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PubMed2004

Differential contributions of dorsal hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning.

The hippocampus is an essential neural structure in developing contextual memory in a situation in which rapid development of associative learning should occur. We tested a subregion-specific contribution in the hippocampus to memory acquisition and retrieval, using the contextual fear-conditioning paradigm. The current results suggest that all three subregions (i.e., CA3, CA1, and dentate gyrus) of the hippocampus contribute to rapid acquisition of contextual memory in the initial phase of acquisition. The involvement of CA3 seems to be important at the earliest stage of acquisition, presumably for developing instant representation of a context. The role of CA3, however, was minimal in retrieving contextual memory after a long time period (i.e., 24 h), whereas the other subregions (i.e., CA1 and dentate gyrus) were critically involved. The results indicate time-dependent differential contributions of the hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning.

Animals↗
PubMed2003

Activation of the amygdalo-entorhinal pathway in fear-conditioning in rat.

Several studies implicate a role for the amygdala in processing of emotional memories that might partially occur in the connections between the amygdala and the hippocampal-parahippocampal areas. The present study was designed to determine if the pathway from the amygdala to the entorhinal cortex becomes activated during acquisition of fear-conditioning. First, the retrograde tracer Fluoro-Gold (FG) was iontophoresed into the entorhinal cortex in rats. Following habituation, animals were divided into five groups: (i) controls that received another habituation session; (ii) animals given a tone only; (iii) animals given a footshock only; (iv) animals given an unpaired presentation of a shock and a tone; and (v) conditioned animals that received a single tone-footshock pairing. Then double-immunohistochemistry against c-Fos and FG or glutamate decarboxylase (GAD67) was performed. The numbers and densities of labelled neurons were calculated in the lateral and basal nuclei of the amygdala. In conditioned animals the number and density of c-Fos-positive nuclei increased in dorsolateral and medial divisions of the lateral nucleus compared with the control group (P < 0.05). Additionally, in the medial division of the lateral nucleus, the percentage of c-Fos/FG double-labelled neurons was higher in the conditioned animals compared with the other groups (P < 0.05). Only a very few GAD67-positive interneurons expressed c-Fos. These data indicate that a part of the amygdalo-entorhinal pathway is activated during acquisition of fear-conditioning. These data support the idea that emotionally relevant sensory information in the lateral nucleus can influence information processing in the hippocampal and parahippocampal areas via the amygdalo-entorhinal pathway.

Amygdala↗
PubMed2005

Targeted invalidation of CCK2 receptor gene induces anxiolytic-like action in light-dark exploration, but not in fear conditioning test.

RATIONALE: Evidence suggests that gamma-aminobutyric acid (GABA) and cholecystokinin (CCK) have opposite roles in the regulation of anxiety. OBJECTIVES: The aim of our work was to study the behaviour of CCK(2) receptor deficient mice in light-dark exploration and fear conditioning tests. Moreover, the action of diazepam and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), having the opposite effect on GABA(A) receptors, was evaluated on the exploratory behaviour in these mice. Expression levels of GABA(A) receptor subunit genes were also measured. METHODS: Light-dark exploration and fear conditioning tests were used to determine changes in anxiety of mice. The action of diazepam (0.5-2 mg/kg i.p.) and DMCM (0.25-1 mg/kg i.p.) was studied in the light-dark box. The effect of DMCM was also evaluated in the motor activity test to demonstrate that its anti-exploratory action was not related to motor suppression. Expression levels of GABA(A) receptor subunit genes were determined by means of real-time polymerase chain reaction (qRT-PCR). RESULTS: Female mice lacking CCK(2) receptors displayed increased exploratory activity in the light-dark box compared to their wild-type (+/+) littermates. Locomotor activity in the motility boxes and the intensity of freezing did not differ in wild-type (+/+) and homozygous (-/-) mice. Treatment with diazepam (0.5 mg/kg) increased the number of transitions in wild-type (+/+) animals, whereas in homozygous (-/-) mice diazepam (0.5-2 mg/kg) reduced exploratory activity. Administration of DMCM (0.25-1 mg/kg) induced an anxiogenic-like effect in homozygous (-/-) mice, but did not change their locomotor activity. Gene expression analysis established a 1.6-fold increase in the expression of the alpha2 subunit of GABA(A) receptors in the frontal cortex of homozygous (-/-) mice. CONCLUSION: Genetic invalidation of CCK(2) receptors induced an anxiolytic-like action in exploratory, but not in conditioned models of anxiety. The observed reduction in anxiety in homozygous (-/-) mice is probably related to an increased function of GABAergic system in the brain.

