Research reportRole of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation
Introduction
Rats exposed to tone-footshock pairings, later display defensive fear responses when re-exposed to either the environmental context where shock occurred (contextual-fear conditioning) or to the tone that preceded shock (auditory-cue fear conditioning). Contextual and auditory-cue fear conditioning are interesting because they are thought to depend on different neural processes. Evidence for this comes from the findings that contextual but not auditory-cue fear conditioning can be disrupted by hippocampal damage [13], [32], [33], adrenalectomy [35], treatment with dehydroepiandrosterone (DHEA) [9] and morphine injection into the nucleus accumbens [44].
Rats that are socially isolated for several hours after conditioning also show impaired contextual but normal auditory-cue fear conditioning [39].
Because of the stressful nature of social isolation, we have previously examined the role of corticosterone in producing this impairment in contextual fear conditioning. This is because the hippocampus (which is critical to contextual fear conditioning, [13], [32], [33] is rich in glucocorticoid receptors [21], [22], and high glucocorticoid levels are thought to impair learning and memory [23]. However, when we attempted to block the isolation induced impairment in contextual fear conditioning with glucocorticoid receptor antagonists, neither Type I, Type II, nor the combination of both Types, was able to attenuate the impairment in contextual fear caused by isolation. Rather, Type I, Type II [34], and Type I and II glucocorticoid receptor antagonists in combination (unpublished data) actually produced impairments in contextual but not auditory-cue fear. In addition, Pugh et al. [35] reported that adrenalectomized rats showed impaired contextual fear conditioning and that this impairment could be eliminated by corticosterone replacement. Finally, post-conditioning corticosterone administration actually enhanced contextual but not auditory-cue fear [40]. Based on these results, it seems unlikely that the isolation induced impairment in contextual fear can be attributed to stress induced corticosterone release.
The present experiments were designed to explore another potential mediator of the impairment in contextual fear caused by isolation, interleukin-1β (IL-1β). IL-1β is a cytokine produced by a number of peripheral cell types and is involved in a variety of immune and inflammatory responses [8], [29], [20].
More recently, IL-1β has also been implicated in neurochemical and behavioral consequences of stressors. For example, immobilization stress increases IL-1β mRNA [24] and bioactivity [41] in the brain, while inescapable tail shock stress increases IL-1β protein levels [26] in brain. IL-1β appears to play a role in these stress responses because central IL-1β administration produces endocrine, neurochemical, and behavioral changes similar to those produced by stressors [42]. Central injection of IL-1 receptor antagonist (IL-1ra) also significantly inhibits both the brain monoamine and pituitary adrenal responses to immobilization stress [43] and the potentiation of fear conditioning and escape learning failure following inescapable tail shock [19].
IL-1β may be a key mediator in the isolation induced impairment in contextual fear because increased levels of IL-1β interfere with long-term potentiation (LTP), an electrophysiological correlate of learning and memory [12], [2]. IL-1β also increases serotonin release in the hippocampus [17], [18], which can depress the expression of LTP [4], [45]. Furthermore, we reported that peripheral lipopolysaccharide (a constituent of cell walls of gram-negative bacteria that increase brain IL-1β gene expression; [14], [15]) administration impairs contextual but not auditory-cue fear, and that this effect is blocked by IL-1ra [36]. For these reasons we explored whether social isolation stress impairs contextual fear by inducing an increase in brain IL-1β.
Section snippets
Subjects
Adult (400–450 g) male Sprague–Dawley (Harlan, Indianapolis, IN, USA) rats were housed 4 to a cage at 25°C on a 12 h light/dark cycle (lights on at 06:45 h). Rats were allowed free access to food and water and were given 1 week to acclimate to colony conditions before experimentation began. All experiments were conducted in accordance with protocols approved by the University of Colorado Animal Care and Use Committee.
