Biomedical subjects

J W Rudy

Publications and source records attributed to J W Rudy.

At least 19 recordsLinked to original sources

PubMed2004

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.

Amygdala↗

PubMed2003

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.

Animals↗

PubMed2001

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.

Animals↗

PubMed2001

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.

Animals↗

PubMed2001

Conjunctive representations, the hippocampus, and contextual fear conditioning.

The context in which events occur can be represented as both (1) a set of independent features, the feature representation view, and (2) a set of features bound into a unitary representation, the conjunction representation view. It is assumed that extrahippocampal (e.g., neocortical) areas provide a basis for feature representations, but the hippocampal formation makes an essential contribution to the automatic storage of conjunctive representations. We develop this dual-representation view and explore its implications for hippocampal contributions to contextual fear conditioning processes. To this end, we discuss how our framework can resolve some of the conflicts in the recent literature relating the hippocampus to contextual fear conditioning. We also present new data supporting the role of a key mechanism afforded by conjunctive representations--pattern completion (the ability of a subset of a memory pattern to activate the complete memory)--in contextual fear conditioning. As is implied by this mechanism, we report that fear can be conditioned to the memory representation of a context that is not actually present at the time of shock. Moreover, this result is predicted by our computational model of cortical and hippocampal function. We suggest that pattern completion demonstrated in animals and by our model provides a mechanistic bridge to human declarative memory.

Animals↗

PubMed2000

Human immunodeficiency virus-1 coat protein gp120 impairs contextual fear conditioning: a potential role in AIDS related learning and memory impairments.

Many AIDS patients suffer from cognitive impairments including deficits in learning and memory. The Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein gp120 is one possible mediator of these impairments. This is because gp120 activates brain microglial cells and astrocytes, and in vivo activation of glia leads to the release of the proinflammatory cytokine interleukin-1 beta (IL-1beta). gp120 induced IL-1beta release could be involved in producing memory impairments associated with AIDS because central IL-1beta activity adversely affects cognitive function. The reported experiments evaluated the effects of i.c.v. gp120 administration and subsequent IL-1beta activity on learning and memory processes in the rat. Intracerebroventricular gp120 produced memory impairments on hippocampally dependent contextual fear conditioning, but not hippocampally independent auditory-cue fear conditioning following post-conditioning gp120 administration. Central gp120 administration also caused increases in IL-1beta protein levels in the hippocampus and frontal cortex but not in the hypothalamus. gp120 induced memory impairments were blocked by 2 different IL-1 antagonists, alpha melanocyte stimulating hormone (alphaMSH) and interleukin-1 receptor antagonist (IL-1ra). Finally, heat denaturation of the tertiary structure of gp120 abolished its effects on fear conditioning, suggesting that gp120 impairs contextual fear conditioning by binding to its receptors on glia.

AIDS Dementia Complex↗

PubMed2000

Computational principles of learning in the neocortex and hippocampus.

We present an overview of our computational approach towards understanding the different contributions of the neocortex and hippocampus in learning and memory. The approach is based on a set of principles derived from converging biological, psychological, and computational constraints. The most central principles are that the neocortex employs a slow learning rate and overlapping distributed representations to extract the general statistical structure of the environment, while the hippocampus learns rapidly, using separated representations to encode the details of specific events while suffering minimal interference. Additional principles concern the nature of learning (error-driven and Hebbian), and recall of information via pattern completion. We summarize the results of applying these principles to a wide range of phenomena in conditioning, habituation, contextual learning, recognition memory, recall, and retrograde amnesia, and we point to directions of current development.

Hippocampus↗

PubMed1999

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.

Acoustic Stimulation↗

PubMed1999

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.

Analysis of Variance↗

PubMed1999

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.

Animals↗

PubMed1998

Repeated neonatal phencyclidine treatment impairs performance of a spatial task in juvenile rats.

The present study was designed to determine whether repeated postnatal blockade of N-methyl-D-aspartate (NMDA) channel produces cognitive deficit in juvenile rats. Rats receive phencyclidine (PCP) intraperitoneally (i.p.) from postnatal Day 5 and continued daily till Day 15. On Day 28, saline- and PCP-treated rats were trained in the Morris water maze task. PCP-treated rats performed as well as the saline-treated rats on the first day of testing, but on the second day of testing they did significantly poorly compared to saline-treated controls. These data suggest that chronic postnatal NMDA channel blockade by PCP impairs processes that enable rats to retain spatial information.

Aging↗

PubMed1998

Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning.