Animals↗
PubMed2006

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning.

Analysis of Variance↗
PubMed2000

Is the hippocampus necessary for contextual fear conditioning?

The hippocampus is widely believed to be essential for learning about the context in which conditioning occurs. This view is based primarily on evidence that lesions of the dorsal hippocampus disrupt freezing to contextual cues after fear conditioning. However, lesions that disrupt freezing produce no effect on fear-potentiated startle, a second measure of contextual fear. Moreover, hippocampal lesions also do not disrupt the contextual 'blocking' phenomenon, which provides an indirect measure of contextual fear. In these paradigms, at least, it appears that hippocampal lesions disrupt the expression of freezing, rather than contextual fear itself. This interpretation is supported by the finding that rats showing preserved contextual blocking after hippocampal lesions show deficits not only in contextual freezing, but also in unconditioned freezing. These findings are consistent with a growing body of data from other conditioning paradigms that contextual learning is spared after lesions of the dorsal hippocampus. Nonetheless, there remain some reports of impaired contextual fear conditioning after hippocampal lesions that cannot be attributed easily to a disruption of freezing. Thus, it is concluded that the hippocampus may be involved in contextual learning under certain--as yet, unspecified--circumstances, but is not critical for contextual learning in general.

Animals↗
PubMed1988

Cerebral glucose utilization after aversive conditioning and during conditioned fear in the rat.

Regional cerebral glucose utilization (rCMRglu) was studied in rats with and without previous aversive conditioning. Four groups of rats were studied. Two groups of rats were aversely conditioned by placing them in a shock chamber (conditioned stimulus) where they received random footshocks. The two remaining groups were placed in the shock chamber but not conditioned. Regional CMRglu and systemic parameters (heart rate, mean arterial blood pressure (MABP), blood gases and pH, plasma catecholamines, and plasma glucose) were measured in unconditioned and conditioned rats in the presence and in the absence of the conditioned stimulus. The changes in rCMRglu described below appeared to be global and not limited to specific regions. Results are as follows: (1) transferring unconditioned rats to the shock chamber had no significant effect on rCMRglu even though the systemic parameters indicated a stress response. It appears that stress capable of inducing changes in heart rate, MABP, and plasma catecholamines is not necessarily accompanied by increases in cerebral glucose utilization. (2) Conditioned rats not exposed to the shock chamber at the time rCMRglu was measured had decreased rates of rCMRglu compared to rats that were not conditioned. Except for plasma epinephrine, which increased after conditioning, systemic parameters were not affected. (3) Conditioned fear, elicited by transferring conditioned rats to the shock chamber, increased rCMRglu when compared to a control group that was conditioned to footshock using the same paradigm but not exposed to the shock chamber at the time rCMRglu was measured. The systemic parameters indicated a stress response in conditioned rats transferred to the shock chamber.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Scopolamine and Pavlovian fear conditioning in rats: dose-effect analysis.

Muscarinic-cholinergic antagonism produces learning and memory deficits in a wide variety of hippocampal-dependent tasks. Hippocampal lesions produce both acquisition deficits and retrograde amnesia of contextual fear (fear of the place of conditioning), but do not impact fear conditioning to discrete cues (such as a tone). In order to examine the effects of muscarinic antagonism in this paradigm, rats were given 0.01 to 100 mg/kg of scopolamine (or methylscopolamine) either before or after a fear conditioning session in which tones were paired with aversive footshocks. Fear to the context and the tone were assessed by measuring freezing in separate tests. It was found that pretraining, but not post-training, scopolamine severely impaired fear conditioning; methylscopolamine was ineffective in disrupting conditioning. Although contextual fear conditioning was more sensitive to cholinergic disruption, high doses of scopolamine also disrupted tone conditioning. Scopolamine did not affect footshock reactivity, but did produce high levels of activity. However, hyperactivity was not directly responsible for deficits in conditioning. It was concluded that scopolamine disrupts CS-US association formation or CS processing, perhaps through an attenuation of hippocampal theta rhythm.

Acoustic Stimulation↗
PubMed2006

Age-related naturally occurring depression of hippocampal neurogenesis does not affect trace fear conditioning.

