NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: Immunization against amnesia by context preexposure.

Hippocampal lesions in rats produce both a retrograde and an anterograde amnesia of contextual fear conditioning. The present experiments examined the anterograde deficit in context conditioning involving a total of 113 rats in 4 experiments. The deficit produced by electrolytic hippocampal lesions was apparent when training occurred on 7, 14, or 28 days following surgery, confirming the durability of the amnesia. The role of the hippocampus in context conditioning may be related to an N-methyl-D-aspartate (NMDA) receptor-mediated process. Both NMDA hippocampal lesions and intrahippocampal administration of an NMDA antagonist produced anterograde amnesia. Ss preexposed to the conditioning context 28 days prior to hippocampal lesioning were protected from the deficit normally produced by the lesions. Thus, the hippocampus must form a contextual representation during preexposure that is subsequently stored elsewhere. Once formed this representation of the context can be associated with an unconditioned stimulus/stimuli (UCS). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Parallel augmentation of hippocampal long-term potentiation, theta rhythm, and contextual fear conditioning in water-deprived rats.

The influence of water deprivation on hippocampal long-term potentiation (LTP), theta rhythm, and contextual fear conditioning in 56 adult male rats was examined. In Exp 1, hippocampal EEG activity and perforant path LTP were assessed in pentobarbital-anesthetized rats. Water deprivation did not affect baseline cell excitability or low-frequency synaptic transmission in the dentate gyrus, but it increased the magnitude of perforant path LTP and elevated the proportion of theta rhythm in the EEG. In Exp 2, rats were classically conditioned to fear a novel context through the use of aversive footshocks. Water deprivation facilitated the rate of contextual fear conditioning but did not alter the asymptote of learning. Exp 3 demonstrated that the facilitation of contextual fear conditioning was not due to a change in unconditional shock sensitivity. These results suggest that water deprivation exerts an influence on contextual fear conditioning by modulating hippocampal LTP and theta rhythm and that these processes serve to encode contextual information during learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired trace and contextual fear conditioning in aged rats.

Trace and contextual fear conditioning were evaluated in adult (3-6 months), early middle-aged (8-12 months), late middle-aged (16-20 months), and aged (24-33 months) Sprague-Dawley rats. After trace conditioning, aged animals exhibited significantly less freezing to the tone conditioned stimulus and training context. Levels of trace-cue and context conditioning were negatively correlated with age (r = -0.56 and -0.59, respectively) and positively correlated with each other (r = +0.52). Aged rats showed robust conditioning in short- and long-delay fear paradigms, suggesting that the trace interval, rather than the use of a long interstimulus interval, is responsible for the aging-related deficits in trace fear conditioning. The authors suggest that these aging-related conditioning deficits furnish useful indices of functional changes within hippocampus or perirhinal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of ethanol on encoding, consolidation, and expression of extinction following contextual fear conditioning.

Studies of contextual fear conditioning have found that ethanol administered prior to a conditioning session impairs the conditioned freezing response during a test session the next day. The present experiments examined the effects of ethanol on extinction, the loss of conditioned responding that occurs as the animal learns that a previously conditioned context no longer signals shock. Ethanol (1.5 g/kg) administered prior to single (Experiment 1) or multiple (Experiment 2) extinction sessions impaired extinction. Ethanol administered prior to a test session disrupted the expression of freezing after extinction (Experiments 3-5). There was some evidence that ethanol served as an internal stimulus signaling the operation of conditioning or extinction contingencies (Experiments 4-5). In Experiment 6, postsession injections of 1.5 g/kg ethanol had no effect on extinction with brief (3 min) or long (24 min) exposures to the context, but injections of 3 g/kg after long exposures impaired extinction. Together, these results indicate that ethanol affects extinction by acting on multiple learning and performance processes, including attention, memory encoding, and memory expression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age-related deficits on the radial maze and in fear conditioning: hippocampal processing and consolidation

