Hippocampal lesions impair contextual fear conditioning in two strains of mice.

Two different strains of mice, C57BL/6J and BALB/c, with hippocampal, cortical, or sham lesions, underwent contextual fear conditioning. In both strains, contextual fear, as measured by the freezing response, was significantly impaired in hippocampus-lesioned animals compared with sham control animals. Fear conditioning was not affected in the cortical-lesioned group. Moreover, there was a strain difference in fear conditioning: The C57BL/6J mice exhibited freezing more frequently than the BALB/c mice. Consistent with previous hippocampal lesion studies in rats, these results indicate that contextual fear conditioning in mice also requires the intact hippocampus. This study provides a basis for evaluating hippocampal synaptic mechanisms in relation to contextual fear conditioning in widely available gene knockout or transgenic mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence of contextual fear after lesions of the hippocampus: a disruption of freezing but not fear-potentiated startle

The roles of the dorsal hippocampus and the central nucleus of the amygdala in the expression of contextual fear were assessed using two measures of conditioned fear: freezing and fear-potentiated startle. A discriminable context conditioning paradigm was developed that demonstrated both conditioned freezing and fear-potentiated startle in a context paired previously with foot shock, relative to a context in which foot shock had never been presented. Post-training lesions of the central nucleus of the amygdala completely blocked both contextual freezing and fear-potentiated startle. Post-training lesions of the dorsal hippocampus attenuated contextual freezing, consistent with previous reports in the literature; however, these same lesions had no effect on fear-potentiated startle, suggesting preserved contextual fear. These results suggest that lesions of the hippocampus disrupt the freezing response but not contextual fear itself.     

Differential behavioral effects of lesions of the medial or dorsal raphe nuclei in rats: Open field and pain-elicited aggression.

Electrolytic lesions were placed in either the dorsal or median raphe nuclei of 32 male adult Sprague-Dawley rats. Both lesions produced significant reductions in forebrain serotonin levels. Lesions of the dorsal nucleus produced a long-lasting increase in pain-elicited aggression, whereas median lesions were without effect. By contrast, lesions of the median nucleus produced significant increases in open-field activity, which began immediately and lasted for at least 3 mo, whereas lesions of the dorsal nucleus had no such effect. Similarly, when 22 Ss with dorsal or sham lesions were tested in an open field and then given a brief noncontingent footshock, their open-field activity was markedly reduced on the following day. Median Ss, however, showed little or no decrease in open-field activity on the day after footshock. Results suggest that the serotonin-containing neurons of the median raphe nucleus may exert an influence over the emotional responsivity of the rat. Overall results extend previous reports that lesions specific to the dorsal nucleus produce markedly different behavioral effects than lesions confined to the median nucleus. They also challenge the utility of manipulations that fail to take this into account. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-lasting increase in anxiety after electrolytic lesions of the pedunculopontine tegmental nucleus.

This study examined the effect of electrolytic lesions of the pedunculopontine tegmental nucleus (PPTg) on emotionality in rats. Rats with PPTg or sham lesions were tested in the elevated plus-maze, the social interaction test, the open-field test, and the conditioned fear paradigm. Histology showed that lesions were concentrated on the caudal half of the PPTg. In the plus-maze, behavioral scores were biased toward increased "anxiety" on the 1st testing day. Five consecutive exposures to the apparatus led to marked habituation in sham-lesioned but not in PPTg-lesioned rats. On the 5th day, most indexes of emotionality indicated elevated anxiety in PPTg-lesioned rats. Increased anxiety was also found in PPTg-lesioned rats in the social interaction test. In the conditioned fear paradigm, movement suppression during the postconditioned stimulus period was found in both groups on the 1st day of extinction but only in PPTg-lesioned rats on the 2nd extinction day, indicating extinction was slower in PPTg-lesioned rats. Lesions of the caudal PPTg appear to produce long-lasting anxiety in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock

It has been argued that exposure to inescapable shock produces later behavioral changes such as poor shuttle box escape learning because it leads to the conditioning of intense fear, which later transfers to the shuttle box test situation and interferes with escape. Both fear, as assessed by freezing, and escape were measured in Sprague-Dawley rats 24 hr after exposure to inescapable shock. Lesions of the basolateral region and central nucleus of the amygdala eliminated the fear that transfers to the shuttle box after inescapable shock, as well as the fear conditioned in the shuttle box by the shuttle box shocks. However, the amygdala lesions did not reduce the escape learning deficit produced by inescapable shock. In contrast, dorsal raphe nucleus lesions did not reduce the fear that transfers to the shuttle box after inescapable shock, but eliminated the enhanced fear conditioning in the shuttle box as well as the escape deficit. The implications of these results for the role of fear and anxiety in mediating inescapable shock effects are discussed.     

Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination

We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone-shock pairings in one context (remote memory) and 10 tone-shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.     

Both pre- and posttraining excitotoxic lesions of the basolateral amygdala abolish the expression of olfactory and contextual fear conditioning

The present study examined whether the basolateral amygdaloid complex (BLA) participates in the expression of fear conditioned to both an olfactory conditioned stimulus (CS) and the training context. In Experiment 1, pretraining excitotoxic lesions of the BLA abolished immediate postshock freezing, conditioned freezing to an olfactory CS, and conditioned freezing to the training context. Control experiments indicated that lesioned and sham-lesioned subjects did not differ in locomotor activity or in acquisition of a successive-cue odor discrimination task, suggesting that deficits in freezing behavior exhibited by BLA subjects were not due to an impairment in primary aspects of olfaction or to a general enhancement of locomotor activity. In Experiment 2, excitotoxic lesions of the BLA produced either 1 day or 15 days after olfactory fear conditioning abolished both odor-elicited and contextual freezing. Collectively, these data support the notion that the BLA participates in an enduring manner in the expression of conditioned freezing behavior elicited by both olfactory and contextual stimuli.     

Influence of medial septal and entorhinal cortex lesions on theta activity recorded from the hippocampus and median raphe nucleus

The electrophysiological relationship between the hippocampus (HP) and the median raphe nucleus (MRN) was examined in the freely moving rat. Bilateral HP recording electrodes were implanted in all animals (n = 15). In the first group of animals, placement of a monopolar recording electrode in the MRN allowed for simultaneous recording of field activity from the HP and MRN, both prior to and following electrolytic destruction of the medial septum (MS) (n = 10). Immediately following MS lesions, theta activity recorded from both sites was abolished. These data suggest that the MS may serve as a pacing input to both the HP and MRN. In a second group of animals, field activity was recorded from the HP and MRN, both prior to and following electrolytic destruction of the entorhinal cortex (EC) (n = 5). Type 1 theta activity recorded from both the HP and MRN was attenuated by EC lesions; however, detomidine-induced immobility-related theta activity was unaffected by destruction of the EC. In light of these findings, the plausibility of EC inputs to the MRN was discussed. The present results suggest that theta activity recorded from the MRN is dependent on the same neural mechanisms that control theta production in the HP.     

Predator odor as an unconditioned fear stimulus in rats: Elicitation of freezing by trimethylthiazoline, a component of fox feces.

Four experiments tested whether an odor from a rat predator can unconditionally elicit a fear response in rats. In a large chamber, rats displayed fear-related behaviors to trimethylthiazoline (TMT, a volatile compound isolated from fox feces), including avoidance and immobility, while showing less exploratory behavior. In a smaller chamber, TMT induced a species-typical fear response, freezing, whereas other odors did not. In addition, TMT systematically elicited more freezing as the amount of TMT increased. Moreover, there was no within-sessions or between-sessions habituation of freezing to TMT, nor did TMT promote contextual conditioning. The results indicate that the predator odor, TMT, can induce a fear-related behavioral response in rats that is controllable and quantifiable, suggesting that TMT-induced freezing may be a useful paradigm for a neurobehavioral system analysis of ecologically relevant, unconditioned fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in the acquisition and expression of Pavlovian fear conditioning in rats.

The effects of neurotoxic or electrolytic ventral subicular (vSUB) lesions on the acquisition and expression of Pavlovian fear conditioning in rats were examined. Conditioning consisted of the delivery of tone–footshock trials in a novel observation chamber, and freezing served as the measure of conditional fear. Pretraining vSUB lesions produced a severe tone freezing deficit and a modest context freezing deficit, whereas posttraining lesions produced severe deficits in freezing to both a tone -and a context conditional stimulus (CS). Similar impairments were produced by neurotoxic and electrolytic lesions. Increases in motor activity associated with the lesions could not account for freezing deficits. These results reveal that neurons in the vSUB have an important role in both the acquisition and expression of Pavlovian fear conditioning to contextual and acoustic CSs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: Absence of a temporal gradient.

