the CeA than F344 rats (p < 0.05) with a trend toward higher levels than Wistar rats (p = 0.06). Wistar rats had similar indices of anxiety with F344 rats and comparable levels of CRF mRNA in the CeA. Basal plasma corticosterone was similar for all three strains and repeated experience with the plus-maze had no effect on basal corticosterone levels or CRF mRNA levels in the paraventricular nucleus of the hypothalamus (PVN) for Wistar or WKY rats. Consistent with reported hyperactivity of the hypothalamopituitary adrenal axis of F344 rats with repeated stress, we observed elevated corticosterone following repeated exposure to the elevated plus-maze in F344 rats (p < 0.01) with a trend toward increased CRF mRNA levels in the PVN (p = 0.09). Heightened expression of CRF in the CeA of WKY rats may be involved in anxiety-like behaviors observed in this strain.     

Selective involvement of GABAergic mechanisms of the dorsal periaqueductal gray and inferior colliculus on the memory of the contextual fear as assessed by the fear potentiated startle test

The inferior colliculus (IC) together with the dorsal periaqueductal gray (dPAG), the amygdala and the medial hypothalamus make part of the brain aversion system, which has mainly been related to the organization of unconditioned fear. However, the involvement of the IC and dPAG in the conditioned fear is still unclear. It is certain that GABA has a regulatory role on the aversive states generated and elaborated in these midbrain structures. In this study, we evaluated the effects of injections of the GABA-A receptor agonist muscimol (1.0 and 2.0 nmol/0.2 μL) into the IC or dPAG on the freezing and fear-potentiated startle (FPS) responses of rats submitted to a context fear conditioning. Intra-IC injections of muscimol did not cause any significant effect on the FPS or conditioned freezing but enhanced the startle reflex in non-conditioned animals. In contrast, intra-dPAG injections of muscimol caused significant reduction in FPS and conditioned freezing without changing the startle reflex in non-conditioned animals. Thus, intra-dPAG injections of muscimol produced the expected inhibitory effects on the anxiety-related responses, the FPS and the freezing whereas these injections into the IC produced quite opposite effects suggesting that descending inhibitory pathways from the IC, probably mediated by GABA-A mechanisms, exert a regulatory role on the lower brainstem circuits responsible for the startle reflex.     

Genetic strain differences in platelet aggregation and thrombus formation of laboratory rats

Rats are employed to investigate the role of platelets in thrombus formation under flow conditions in vivo and to evaluate the pre-clinical potential of antiplatelet drugs. While Wistar and Sprague-Dawley (SD) strains are commonly used in thrombosis models, a number of rat strains have been established. Each strain possesses genetically unique characteristics such as hypertension, hyperglycemia or hyperlipidemia. The appropriate selection of a strain might have advantages for physiological and pharmacological studies. Comparative investigation of platelet aggregation among laboratory strains of rats is useful for the development of thrombosis models. In the present study, platelet aggregation response in eight laboratory rat strains, ACI, Brown Norway (BN), Donryu, Fischer 344 (F344), LEW, SD, Wistar and WKAH, were compared. Considerable strain differences were observed in ADP-, collagen- and TRAP-induced platelet aggregation. SD and BN are high-platelet-aggregation strains, while F344 and ACI are low-response strains. In the arteriovenous shunt thrombosis model, SD formed larger thrombi than F344 and Wistar rats. In the FeCl(3)-induced thrombosis model with the carotid artery, the time to occlusion of SD was significantly shorter than of F344 and ACI rats. F344 and ACI rats had significantly increased bleeding times compared with SD rat. The present study demonstrates that there are considerable strain differences in platelet aggregation among laboratory rats, which reflect thrombus formation.     

Variation in visual acuity within pigmented,and between pigmented and albino rat strains

Many researchers assume that laboratory rats have poor vision, and accordingly, that they need not consider differences in the visual function of rats as a consequence of strain or experience. Currently, it is not specifically known whether rat domestication has negatively affected the visual function of laboratory rat strains, what the effects of strain albinism are on rat visual function, or whether there are strain differences in the visual function of laboratory rats that are independent of pigmentation. In order to address these questions, we measured psychophysically the vertical grating acuity of three pigmented (Dark Agouti, Fisher-Norway, Long-Evans) and three albino (Fisher-344, Sprague-Dawley, Wistar) strains of laboratory rats, and compared their acuity with that of wild rats. The grating thresholds of Dark Agouti, Long-Evans and wild strains clustered around 1.0 cycle/degree (c/d) and did not significantly differ from one another. Fisher-Norway rats, however, had a significantly higher threshold of 1.5 c/d. The grating thresholds of Fisher-344, Sprague-Dawley, and Wistar strains, which were clustered around 0.5 c/d, were significantly lower than those of the pigmented strains. These data demonstrate that there is significant strain variability in the visual function of laboratory rats. Domestication of Long-Evans and Dark Agouti strains does not appear to have compromised visual acuity, but in the case of Fisher-Norway rats, selective breeding may have enhanced their acuity. Strain selection associated with albinism, however, appears to have consistently impaired visual acuity. Therefore, a consideration of strain differences in visual function should accompany the selection of a rat model for behavioral tasks that involve vision, or when comparing visuo-behavioral measurements across rat strains.     

