Odor-aversion learning in neonatal rats.

Two-day-old rats were exposed to a novel odor and injected with an illness-inducing drug, lithium chloride. When tested at 8 days of age, these pups avoided pine shavings scented with the odor, whereas control pups did not. These results imply that rat pups are capable of associative learning at a much earlier age than was thought possible.

Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus.

The intra-hippocampal administration of interleukin-1beta (IL-1beta) as well as the induction of elevated but physiological levels of IL-1beta within the hippocampus interferes with the formation of long-term memory. There is evidence suggesting that the induction of prostaglandin (PG) formation by IL-1beta is involved in impairments in working and spatial memory following IL-1beta. The present experiments extend these findings by showing that PGs are responsible for memory deficits in contextual fear conditioning that occur following IL-1beta injection into the dorsal hippocampus of Sprague-Dawley rats. Cyclooxygenase (COX) inhibition blocked the disruption in contextual fear conditioning produced by IL-1beta and COX inhibition alone also disrupted contextual memory, suggesting an inverted U-shaped relationship between PG levels and memory. In addition to demonstrating the necessity of PGs in IL-1beta-mediated memory deficits, we also show that PGs injected directly into the dorsal hippocampus are sufficient to impair context memory and significantly reduce post-conditioning levels of BDNF within the hippocampus, suggesting a possible mechanism for the memory-impairing effects of PGs.

Understanding contextual fear conditioning: insights from a two-process model.

Contextual fear conditioning is an important behavioral paradigm for studying the neurobiology of learning and memory and the mnemonic function of the hippocampus. We suggest that research in this domain can profit by a better theoretical understanding of the processes that contribute to this phenomenon. To facilitate this understanding, we describe a theory which assumes that physical elements of a conditioning context represented in the brain as either (a) a set of independent features or (b) features bound into a conjunctive representation by the hippocampus which supports pattern completion. Conditioning produced by shocking a rat in a particular context, in principle, can be produced by strengthening connections between the feature representations and/or the conjunctive representation and basolateral region of the amygdala. We illustrate how this theory clarifies some of the complexities associated with the existing literature and how it can be used to guide future empirical work. We also argue that the mechanisms (conjunctive representations and pattern completion) that mediate the contribution the hippocampus makes to contextual fear conditioning are the same ones that enable the hippocampus to support declarative memory in humans.

The immune system and memory consolidation: a role for the cytokine IL-1beta.

Interleukin-1 beta (IL-1beta), known to play a role in orchestrating the physiological and behavioral adjustments that occur during sickness, has also been shown to significantly influence memory consolidation. To support this assertion we present neurobiological evidence that the substrates for IL-1beta to influence memory processing and neural plasticity exist. We then present behavioral evidence that central IL-1beta administration and agents that induce central IL-1beta activity impair the consolidation of memories that depend on the hippocampal formation but have no effect on the consolidation of hippocampal-independent memories. Further, we demonstrate that the impairments in hippocampal-dependent memory consolidation produced by agents that induce IL-1beta activity are blocked by antagonizing the actions of IL-1beta. Finally, we discuss these data in terms of their implications for a physiological role of IL-1beta in memory consolidation processes and a potential role of IL-1beta in producing memory impairments associated with stress, aging, Alzheimer's disease, and AIDS related dementia complex.

Conjunctive representations in learning and memory: principles of cortical and hippocampal function.

The authors present a theoretical framework for understanding the roles of the hippocampus and neocortex in learning and memory. This framework incorporates a theme found in many theories of hippocampal function: that the hippocampus is responsible for developing conjunctive representations binding together stimulus elements into a unitary representation that can later be recalled from partial input cues. This idea is contradicted by the fact that hippocampally lesioned rats can learn nonlinear discrimination problems that require conjunctive representations. The authors' framework accommodates this finding by establishing a principled division of labor, where the cortex is responsible for slow learning that integrates over multiple experiences to extract generalities whereas the hippocampus performs rapid learning of the arbitrary contents of individual experiences. This framework suggests that tasks involving rapid, incidental conjunctive learning are better tests of hippocampal function. The authors implement this framework in a computational neural network model and show that it can account for a wide range of data in animal learning.

Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist.

Manipulations that increase the expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in the hippocampus (e.g. peripheral administration of lipopolysaccharide, i.c.v. glycoprotein 120, social isolation) as well as the intrahippocampal injection of IL-1beta following a learning experience, dramatically impair the memory of that experience if the formation of the memory requires the hippocampus. Here we employed social isolation to further study this phenomenon, as well as its relation to brain-derived neurotrophic factor (BDNF). BDNF was studied because of its well-documented role in the formation of hippocampally based memory. A 6 h period of social isolation immediately after contextual fear conditioning impaired memory for context fear measured 48 h later, and decreased BDNF mRNA in the dentate gyrus and the CA3 region of the hippocampus assessed immediately after the isolation. Moreover, an intrahippocampal injection of the IL-1 receptor antagonist prior to the isolation period prevented both the BDNF downregulation and the memory impairments produced by the isolation. These data suggest that hippocampal-dependent memory impairments induced by elevated levels of brain IL-1beta may occur via an IL-1beta-induced downregulation in hippocampal BDNF.

