Jerry W. Rudy

Configural association theory: The role of the hippocampal formation in learning, memory, and amnesia

It is proposed that the hippocampal formation makes a unique contribution to memory by providing the neural basis for the initial acquisition and storage of configural associations among events. A distinction is made between two kinds of memory processes: a simple associative process, which does not depend on the hippocampal formation, and a configural associative process, which does. The simple associative system records the organism’s experiences as changes in the strength of associations between elementary stimulus events. The configural associative system combines the representations of elementary stimulus events to construct unique representations and allows for the formation of associations between these configural representations and other elementary representations. In the present paper, the results of two experiments designed to test predictions of our theory are described. We then illustrate how the theory can be applied to explain a wide range of impairments that have been observed when learning and memory tasks have been employed to assess the effect of hippocampal formation damage. These include tasks that measure place learning, recognition memory, latent inhibition, serial-compound conditioning, discrimination-reversal learning, and stimulus-selection processes. The relationship of our position to some other views of hippocampal function is discussed, and we conclude with suggestions for future research.

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 Role of the Dorsal Hippocampus in the Acquisition and Retrieval of Context Memory Representations

It is argued that the hippocampus contributes to contextual fear conditioning by supporting the acquisition of a conjunctive memory representation of context, which associates with shock. This function was examined by studying the context pre-exposure facilitation effect (CPFE). A rat that is shocked immediately after being placed into a context subsequently displays almost no fear of that context. However, if it is pre-exposed to the context the day before immediate shock, it displays significant freezing to that context. By using 5-aminomethyl-3-hydroxysoxazole to temporarily inactivate the dorsal hippocampus (DH) at three different phases of the procedure, which produces the CPFE, we show that the hippocampus is necessary for the following: (1) acquisition of the context memory, (2) retrieval of this memory at the time of immediate shock, and (3) retrieval of the context-shock memory at the time of testing. In contrast, inactivating the DH before a standard contextual shock experience had no effect on contextual fear conditioning. These results support the view that two processes can support contextual fear conditioning: (1) conditioning to the conjunctive representation, which depends on the hippocampus, and (2) conditioning to the features that make up the context, which does not.

The hippocampal formation is necessary for rats to learn and remember configural discriminations

A negative patterning discrimination problem was arranged by reinforcing rats for bar pressing when either a light or tone was presented (L+/T+) but not reinforcing the response when the compound stimulus, light and tone, was presented (LT-). To solve this problem, the animal must be able to construct a unique configural representation of the compound that can be distinguished from the representations of the individual elements. We have proposed that the hippocampal formation is essential for the acquisition and retention of associations involving configural representations. Thus, our theory predicts that animals with hippocampal formation damage will not learn the negative patterning problem and that animals who learned this problem before receiving hippocampal formation damage will not retain the solution. These predictions were confirmed by the results of two experiments. The animals with hippocampal formation damage were unable to solve the negative patterning problem. These animals were able to solve a simple discrimination in which responding in the presence of a light was rewarded but responding in the presence of a tone was not rewarded. These results are discussed in relation to several other theories of hippocampal formation function.

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

Abstract Interleukin-1 beta (IL-1β), 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-1β to influence memory processing and neural plasticity exist. We then present behavioral evidence that central IL-1β administration and agents that induce central IL-1β 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-1β activity are blocked by antagonizing the actions of IL-1β. Finally, we discuss these data in terms of their implications for a physiological role of IL-1β in memory consolidation processes and a potential role of IL-1β in producing memory impairments associated with stress, aging, Alzheimers disease, and AIDS related dementia complex.

Peripheral infection and aging interact to impair hippocampal memory consolidation

We report that a peripheral injection of Escherichia coli produces both anterograde and retrograde amnesia in 24 month old, but not 3 month old rats for memories that depend on the hippocampus, that is, memory of context, contextual fear, and place learning. The anterograde effect was restricted to measures of long-term memory. Short-term memory was not affected, nor did E. coli produce amnesia for auditory-cue fear conditioning. There were no age related effects on memory in vehicle-treated rats. In addition to these age-related cognitive effects of E.coli, we report that it produced a marked increased in IL-1beta levels in the hippocampus, but not in parietal cortex or serum. These findings support the hypothesis that age is a vulnerability factor that increases the likelihood that an immune challenge will produce a cognitive impairment. It is possible that this cognitive vulnerability is mediated by age-related changes in the glial environment that results in an exaggerated brain pro-inflammatory response to infection.

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, corticosterones 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.

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.

Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation.

Isolating rats immediately after conditioning impairs contextual but not auditory-cue fear conditioning. The reported experiments examine the involvement of brain interleukin-1beta (IL-1beta) in the impairment in contextual fear conditioning caused by social isolation. As measured by the conditioned freezing response, 5 h of social isolation after conditioning, impaired contextual but not auditory-cue fear conditioning in adult male Sprague-Dawley rats. Social isolation for 1 or 3 h after conditioning also increased IL-1beta protein in the hippocampus and cerebral cortex. No differences in IL-1beta protein levels were found in the pituitary or the hypothalamus. Intracerebroventricular (ICV) IL-1 receptor antagonist (IL-1ra) given after conditioning prevented the impairment in contextual fear conditioning caused by isolation. ICV IL-1ra had no effect on auditory-cue fear conditioning in these same animals, nor did it affect the level of contextual fear conditioning displayed by home cage controls. Like isolation, ICV IL-1beta (10 or 20 ng) after conditioning also impaired contextual but not auditory-cue fear conditioning. These results suggest that increased levels of brain IL-1beta play a role in producing the impairment in contextual fear conditioning produced by social isolation. These findings also add to the generality of the idea that stressors induce IL-1beta activity in the brain and that IL-1beta may play physiological roles in the uninjured brain.

Separate neural substrates for skill learning and performance in the ventral and dorsal striatum.

It is widely accepted that the striatum of the basal ganglia is a primary substrate for the learning and performance of skills. We provide evidence that two regions of the rat striatum, ventral and dorsal, play distinct roles in instrumental conditioning (skill learning), with the ventral striatum being critical for learning and the dorsal striatum being important for performance but, notably, not for learning. This implies an actor (dorsal) versus director (ventral) division of labor, which is a new variant of the widely discussed actor-critic architecture. Our results also imply that the successful performance of a skill can ultimately result in its establishment as a habit outside the basal ganglia.