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.     

Phenytoin normalizes exaggerated fear behavior in p-chlorophenylalanine (PCPA)-treated rats

Temporal lobe epilepsy may be associated with emotional difficulties such as depression and anxiety. Because the amygdala is involved in both epilepsy and emotion, common neural mechanisms in this temporal lobe structure may underlie the emotional disturbances observed in people with epilepsy. The neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) is implicated in many psychopathologies, and 5-HT also modulates amygdala excitability. Therefore, the present study uses the fear-potentiated startle (FPS) paradigm to investigate the effect of neuronal excitability on fear behavior in rats treated with p-chlorophenylalanine (PCPA) to chronically inhibit 5-HT synthesis. PCPA treatment selectively enhanced FPS in individually housed rats. The exaggerated FPS response was reduced to control level by the anticonvulsant phenytoin at 10mg/kg, and phenytoin at 30mg/kg further decreased FPS behavior. These data suggest that a subseizure state of neuronal excitability mediated by low 5-HT in brain fear circuits may be associated with pathological fear behavior.     

Associative learning deficits increase symptoms of anxiety in humans.

BACKGROUND: Unpredictability has been postulated to be fundamental to anxiety and mood disorders. The origin of this unpredictability remains obscure. Because classical conditioning promotes predictability, this study investigated whether failure to learn conditioned stimulus (CS)-unconditioned stimulus (US) relationship during fear conditioning increased anxiety and avoidance. METHODS: Healthy subjects participated in two similar differential fear conditioning sessions separated by 1 week (n = 72) or a month (n = 61) in which one of two conditioned stimuli was associated with a shock/US. Following initial acquisition, subjects' awareness of CS-US relationship was assessed. Conditioned responses (CR) to the CS and to the experimental context were examined using the startle reflex and the skin conductance. Avoidance was operationally defined as failure to return for the second session. RESULTS: Only aware subjects showed differential CR. In the unaware subjects, the deficit in differential conditioning was associated with increased signs of anxiety during the first and second sessions. In addition, there was greater avoidance in the unaware subjects. CONCLUSIONS: Deficits in explicit cue fear conditioning can enhance anxiety. These findings are consistent with theories that associate anxiety and mood disorders with perceived unpredictability. Contextual conditioning models may be relevant to study chronic forms of anxiety.     

Nicotine enhances trace cued fear conditioning but not delay cued fear conditioning in C57BL/6 mice

Nicotine facilitates hippocampus-dependent contextual but not hippocampus-independent cued delay fear conditioning. To test if the effects of nicotine are specific to contextual fear conditioning or would extend to another hippocampus-dependent version of fear conditioning, we compared the effects of nicotine on cued delay and cued trace fear conditioning in male and female C57BL/6 mice. Unlike cued delay fear conditioning, cued trace fear conditioning is hippocampus dependent. Thus, if nicotine enhances hippocampus-dependent fear conditioning, nicotine should enhance trace fear conditioning. For both trace and delay conditioning, five 30 s, 85 dB white noise conditioned stimuli (CS) were paired with five 2 s, 0.5 mA footshock unconditioned stimuli (US). In the trace paradigm, a 30-s period was inserted between CS offset and US onset. The CS and US co-terminated in the delay paradigm. Testing occurred 24 h later. The data indicate that nicotine (given on training and testing day) enhances trace but not delay cued fear conditioning. No sex differences were found. For delay cued fear conditioning a high level of freezing to the CS was found. Thus, a second experiment examined if the lack of enhancement of delay cued fear conditioning by nicotine was due to a ceiling effect. The CS duration was decreased to 15 s and only one CS-US pairing was used for delay and trace cued fear conditioning. Although overall levels of freezing to the cue were lower in the second experiment, nicotine still enhanced trace fear conditioning but did not enhance delay fear conditioning. Taken together, the results of the present experiments suggest that nicotine enhances hippocampus-dependent versions of fear conditioning.     

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans

Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non‐epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike‐wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety‐like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety‐like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.     

The effect of long context exposure on cued conditioning and c-fos expression in the rat forebrain

The c-fos expression was used to study the neural substrates of the cued fear conditioning acquisition, preceded by a short exposure versus a long exposure to the conditioning context. A long-context exposure (either during the night or during the day) prior to conditioning, was associated with low freezing in the learning test. Differences in the c-fos expression of CA1, CA3, BL Amygdala, LS and BNST were found between the short- or long-context groups with a pre-exposure before cued conditioning. Ce Amygdala showed no differences in the c-fos expression labeling. We reported the hippocampal c-fos activation during the cued fear conditioning acquisition. Specifically, the CA1 activation could be related with the context-US processing during the CS-US association acquisition, which might prove that the CS-US associations cannot be made without an integrated context participating. The results showed that a long-context exposure prior to cued conditioning produces an inhibition of the CR (freezing), and this phenomenon is related with a specific c-fos expression in CA1, CA3, BL Amygdala, LS and BNST during the fear acquisition.