New neuron production throughout adulthood in granule cell layer (GCL) of rat hippocampus is a well-known phenomenon. A role of new neurons in hippocampal learning has been proposed, but the question is still open. A reduction of neural precursor proliferation in GCL of 2-month-old rats to about 20%, induced by the cytostatic agent methylazoxymethanol, was found to cause impairment in trace conditioning, suggesting a role of immature neurons in this kind of hippocampus-dependent learning (Shors et al., Hippocampus 2002;12:578-584). Neurogenesis decreases with increasing age. In this study, neural precursor proliferation and newborn cell survival were evaluated in GCL of adult rats within a range of ages following development and preceding old age. In 5-month-old rats, neural precursor proliferation was reduced to 57% and newborn cell survival was reduced to 40% in comparison to rats of 2 months of age; in 12-month-old rats, the decrease was to 5 and 4%, respectively. Consistently, the density of immature neurons decreased to 41 and 13% in 5- and 12-month-old rats, respectively. The role of neurogenesis in trace fear conditioning was studied in this natural model of neurogenesis depression. No impairment in trace fear conditioning was found both in 5- and 12-month-old rats in comparison to 2-month-old rats, notwithstanding the decrease of neurogenesis that is marked in 12-month-old rats. This finding shows that a lower rate of neurogenesis is sufficient for learning in 12-month-old rats in comparison to young rats.

Aging↗
PubMed2001

Potentiated amygdaloid auditory-evoked potentials and freezing behavior after fear conditioning in mice.

Elucidation of cellular and molecular mechanisms underlying fear-related memory would greatly benefit from the possibility of combined behavioral and electrophysiological recordings in genetically modified mice. As a first step to this goal, we implanted adult C57BL/6J mice with recording electrodes aimed at the basolateral amygdaloid complex and trained them in an auditory fear conditioning paradigm. After conditioning, animals with paired tone and footshock presentation showed not only intensified freezing behavior lasting for 2 days, but also increases, lasting 4 days, in slope and amplitude of the most negative component of auditory-evoked potentials triggered by the conditioned stimulus. These effects could not be observed in animals with unpaired tone and footshock presentation. Thus, our data show that a long-lasting association of a former neutral tone with an aversive situation is accompanied by a long-lasting increase of auditory-evoked potentials in freely moving mice. However, extinction of the potentiation of auditory-evoked potentials and freezing behavior followed different time courses, thus making a direct relationship between these responses unlikely.

Acoustic Stimulation↗
PubMed2001

Contextual fear conditioning is disrupted by lesions of the subcortical, but not entorhinal, connections to the hippocampus.

Recent studies have questioned the importance of the entorhinal cortex (ERC) for normal hippocampal function. For example, fibre-sparing ERC lesions have been found to have no effect on spatial learning in the watermaze. There is also doubt as to the importance of the ERC for contextual fear conditioning, with previous studies having yielded conflicting results. In an attempt to resolve this issue, the present study compared aspiration and cytotoxic ERC lesioned rats, along with fimbria-fornix (FFX) lesioned animals and sham operated controls, on an unsignalled contextual fear conditioning paradigm. The results of the present study show that whereas lesions of the FFX disrupted contextual freezing, neither aspiration nor cytotoxic ERC lesions had any effect on this behaviour. Aspiration ERC lesioned rats, however, like FFX lesioned animals, did display hyperactivity prior to the delivery of footshock. These results suggest that whereas projections between the hippocampus and subcortical structures are important for normal levels of contextual freezing, projections from the entorhinal cortex are not essential.

Animals↗
PubMed1995

Benzodiazepine (omega) receptor partial agonists and the acquisition of conditioned fear in mice.

It is well established that benzodiazepines can produce anterograde amnesia in humans and interfere with the acquisition of passive avoidance and spatial responses in rodents. However, the extent to which the disruption of learning is a secondary effect of the sedation produced by these drugs has not been clearly established. In order to investigate this question, the effects of several BZ (omega) receptor partial agonists were studied on the acquisition of conditioned fear (passive avoidance learning) in mice. As these drugs have been shown to produce anticonvulsant and anxiolytic-like effects without sedation or depression of motor activity, it was of interest to see whether they could disrupt learning. Clear effects on the acquisition of conditioned fear were produced by imidazenil (0.01-1.0 mg/kg), divaplon (1-60 mg/kg), ZK 91296 (3-60 mg/kg), and Ro 17-1812 (0.1-10 mg/kg). However, bretazenil (0.1-10 mg/kg) did not produce statistically significant effects. Only the high dose of imidazenil (1.0 mg/kg) decreased levels of exploratory behaviour. These results show that BZ (omega) receptor partial agonists without apparent sedative actions can disrupt fear learning, indicating that the effects of this class of drugs on passive avoidance learning can be dissociated from sedation. The reasons for the observed differences between the different compounds studied are unclear at present and may be related to differences in intrinsic activity or receptor subtype selectivity.

Animals↗
PubMed2002

Aniracetam improves contextual fear conditioning and increases hippocampal gamma-PKC activation in DBA/2J mice.