Young adult, middle-aged, and old male F-344 rats were assessed for their hippocampal ability. This was accomplished by examining the animals on two different paradigms, each incorporating a simultaneous measure of hippocampal-dependent and -independent processing. The animals were fear conditioned and then tested for retention of the conditioning context and tone. This was followed by an 8-arm radial maze task which combined spatial working and cued reference memory elements. The two paradigms are compared in terms of task demands, potential confounds, and validity for aging studies. The results indicate that the performance of the animals on the two tasks is correlated. Age-related deficits limited to the hippocampal aspects of the above tasks were found, with no deficits found in the analogous but hippocampus-independent aspects of these tasks. The function of the hippocampus in incorporating new memories is time-related. Therefore, the possibility of age-related changes in consolidation was examined. It has previously been shown on the fear conditioning paradigm that the hippocampus is involved in retention of the aversive context for approximately 28 days. In the present study, an attempt was made to test the animals for retention of the conditioning context both early into the period of consolidation (10 days) and after consolidation should have been completed (52 days). The results indicate that, initially, the old animals show comparable retention to young rats. When examined later, young animals showed a stronger retention of the conditioning context than they had previously. The aged rats, however, did not seem to benefit from this additional period of time and in fact showed a decrease in retention of the conditioning context. The data are interpreted in terms of consolidation, alternative explanations of the data are presented, and suggestions are given for future research. Finally, the implications of such age-related changes in hippocampal consolidation on learning and memory are discussed.     

Hippocampectomy disrupts auditory trace fear conditioning and contextual fear conditioning in the rat

The hippocampus is believed to be an important structure for learning tasks that require temporal processing of information. The trace classical conditioning paradigm requires temporal processing because the conditioned stimulus (CS) and the unconditioned stimulus (US) are temporally separated by an empty trace interval. The present study sought to determine whether the hippocampus was necessary for rats to perform a classical trace fear conditioning task in which each of 10 trials consisted of an auditory tone CS (1 5-s duration) followed by an empty 30-s trace interval and then a fear-producing floor-shock US (0.5-s duration). Several weeks prior to training, animals were anesthetized and given aspiration lesions of the neocortex (NEO; n = 6), hippocampus and overlying neocortex (HIPP; n = 7), or no lesions at all (control; n = 6). Approximately 24 h after trace conditioning, NEO and control animals showed a significant decrease in movement to a CS-alone presentation that was indicative of a conditioned fear response. Animals in the HIPP group did not show conditioned fear responses to the CS alone, nor did a pseudoconditioning group (n = 7) that was trained with unpaired CSs and USs. Furthermore, all groups except the HIPP group showed conditioned fear responses to the original context in which they received shock USs. One week later, HIPP, NEO, and control animals received delay fear-conditioning trials with no trace interval separating the CS and US. Six of seven HIPP animals could perform the delay version, but none could perform the trace version. This result suggests that the trace fear task is a reliable and useful model for examining the neural mechanisms of hippocampally dependent learning.     

Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning.

The role of adult hippocampal neurogenesis in contextual fear conditioning (CFC) is debated. Several studies demonstrated that blocking adult hippocampal neurogenesis in rodents impairs CFC, while several other studies failed to observe an impairment. We sought to determine whether different CFC methods vary in their sensitivity to the arrest of adult neurogenesis. Adult neurogenesis was arrested in mice using low-dose, targeted x-irradiation, and the effects of irradiation were assayed in conditioning procedures that varied in the use of a discrete conditioned stimulus, the number of trials administered, and the final level of conditioning produced. We demonstrate that irradiation impairs CFC in mice when a single-trial CFC procedure is used but not when multiple-trial procedures are used, regardless of the final level of contextual fear produced. In addition, we show that the irradiation-induced deficit in single-trial CFC can be rescued by providing preexposure to the conditioning context. These results indicate that adult hippocampal neurogenesis is required for CFC in mice only when brief training is provided. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Time of conditioning selectively influences contextual fear conditioning: further support for a multiple-memory systems view of fear conditioning

Three classical conditioning models (the conditioned compensatory response, conditioned withdrawal, and conditioned appetitive motivational models) postulate that drug cues evoke physiological and emotional responses associated with motivational states that prompt drug use. There is accumulating evidence to suggest that factors other than classical conditioning can influence emotional and physiological reactivity to drug stimuli. This study tested whether stage of change affects the nature of reactivity to smoking cues among continuing smokers. Precontemplators (smokers not considering quitting) and contemplators (smokers considering quitting in the near future) watched videotapes containing smoking cues. Emotional and physiological responses to the smoking video were contrasted with responses to a neutral videotape. Precontemplators had lower heart rates than did contemplators in response to the smoking videotape. Both contemplators and precontemplators evinced increased positive affect in response to the smoking cue. A comparison sample of nonsmokers did not show any reactivity to the smoking cue. Implications of these findings for conditioning theories of smoking are discussed.     