Contextual conditioning and auditory cue conditioning dissociate during development.

Following a single shock presentation, fear conditioning to an auditory cue and to the experimental context was assessed by measuring the rat's tendency to freeze. On the conditioning day 18-day-old rats showed as much freezing to the auditory cue as older rats. However, 18-day-old pups displayed much less freezing to the training context than pups 21- to 27-days old. The developmental dissociation between contextual and auditory cue conditioning parallels the dissociation produced by damage to the adult rat's hippocampal system (Kim & Fanselow, 1992; Phillips & LeDoux, 1992). The dissociation is also consistent with the developmental hypothesis that the configural association system develops late in comparison with the elemental association system (Rudy, 1991, 1992). The implications of the findings for the maturation of the neural components of the fear-conditioning circuit also are discussed.

Postconditioning isolation disrupts contextual conditioning: an experimental analysis.

Contextual-fear conditioning requires a lengthy retention period to fully emerge. This phenomenon might reflect the consolidation of a representation of the context that can be used to evoke fear. To investigate this hypothesis, 25 day-old rats that were returned to their home cages after conditioning were compared with rats that were isolated in a novel room. Isolation disrupted contextual but not auditory-cue fear conditioning when the conditioning-isolation interval was 2 hr or less, but not when it was 24 hr. Preexposure to the context prevented the isolation effect, and isolation disrupted this effect of context preexposure. These results support the consolidation hypothesis and the view that contextual- and auditory-cue fear conditioning depend on different processes.

Ontogeny of contextual fear conditioning in rats: implications for consolidation, infantile amnesia, and hippocampal system function.

The authors present developmental evidence that contextual fear conditioning is supported by a short-term memory system that supports conditioning immediately after a shock and by a long-term memory system that supports contextual conditioning 24 hr after training. This is based on the finding that after 1 conditioning trial, rats 18 to 32 days old show the same amount of conditioned freezing when tested immediately after conditioning but 18-day-old rats show much less conditioned freezing than the older rats when the retention interval is 24 hr. The data also suggest that the long-term memory representation of context that mediates conditioned fear is not available until several hours after the conditioning trial. Implications of these findings for memory consolidation processes, infantile amnesia, and hippocampal formation development are discussed.

Development of interocular equivalence in rats trained on a distal-cue navigation task.

What is learned about the visual world through one eye can be retrieved and used to guide behavior by the other eye. To study the development of this phenomenon, called interocular equivalence, we trained rats on a spatial learning task. Rats only 22 days old were able to learn this task with one eye, but they demonstrated no interocular equivalence. This capacity began to emerge when pups were 25 days old but was not robust until pups were 28 days old. That interocular equivalence emerges gradually during development suggests that the young rat, in some ways, may function as a split-brain animal.

Development of interocular equivalence of place learning in the rat requires convergence sites established prior to training.

Interocular equivalence for spatial-navigation learning requires that the neural pathways originating in each eye converge on common memory sites. Rats fail to display interocular equivalence if they are trained and tested on the Morris (1981) place-navigation task when they are 22 days old, but they succeed if they are trained and tested when they are 28 days old (Rudy & Stadler-Morris, 1987). This delay suggests that there is a period in development when the interhemispheric connections necessary for convergence are immature and rats behave temporarily as split-brain organisms. In the present experiment, rats completed training when they were 22 days old but were not tested for interocular equivalence until they were 28 days old. Nevertheless, these subjects failed to demonstrate equivalence. Thus, for interocular equivalence to be observed, the neural pathways from each eye must converge on common neural sites that are functional at the time the memory representation is established.

Rats with damage to the hippocampal-formation are impaired on the transverse-patterning problem but not on elemental discriminations.

We assessed the effects of hippocampal-formation (HF) damage on the rat's ability to learn two sets of concurrent visual discriminations. Each set included three problems. One set, called the transverse-patterning problem, was constructed so that each choice stimulus was ambiguous; sometimes it was the correct (+) and sometimes it was the incorrect (-) choice as follows: A+ vs. B-, B+ vs. C-, and C+ vs. A-. It could not be solved unless rats used configural associations. The stimuli were not ambiguous in the second, elemental problem set, A+ vs. B-, C+ vs. D-, and E+ vs. F-. Rats could solve this set without the use of configural associations. Rats with HF damage solved the set of elemental problems, but their performance on the transverse-patterning problem was impaired. These results support Sutherland and Rudy's (1989) theory that the hippocampal formation is critical for the acquisition of configural associations.

A comparison of kainic acid plus colchicine and ibotenic acid-induced hippocampal formation damage on four configural tasks in rats.