The role of the basolateral amygdala (BLA) in the acquisition and expression of Pavlovian fear conditioning was examined in 80 rats. Excitotoxic lesions were made in the BLA using N-methyl-{d}-aspartate 7 days before or 1, 14, or 28 days after Pavlovian fear conditioning. Conditioning consisted of three pairings of a tone with an aversive footshock in a novel chamber, and freezing behavior served as an index of conditional fear. BLA lesions abolished conditional freezing to both the contextual and acoustic conditional stimuli at all training-to-lesion intervals, and the magnitude of the impairment did not vary as a function of the training-to-lesion interval. Reacquisition training elevated levels of freezing in rats with BLA lesions but did not reduce the magnitude of their deficit in relation to that of controls. These results reveal that neurons in the BLA have an enduring role in the expression of conditional fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear.

Examines the effects of amygdala, hippocampus, and periaqueductal gray (PAG) lesions on contextual fear conditioning in 48 female rats. Freezing behavior served as the measure of conditioning. Unlesioned control Ss showed reliable conditional freezing in the testing chamber when observed both immediately and 24 hrs after footshocks. In contrast, Ss with amygdala or ventral PAG lesions exhibited a significant attenuation in freezing both immediately and 24 hrs after the shocks. Dorsal PAG lesions had no effect on freezing at either time. Ss with hippocampal lesions displayed robust freezing behavior immediately following the shock, even though they showed a marked deficit in freezing 24 hrs after the shock. These results indicate that there are anatomically dissociable short- and long-term conditional fear states. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats

NMDA receptors in the amygdala seem to be critical for fear conditioning in naive rats. Recent spatial-learning studies suggest that previous learning protected animals from the amnesic effect of NMDA antagonists on new learning (of a similar behavioral task). Therefore, the present study examined whether blocking of NMDA receptors in the basolateral nucleus of the amygdala (BLA) prevents new fear learning in previously fear-conditioned rats, as measured by freezing behavior. Intra-BLA infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) completely blocked fear conditioning to a tone stimulus in animals that had previously been fear-conditioned to a light stimulus. Similar results were obtained with intra-BLA infusions of APV before contextual fear conditioning in rats that had been fear-conditioned to a different context. Additional experiments showed that intra-BLA APV infusions substantially interfere with the expression and extinction of conditioned fear to tone, light, and context stimuli. Together, these results indicate that NMDA receptors in the BLA are crucial for the encoding of new fear memories (i.e., the formation of specific conditioned stimulus-unconditioned stimulus association), the expression of conditioned fear responses, and the extinction of acquired fear.     

Water deprivation enhances fear conditioning to contextual, but not discrete, conditional stimuli in rats.

Water-deprived and nondeprived rats were fear conditioned with a discrete tone CS and an aversive footshock unconditioned stimulus/stimuli (UCS). 24 and 48 hrs following conditioning, conditional fear to the tone CS and the context cues of the conditioning chamber, respectively, were assessed by measuring freezing behavior. Water deprivation had no effect on baseline responding to either tone or contextual stimuli. Following either 1 or 3 tone-shock pairings, however, water deprivation selectively enhanced conditional freezing to the contextual cues of the training chamber; conditional freezing to the tone was unaffected by water deprivation. These results are consistent with the view that water deprivation affects fear conditioning via an influence on the hippocampus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of tamoxifen on the cytology of the uterine cervix in breast cancer patients

Knowledge about the central innervation of the lower urinary tract is limited. The spinal cord and the pontine micturition center have been investigated most thoroughly, whereas high centers have received little attention. Pseudorabies virus (PRV), a self-amplifying and transneuronal tracer was injected into the bladder trigone of 21 Sprague-Dawley rats. The animals were killed after 72, 96, and 120 h. The whole CNS was sectioned and immunostained for PRV. CNS centers directly connected to the bladder include the intermedio lateral cell column, the central autonomic nucleus, and the nucleus intercalatus at the spinal cord levels T12-L2 and L6-S2. The raphe pallidus et magnus, the A5 nor-adrenergic area, the pontine micturition center, the locus coeruleus, the periaquaductal gray, the nucleus para- et periventricularis of the hypothalamus, the red nucleus, the medial preoptic area, and the cortex are supraspinal centers connected to the bladder. Lower urinary tract function is a complex multilevel and multineuronal interaction. It involves facilitation and inhibition at many levels of the CNS.     