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)     

Recovery of fear memories in rats: Role of gamma-amino butyric acid (GABA) in infantile amnesia.

Infantile amnesia is a ubiquitous phenomenon, but its neural bases remain largely unknown. The authors identify a role for GABAergic transmission in suppressing retrieval of memories acquired in infancy. Eighteen-day-old rats received pairings of white noise and shock; considerable forgetting of this experience (assessed by freezing) occurred after 10 days. The memory was recovered by pretest administration of the GABAA inverse agonist FG7142 10 days, but not 2 months, after training. This effect of FG7142 generalized when a passive avoidance procedure was used. Also, FG7142 decreased fear of a latently inhibited conditioned stimulus, showing that the observed memory recovery effect was not due to a state-dependent process. It appears that GABA may be involved in infantile amnesia regardless of the emotional content of the memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factors governing single-trial contextual fear conditioning in the weanling rat.

Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The authors adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that N-methyl-D-aspartate (NMDA) receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of nociceptin/orphanin FQ in the acquisition of contextual and tone fear conditioning in rats.

Nociceptin, or orphanin FQ (N/OFQ), the endogenous ligand of NOP receptors, is known to regulate learning and memory processes. To verify the role of N/OFQ in the acquisition of contextual (CFC) and tone fear conditioning (TFC), Wistar male rats received intracerebroventricular injections of N/OFQ (0.1-5.0 nmol) before training, and were tested 24 and 48 hr later to access the freezing response to context and tone, respectively. The intermediate doses (1.0 and 2.5 nmol) impaired the CFC test, sparing TFC. The highest dose (5.0 nmol) reduced freezing during both tests, a result that may be due to nonspecific effects. The posttraining injection of N/OFQ (1 or 5 nmol) did not interfere with CFC and TFC, suggesting a specific effect of the peptide in acquisition processes. Moreover, the impairment observed with N/OFQ (1 nmol) in CFC cannot be attributed to a state-dependent learning because it was not reversed by its pretest administration. The data support the negative role of N/OFQ in the acquisition of aversively motivated tasks, which encompass a spatial component and depend on the hippocampus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Isolation reduces contextual but not auditory-cue fear conditioning: A role for endogenous opioids.

Isolation for several hours after fear conditioning reduces contextual but not auditory-cue fear conditioning (J. W. Rudy, 1996). This isolation effect is reversed by both centrally and peripherally acting opioid receptor antagonists. As in isolation, systemically administered morphine given immediately after conditioning also reduces contextual fear conditioning. Morphine's effect is also reversed by both centrally and peripherally acting opioid receptor antagonists. Exposure to the conditioning context has been shown to eliminate the effect of isolation on contextual fear conditioning (J. W. Rudy, 1996). Context preexposure also eliminated the effect of morphine on contextual fear conditioning. These results imply that opioids released in the periphery play an important role in producing the isolation effect and that they do so by disrupting the postconditioning memory consolidation processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.

The contribution of the amygdala and hippocampus to the acquisition of conditioned fear responses to a cue (a tone paired with footshock) and to context (background stimuli continuously present in the apparatus in which tone–shock pairings occurred) was examined in rats. In unoperated controls, responses to the cue conditioned faster and were more resistant to extinction than were responses to contextual stimuli. Lesions of the amygdala interfered with the conditioning of fear responses to both the cue and the context, whereas lesions of the hippocampus interfered with conditioning to the context but not to the cue. The amygdala is thus involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli (CS) as well as to complex, polymodal stimuli, whereas the hippocampus is only involved in fear conditioning situations involving complex, polymodal events. Findings suggest an associative role for the amygdala and a sensory relay role for the hippocampus in fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulus configuration, classical conditioning, and hippocampal function.