The reported experiments explore the effects of peripheral LPS administration on learning and memory processes. As measured by the conditioned freezing response, intraperitoneal LPS administration given after conditioning impaired contextual but not auditory-cue fear conditioning in both juvenile (hooded Long Evans) and adult rats (albino Sprague Dawley) of two different strains. This impairment in contextual fear conditioning was not dependent on the presence of the tone. Preexposure to the context eliminated the effect of LPS on contextual fear conditioning, and in addition, LPS given after context preexposure negated the beneficial effects of preexposure on contextual fear. These results suggest that LPS disrupts posttrial memory consolidation processes. In support of the hypothesis that LPS-induced proinflammatory cytokine release is involved in producing the impairment in contextual fear caused by LPS, peripheral interleukin-1 receptor antagonist (IL-1ra) administered subcutaneously at a dose of 100 mg/kg prevented the impairment in contextual fear caused by LPS. These experiments provide evidence for a role of immune activation and cytokine activity in learning and memory processes.

Acoustic Stimulation↗

PubMed1998

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

Time of conditioning influences long-term retention of contextual but not auditory-cue fear conditioning. Long-Evans rats (Rattus norvegicus) conditioned at 12 noon displayed reduced contextual fear conditioning compared to rats conditioned at 8 a.m. or 4 p.m. This effect was eliminated by exposure to the context 24 hr prior to conditioning and by a posttrial injection of corticosterone (1.0 mg/kg). Time of conditioning did not influence short-term retention of contextual fear. These results suggest that time of conditioning influences the posttrial processes that construct a memory representation of the context. They also support the view that contextual and auditory-cue fear conditioning depend on different processes. These results are discussed in relation to the concept of memory storage modulators.

Animals↗

PubMed1997

Type II glucocorticoid receptor antagonists impair contextual but not auditory-cue fear conditioning in juvenile rats.

There is evidence that glucocorticoids may play a role in learning and memory. To further explore this possibility, we examined the effect of the Type II glucocorticoid antagonists on contextual fear conditioning. This conditioning task is dependent on the hippocampal formation, a brain structure known to be rich in glucocorticoid receptors. Rats systemically injected with a Type II antagonist either 1 h prior to conditioning (RU 38486 and RU 40555) or immediately after conditioning displayed less contextual fear conditioning than rats injected with vehicle. Although RU impaired contextual fear conditioning, it had no effect on auditory fear conditioning. These data are consistent with other reports that contextual fear conditioning and auditory-cue fear conditioning depend on different processes and with the hypothesis that glucocorticoid activity contributes to the processes involved in the consolidation of some forms of memory.

Animals↗

PubMed1997

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.

Acoustic Stimulation↗

PubMed1997

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.

Acoustic Stimulation↗

PubMed1996

A developmental analysis of contextual fear conditioning.

Contextual fear conditioning by 18- and 23-day-old rats was compared in two training contexts, a transparent Plexiglas chamber or a black Plexiglas chamber. As measured by a conditioned defensive freezing response, older rats displayed more contextual fear than younger rats. At both ages conditioning was (a) stronger in the black chamber than in the clear chamber, (b) a nonmonotonic function of retention interval, with freezing being greater at the immediate and 24-hr retention interval than at the 10-min interval, and (c) preexposure to the context 24 hr before conditioning enhanced conditioned freezing observed at the 10-min retention interval. Additional experiments suggest that rats at both ages acquire independent representations of the visual and tactile features of the context. These results support Rudy and Morledge's (1994) hypothesis that contextual fear conditioning is mediated by both a short-term and a long-term memory system and that long-term memory for contextual fear requires the consolidation of a representation of the context. They challenge their view that there is a qualitative developmental difference in long-term memory processes between 18- and 23-day-old rats.

Aging↗

PubMed1996

Scopolamine administered before and after training impairs both contextual and auditory-cue fear conditioning.

When administered before training to 23-day-old Long-Evans rats, scopolamine hydrobromide significantly impaired both contextual and auditory-cue fear conditioning in a dose-dependent manner. Methylscopolamine which does not cross the blood-brain barrier, however, had no effect on either form of conditioned fear. Scopolamine administered up to 3 h after training also impaired both forms of fear conditioning when administered following a single pairing of the auditory cue and shock. When rats received three pairings, however, a posttraining treatment with scopolamine only impaired contextual fear conditioning. These results suggest that central cholinergic systems are involved in the posttrial processes that establish the memory trace for the conditioning experience.

Animals↗