DBA/2J (D2) mice display poor contextual learning and have less membrane-bound hippocampal protein kinase C (PKC) compared with C57BL/6 (B6) mice. Aniracetam and oxiracetam were previously shown to improve contextual learning in D2 mice and increase PKC activity. This study investigated a possible mechanism for learning enhancement by examining the effects of aniracetam on contextual fear conditioning and activation of the y isoform of PKC (gamma-PKC) in male D2 mice. In comparison to animals treated with vehicle only (10% 2-hydroxypropyl-beta-cyclodextrin), mice treated with aniracetam (100 mg/kg) 30 min prior to fear conditioning training demonstrated significantly improved contextual learning when tested 30 min and 24 h after training. This corresponded with a significant increase in activated, membrane-bound hippocampal gamma-PKC 30 min after training. No increase in learning or gamma-PKC was found 5 min after training. These results suggest an altered time course of activation of gamma-PKC in response to treatment with aniracetam, which improves learning in D2 mice.

Animals↗
PubMed2005

Hypofunction of the dorsal hippocampal NMDA receptors impairs retrieval of memory to partially presented foreground context in a single-trial fear conditioning in rats.

In the present study, the effects of N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (AP5) bilaterally infused into the dorsal hippocampus (2.0 microl /5 microg), on the retrieval of fear memory to partial and whole foreground cues were evaluated by using a step-through passive avoidance and Pavlovian fear conditioning. In the both conditioning tasks, following a 30-s preshock exposure period to the shock-associated context, rats received a single shock in a foreground manner for fear memory exhibition by freezing. Rats with AP5 infusion 5 min before the retrieval tests showed profound freezing deficits either immediately or 48 h after the shock in the testing section of the passive avoidance chamber where foreground cues was partially presented. In the Pavlovian conditioning chamber where fear conditioning was tested in the whole of the context that was explicitly paired with the shock, AP5 rats in all infusion schedules exhibited robust freezing responses. These results showed that hypofunction of the hippocampal NMDA receptors impaired the retrieval of fear memory to partial, and not whole, foreground cues. This suggests that NMDA receptors of the hippocampus are involved in the formation of background context representations about foreground events when there is a deficit in perceiving certain sensory properties of the foreground retrieval cues.

2-Amino-5-phosphonovalerate↗
PubMed2003

NMDA receptor blockade and hippocampal neuronal loss impair fear conditioning and position habit reversal in C57Bl/6 mice.

The interpretation of learning and memory deficits in transgenic mice has largely involved theories of NMDA receptor and/or hippocampal function. However, there is little empirical data that describes what NMDA receptors or the hippocampus do in mice. This research assessed the effects of different doses of the NMDA receptor antagonist, MK-801, or different-sized hippocampal lesions on several behavioral parameters in adult male C57Bl/6 mice. In the first set of experiments, different doses of MK-801 (0.05-0.3mg/kg, s.c.) were assayed in fear conditioning, shock sensitivity, locomotion, anxiety, and position habit reversal tests. Contextual and cued fear conditioning, and position habit reversal were impaired in a dose-dependent manner. Locomotor activity was increased immediately after injection of the highest dose of MK-801. A second set of experiments determined the behavioral effects of a moderate and large excitotoxic hippocampal lesion. Both lesions impaired contextual conditioning, while the larger lesion interfered with cued conditioning. Reversal learning was significantly diminished by the large lesion, while the moderate lesion had a detrimental effect at a trend level (P<0.10). These results provide important reference data for studies involving genetic manipulations of NMDA receptor or hippocampal function in mice. Furthermore, they serve as a basis for a non-transgenic mouse model of the NMDA receptor or hippocampal dysfunction hypothesized to occur in human cognitive disorders.

Animals↗
PubMed2005

Sex-selective effects of neonatal isolation on fear conditioning and foot shock sensitivity.

Our previous work demonstrates enduring effects of the early life stress of neonatal isolation (ISO). ISO facilitates appetitive response learning in adult female, but not male rats, and enhances corticosterone levels and stress responsivity in infant and juvenile rats of both sexes. Corticosterone acts at brain areas such as hippocampus that are rich in glucocorticoid receptors, differentiate postnatally, are sexually dimorphic, and involved in learning. Thus, ISO is hypothesized to alter aversive learning in adult rats in a sex-specific manner. This study tests this hypothesis using context and cue fear conditioning. Pups were isolated for 1h a day on postnatal (PN) days 2-9 or were non-handled and were then tested in adulthood (PN70-90). In Experiment 1, context- and cue-elicited freezing and ultrasonic vocalizations (USVs; 22 kHz range) were measured. Experiments 2-4, respectively, examined three unconditioned foot shock responses (flinch, jump, vocalization), unconditioned fear (time in center of an open, novel arena), and appetitive (stroking-induced; 50 kHz range) USVs. ISO had a sex-selective effect on context-induced USVs that may reflect changes in foot shock sensitivity. ISO increases foot shock sensitivity and tends to enhance context-induced fear in female rats, whereas ISO tends to impair context-induced fear in male rats. Overall, male rats show greater conditioned fear, and female rats show greater unconditioned fear as well as enhanced responses to the aversive and appetitive stimuli. The sex-specific effect of ISO on context fear may reflect neuronal reorganization in stress responsive areas and/or sex differences in some unconditioned responses.