Hippocampal participation in classical conditioning (CC) is described in terms of a multilayer network that portrays stimulus configuration. The network (1) describes behavior in real time, (2) incorporates a layer of "hidden" units positioned between input and output units, (3) includes inputs that are connected to the output directly as well as indirectly through the hidden-unit layer, and (4) uses a biologically plausible backpropagation procedure to train the hidden-unit layer. Nodes and connections in the neural network are mapped onto regional cerebellar, cortical, and hippocampal circuits, and the effect of lesions of different brain regions is formally studied. Computer simulations of the following CC paradigms are presented: acquisition of delay and trace conditioning, extinction, acquisition–extinction series of delay conditioning, blocking, overshadowing, discrimination acquisition, discrimination reversal, feature-positive discrimination, conditioned inhibition, negative patterning, positive patterning, and generalization. The model correctly describes the effect of hippocampal and cortical lesions in many of these paradigms, as well as neural activity in hippocampus and medial septum during CC… (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurotoxic lesions of retrosplenial cortex disrupt signaled and unsignaled contextual fear conditioning.

The majority of research regarding contextual learning and memory has focused on the contributions of the hippocampus and related medial temporal lobe structures. However, little is known about other possible cortical contributions to these processes. Our laboratory recently demonstrated that electrolytic lesions of the retrosplenial cortex (RSP), a posterior region of cingulate cortex, impaired contextual but not cue-specific fear conditioning. The present experiments further examined the role of RSP in contextual fear memory using fiber-sparing neurotoxic lesions and both signaled and unsignaled fear conditioning paradigms. Despite comparable acquisition of the conditioned fear response, rats with neurotoxic lesions of RSP exhibited impaired contextual memory relative to control animals in both the signaled and unsignaled paradigms. These results further suggest an important role for RSP in contextual learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Odor-guided fear conditioning in rats: 1. Acquisition, retention, and latent inhibition.

Three experiments examined the acquisition, retention, and latent inhibition of odor-guided fear conditioning in rats. The results of Experiment 1 indicate that forward conditioned stimulus (CS)–unconditioned stimulus (US) pairings resulted in robust freezing responses to subsequent presentation of the CS alone. In Experiment 2, rats in one group (PRE) received unreinforced preexposures to the odorant CS, and those in a second group (NON) were not preexposed to the odorant. All rats then received forward CS–US pairings. PRE rats exhibited a marked attenuation of freezing to subsequent exposure to the CS relative to NON rats. All rats were then retested at one of the following posttraining delays: 17, 24, or 31 days. Freezing behavior of the NON rats declined significantly across these delays, whereas rats in the PRE group froze no more at any delay than they had 24 hr after training. Experiment 3 examined the contextual specificity of latent inhibition. Only those rats that were preexposed and were trained in the same context exhibited latent inhibition. These results indicate that odor-guided fear conditioning is a robust and useful paradigm suitable for future studies of the neural bases of associative learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A comparison of contextual and generalized auditory-cue fear conditioning: evidence for similar memory processes

A number of variables influence contextual, but not auditory-cue, fear conditioning. However, several of these variables (isolation, stimulus preexposure, retention interval, and age) affect generalized auditory-cue fear. More generalized fear was found when (a) rats were isolated in a novel environment than when returned to their home cages, (b) the retention interval was 3 hr rather than 24 hr, and (c) in 18-day-old compared with 25-day-old rats. Moreover, preexposure to the auditory cue eliminated the isolation effect. At a behavioral-psychological level, these variables may exert their effects by influencing the processes that construct a memory representation of the stimulus. At a neural systems level, they may influence processing carried out in the thalamo-corticoamygdaloid auditory pathway.     

Contributions of anterior perirhinal cortex to olfactory and contextual fear conditioning

The present experiments examined the effects of excitotoxic lesions of anterior perirhinal cortex (PRH) on the expression of fear conditioned to an explicit olfactory CS and to the context in which CS-US pairing took place. Animals with anterior PRH lesions exhibited an attenuation of fear conditioned to the explicit CS, but no attenuation of fear conditioned to the training context. These data replicate previous findings in our laboratory examining the effects of aspirative lesions of anterior PRH, and are consistent with the notion that this cortical region comprises a critically important component of the neural system mediating the acquisition and/or expression of associations between olfactory cues and footshock.