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

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Abstract

Isolating rats immediately after conditioning impairs contextual but not auditory-cue fear conditioning. The reported experiments examine the involvement of brain interleukin-1β (IL-1β) 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-1β protein in the hippocampus and cerebral cortex. No differences in IL-1β 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-1β (10 or 20 ng) after conditioning also impaired contextual but not auditory-cue fear conditioning. These results suggest that increased levels of brain IL-1β 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-1β activity in the brain and that IL-1β may play physiological roles in the uninjured brain.

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.

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