J.W. Rudy and R.J. Sutherland (1989) suggested that the hippocampal formation (HF) is necessary for performance of configural tasks and that rats with kainic acid + colchicine (K-C) damage to the HF were impaired on the negative patterning problem (A+, B+, AB-). However, M. Gallagher and P.C. Holland (1992) found spared performance on a similar task (AC+, B+, AB-, C-) when ibotenic acid (IBO) was used. This study compared the effects of K-C- and IBO-induced HF damage on 4 configural tasks: (a) negative patterning, (b) the Gallagher-Holland task, (c) transverse patterning, and (d) place learning. Rats with IBO lesions performed like controls on the Gallagher-Holland task (replicating M. Gallagher & P.C. Holland) but were impaired on negative patterning, transverse patterning, and place learning. In contrast, rats with K-C lesions were impaired on all 4 tasks. The implications of these results for theories of HF function are discussed.

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.

Ontogeny of spatial navigation behaviors in the rat: dissociation of "proximal"- and "distal"-cue-based behaviors.

Rats can use both "proximal" and "distal" cues to locate goal objects in their environments (Morris, 1981). In the proximal-cue situation, local stimuli that spatially co-occur with the goal are available to guide behavior. In the distal-cue situation, there are no cues that co-occur with the goal object; thus to directly locate the goal, the rat must learn about the spatial location of the goal relative to distal cues. Using the Morris water maze, we found that these two navigation behaviors are dissociated during ontogeny. Rats only 17-days-old are capable of using proximal cues to locate a safe platform. It was not until the rats were 20-days-old, however, that they began to display minimal evidence of distal-cue utilization. Control experiments indicated that the 17-day-old subjects' failure on the distal problem was likely due to their inadequate spatial learning skills. These results were interpreted within a Jacksonian perspective of brain-behavior relations.

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.

Contextual fear conditioning, conjunctive representations, pattern completion, and the hippocampus.

Impaired contextual fear conditioning produced by damage to the hippocampus has been attributed to the loss of a conjunctive representation of the features of the context. There is, however, no direct evidence that conjunctive representations contribute to contextual fear conditioning. These experiments addressed this issue and found support for the conjunctive representation view. Two results made this point: (a) Preexposure to the conditioning context, but not to its separable features, facilitated contextual fear conditioning, and (b) generalization of fear conditioning to similar contexts was enhanced by preexposure to the context used to test for generalization. These results are interpreted as pattern completion to the preexposed context during the conditioning episode. They support the view that a conjunctive representation of context plays an important role in contextual fear conditioning and that the impairments produced by damage to the hippocampus result from the loss of this conjunctive contribution.

DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning.

It has been proposed that DBA/2 and C57BL/6 mice perform differently on some learning and memory tasks because of functional differences in the hippocampal formation. To evaluate this hypothesis, DBA/2 and C57BL/6 mice were tested on 2 forms of conditioned fear: contextual fear conditioning, which depends on the integrity of the hippocampal formation, and auditory cue conditioning, which does not. Both mouse strains displayed equivalent conditioning when the auditory cue was paired with shock, but DBA/2 mice showed significantly less conditioning to the context in which shock was experienced. These results are consistent with the hypothesis that the pattern of spared and impaired performance, which DBA/2 mice display on a variety of learning and memory tasks, is related to impaired hippocampal formation function.

A selective role for corticosterone in contextual-fear conditioning.

The contribution of corticosterone to contextual- and auditory-cue fear conditioning was examined. Adrenalectomized rats showed reduced contextual-fear conditioning when tested 24 hr after conditioning; however, neither immediate contextual- nor auditory-cue fear conditioning was impaired. Contextual-fear conditioning in adrenalectomized rats with corticosterone replacement during the 4-day interval separating surgery and conditioning matched the level of controls. Moreover, rats exposed to the context prior to adrenalectomy showed normal long-term contextual-fear conditioning. Corticosterone replacement administered after the conditioning episode also negated the effects of adrenalectomy. Thus, corticosterone's role in fear conditioning is selective: It appears to contribute to the neural processes that support the consolidation of a long-term memory representation of the context.

DHEA-S selectively impairs contextual-fear conditioning: support for the antiglucocorticoid hypothesis.

The authors had reported that glucocorticoids play a selective role in fear conditioning. The adrenal steroid dehydroepiandrosterone (DHEA) has been reported to act as a functional antiglucocorticoid. If DHEA has antiglucocorticoid properties, then its effects on fear conditioning might resemble those produced by adrenalectomy. The authors now report that chronic exposure to high levels of dehydroepiandrosterone sulfate (DHEA-S; converted in vivo to DHEA) produced the same pattern of results as adrenalectomy. Specifically, treatment with DHEA-S impaired contextual fear conditioning 24 hr after conditioning but not immediately after conditioning, and like adrenalectomy, DHEA-S had no effect on auditory-cue fear conditioning. Preexposure to the context before drug treatment eliminated the amnestic effects of DHEA-S, suggesting that, like adrenalectomy, DHEA-S exerted its effect by interfering with the construction of a contextual memory representation. Thus, DHEA appears to act as a functional antiglucocorticoid in the processes that mediate learning and memory.