Animals↗
PubMed2005

Two-dimensional neural activity mapping of the entire population of hippocampal CA1 pyramidal cells responding to fear conditioning.

The hippocampus is involved in the encoding, storage, and retrieval of memory. Here, we have developed a novel mapping method for detecting the distribution of neural activity of the entire population of pyramidal cells in the hippocampal CA1 and subiculum regions, where expression profiles of Arc mRNA were used as an indicator of neural activity. The spherical pyramidal cell layer of the intact hippocampus was flattened into a two-dimensional plane, which was then serially sectioned in parallel with the plane to make tangential sections. Tangential sections were hybridized with an Arc cRNA probe and Arc signals from serial tangential sections were stacked and displayed on a two-dimensional plane, allowing one to easily visualize the neural activity of all pyramidal cells. We applied this method to the hippocampus of rats that had experienced contextual fear conditioning, which requires hippocampal function. We observed a net shift of Arc signals from dorsal to ventral CA1/subiculum with an interval prolongation to reconditioning after the initial conditioning. The reconditioning-revealed shift may reflect a reorganization process, which takes place during the period between initial conditioning and reconditioning, in the CA1/subiculum neural network that represents the neural storage and/or retrieval of the contextual fear conditioning.

Animals↗
PubMed2006

Long-term changes in fear conditioning and anxiety-like behavior following nicotine exposure in adult versus adolescent rats.

Adolescent nicotine exposure is associated with long-term use, and it has been suggested that this vulnerability to addiction may relate to lasting anxiogenic effects of the drug. However, few studies have addressed long-term effects of adolescent nicotine, and fewer yet have compared adolescent to adult exposure. Male and female Long-Evans rats continuously received nicotine bitartrate or sodium tartrate via osmotic mini-pumps over 15 days either during adolescence (p28-42) or adulthood (p85-99). Initial nicotine dose (free base) was either low (1 mg/kg/day) or high (2 mg/kg/day). Open field behavior and fear conditioning were assessed in adulthood, 1 month post-dosing. Animals pretreated with nicotine during adolescence showed less center time in a novel open field than sham controls. Conversely, the two nicotine doses differentially affected fear conditioning. Animals pretreated with low nicotine during adolescence demonstrated superior acquisition of the task compared to sham control animals; however, unlike either high nicotine-pretreated or sham control animals, they failed to extinguish the learned behavior. In contrast, animals pretreated during adulthood did not behave significantly different from sham controls on either task. Overall, nicotine-pretreatment during adolescence induced effects on behaviors related to fear and anxiety in adulthood, while comparable pretreatment during adulthood failed to produce significant residual effects.

Age Factors↗
PubMed2005

Magnesium deficiency impairs fear conditioning in mice.

Magnesium (Mg2+) is one of the most abundant cations found in the body. In the central nervous system, Mg2+ plays an important role in the function of N-methyl-D-aspartate (NMDA)-type glutamate receptors, which are centrally involved in memory processing. Despite the relatively large concentration of Mg2+ in the CNS, little is known about the behavioral consequences of Mg2+ deficiency. The purpose of this study was to address this issue by assessing fear conditioning and related behaviors in mice maintained on normal or Mg(2+)-deficient diets. Young adult male C57Bl/6J mice were placed on a control or Mg(2+)-deficient diet, and testing was conducted between 10 and 21 days later. Magnesium-deficient mice exhibited impairments in contextual and cued fear conditioning. These impairments could not be attributed to changes in locomotor activity, exploration, or pain sensitivity. Furthermore, Mg(2+)-deficient mice were more sensitive to the convulsant effects of a peripheral injection of NMDA (100 mg/kg, IP). The results suggest that magnesium deficiency can lead to specific impairments in emotional memory. Such impairments may be related to hypersensitivity of NMDA-type glutamate receptors in Mg(2+)-deficient mice.

Animals↗