Contextual Fear Conditioning Is Associated With Lateralized Expression of the Immediate Early Gene c-fos in the Central and Basolateral Amygdalar Nuclei.

Fos, the protein product of the immediate early gene c-fos, was used to map functional circuitry underlying contextual conditioned fear. Male rats were given footshocks in a distinctive context and later tested using freezing as the behavioral measure and compared with no-shock and no-retention-test control groups. An increased number of Fos-immunoreactive neurons was found in the lateral part of the central nucleus and in the anterior basolateral and lateral amygdalar nuclei in the brains of the conditioned-fear group compared with controls. Further, a greater number of Fos-immunoreactive neurons was observed in the right central and anterior basolateral nuclei compared with the number of labeled neurons in these structures on the left. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampus and Pavlovian Fear Conditioning in Rats: Muscimol Infusions Into the Ventral, but Not Dorsal, Hippocampus Impair the Acquisition of Conditional Freezing to an Auditory Conditional Stimulus.

The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential role of the medial and lateral prefrontal cortices in fear and anxiety.

In the rat, both the medial and lateral prefrontal. cortices (PFC; mPFC and lPFC, respectively) have direct connections with limbic structures that are important in the expression of fear and anxiety. The present study investigated the behavioral effects of excitotoxic lesions of either the mPFC or the lPFC on conditioned and unconditioned fear paradigms. In both unconditioned fear paradigms (open field, elevated plus-maze), lesions of the mPFC decreased anxiety. In fear conditioning, lPFC lesions substantially increased freezing throughout the different phases of the experiment, whereas mPFC lesions increased freezing to contextual cues and showed reduced freezing to discrete cues. These results support the functional role of the PFC in mediating or modulating central states of fear and anxiety and suggest a functional dissociation between the lPFC and mPFC in their role in fear and anxiety. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Doubly dissociable effects of median- and dorsal-raphé lesions on the performance of the five-choice serial reaction time test of attention in rats

Six experiments examined the effects of selective median (MRN)- and dorsal (DRN)-raphé nucleus lesions on the performance of the five-choice serial reaction time task. In this test rats are required to localize brief visual stimuli presented randomly in one of five locations in approximately 30 min sessions of 100 trials. Both accuracy and latency to respond are measured, as well as the incidence of premature and perseverative responding. Selective 5-HT lesions were induced by intra-raphé infusions of 5,7-dihydroxytryptamine following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. Analysis of tissue monoamine content demonstrated that the MRN lesion profoundly depleted hippocampal 5-HT (by about 90%) without affecting noradrenaline and dopamine, whereas the DRN lesion primarily depleted (by about 80%) nucleus accumbens and caudate-putamen 5-HT. Rats with 5-HT lesions of the MRN performed the task with a similar degree of accuracy to that exhibited by sham-operated controls. Although the MRN lesion did not affect the latency to respond correctly to the visual targets the lesioned animals collected the food reward significantly faster than the controls. A transient increase in the number of premature responses also resulted from this lesion. In contrast the DRN lesion produced a transient but significant increase in the accuracy of performance, and increased both the speed and the probability of responding. The similarity of the effects following global forebrain 5-HT depletion and the selective DRN lesion suggests that the 5-HT projections of the DRN rather than the MRN may play an important role in impulsive behaviour following 5-HT depletion.     

Effects of lesions to the hippocampus on contextual fear: Evidence for a disruption of freezing and avoidance behavior but not context conditioning.

The effects of ibotenic lesions of the hippocampus on conditioning to contextual cues during classical fear conditioning in rats were evaluated by (a) the amount of freezing elicited by contextual cues and (b) the relative avoidance of a shock compartment. In Experiment 1, lesions to the hippocampus had no effect on contextual freezing and marginally affected avoidance after repeated sessions. Experiment 2 showed that lesions to the hippocampus disrupted avoidance when tested after a single conditioning session, while leaving unaffected the acquisition of contextual freezing. Experiment 3 indicated that these lesions decreased the acquisition of contextual freezing when higher footshock intensity was used but had no effect on avoidance after repeated conditioning sessions. These results show that freezing and avoidance do not quantify context conditioning similarly. They further indicate that lesions to the hippocampus may disrupt the expression of these behaviors used as measures of context conditioning but not the acquisition of context conditioning per se. (PsycINFO Database Record (c) 2010 APA, all rights reserved)