Surgery and microinjections
Rats were anesthetized with Halothane, and using Bregma as a reference, were
Methods and procedures
Previously, Rudy [39] reported that social isolation after conditioning impaired contextual but not auditory-cue fear conditioning in juvenile rats (35 days old; 100–150 g). The purpose of Experiment 1 was to determine if social isolation would also impair contextual but not auditory-cue fear conditioning in operated adult rats (400–450 g). Rats were implanted with ICV cannulae and allowed 4 weeks to recover. They were conditioned with 2 tone-shock pairings. Immediately after conditioning, half
Methods and procedures
If an increase in brain IL-1β activity is involved in producing the impairment in contextual fear conditioning caused by social isolation, then one might expect to observe an increase in brain IL-1β protein levels in isolated rats. To test this hypothesis, rats were conditioned with 2 tone shock pairings. Immediately after conditioning, rats were either isolated (n=20) or returned to the home cage (n=16). At 1 or 3 h after conditioning, both isolated and home cage rats were sacrificed and the
Methods and procedures
If increased IL-1β protein levels in brain induced by isolation are critical to the impairment in contextual fear conditioning caused by isolation, then the central administration of IL-1ra should be able to block the effect of isolation on contextual fear conditioning. To test this hypothesis, rats were implanted with ICV cannulae and allowed 4 weeks to recover. They were conditioned with 2 tone shock pairings. Immediately after conditioning half of the rats were given an ICV injection of
Methods and procedures
If isolation impairs contextual fear conditioning by inducing an increase in IL-1β protein in brain, then it should be possible to impair contextual fear conditioning by injecting IL-1β centrally. To test the hypothesis that IL-1β is sufficient in itself to produce the impairment in contextual fear conditioning caused by isolation, rats were implanted with ICV cannulae and allowed 4 weeks to recover. Rats were conditioned with two tone-shock pairings, and immediately after conditioning were
General discussion
The present set of experiments strongly implicates central IL-1ß activity in producing the impairment in contextual fear conditioning caused by social isolation. First, 1 and 3 h of isolation after conditioning increased IL-1β protein levels in the hippocampus and posterior cortex but not in the pituitary gland or hypothalamus. Second, central IL-1ra was able to block the impairment in contextual fear conditioning caused by social isolation. Third, like isolation, the administration of central
Acknowledgements
This research was supported by grants NIH MH 5528, NIH MH4505, RSA MH 00314, and NIH F31 MH12148-01, as well as the Undergraduate Research Opportunities Program at the University of Colorado.
References (46)
- et al.
Pyrogens specifically disrupt the acquisition of a task involving cognitive processing in the rat
Brain Behav. Immunol.
(1995) - et al.
Interleukin-1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus
Brain Res.
(1993) - et al.
Occurrence of interleukin-1 in cerebrospinal fluid of the conscious cat
Brain Res.
(1988) - et al.
Serotonin blocks the long-term potentiation induced by primed burst stimulation in the CA1 region of rat hippocampal slices
Neuroscience
(1992) - et al.
Virus infection as a stressor: influenza virus elevates plasma concentrations of corticosterone, and brain concentrations of MHPG and tryptophan
Physiol. Behav.
(1989) - et al.
Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis
Neurosci. Biobehav. Rev.
(1992) - et al.
Interleukin-1 beta inhibits long-term potentiation in the CA3 region of mouse hippocampal slices
Euro. J. Pharmacol.
(1990) - et al.
Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice
Brain Res.
(1994) - et al.
Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock
Brain Res.
(1995) - et al.
Corticosterone binding to hippocampus: nuclear and cytosol binding in vitro
Brain Res.
(1973)
Uptake of corticosterone by rat brain and its concentration by certain limbic structures
Brain Res.
Stress and cognitive function
Curr. Opin. Neurobiol.
Immobilization stress induces interleukin-1b mRNA in the rat hypothalamus
Neurosci. Lett.
Interleukin-1 receptor antagonist does not reverse lipopolysaccharide-induced inhibition of water intake in rat
Eur. J. Pharmacol.
Interleukin-1 beta, but not interleukin-6 impairs spatial navigation learning
Brain Res.
Type II glucocorticoid receptor antagonists impair contextual but not auditory-cue fear conditioning in juvenile rats
Neurobiol. Learn. Mem.
Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide
J. Neuroimmunol.
Serotonin inhibits induction of long-term potentiation at commissural synapses in hippocampus
Brain Res.
Endotoxin produces a depressive-like episode in rats
Brain Res.
A functional behavioristic approach to aversively motivated behavior: predatory imminence as a determinant of the topography of defensive behavior
The inflammatory response in interleukin-1 beta-deficient mice: comparison with other cytokine-related knock-out mice
J. Leukocyte Biol.
DHEA-S selectively impairs contextual-fear conditioning: support for the antiglucocorticoid hypothesis
Behav. Neurosci.
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