Repeated corticosterone enhances the acquisition and recall of trace fear conditioning
Introduction
Chronic stress is known to produce aberrant brain plasticity and maladaptive behaviors. Some of the most prominent neuroplastic changes associated with repeated stress exposure occur in the hippocampus and amygdala as both structures are abundant in glucocorticoid receptors [1], [2]. Within the hippocampus, chronic stress can lead to decreased dendritic branching, decreased mossy-fiber synapses, and decreased adult neurogenesis [3], [4], [5]. This aberrant plasticity has been associated with deficits in hippocampal dependent memory tasks [3], [6]. However, within the amygdala, chronic stress seems to increase dendritic arborization and spine density [7], [8], and learned fear associations that depend on the amygdala are similarly enhanced after either repeated restraint stress or repeated exposure to the stress hormone corticosterone (CORT) [9], [10], [11].
Fear conditioning assesses a rodent's ability to associate neutral cues with an aversive experience. Variations of the fear conditioning paradigm have been developed that require the activation of different brain structures to successfully learn the task [11], [12]. For example, a typical delay fear conditioning protocol where the conditioned stimulus is followed immediately by or co-terminates with the unconditioned stimulus is largely an amygdala-dependent task [11], [13]. In contrast, trace fear conditioning, which separates the conditioned stimulus from the unconditioned stimulus by a temporal gap, relies on an intact hippocampus and is largely amygdala independent [12], [14]. Repeated stress or CORT administration produces a robust increase in fear memory in a delay fear conditioning paradigm [10], [15], [16]. This is thought to occur due to an enhancement of amygdala functioning following chronic stress or glucocorticoid exposure [9]. Trace fear conditioning provides the opportunity to examine whether chronic stress would also enhance fear memories in a hippocampal-dependent task.
Surprisingly few experiments have addressed this question. One group reported that 2 weeks of immobilization stress decreases trace memory recall, with no effect on memory acquisition [17], but another group found that 3 weeks of chronic mild stress enhances trace memory recall [18]. However, immobilization stress can produce variable behavioral effects possibly as a result of habituation effects, and both immobilization stress and chronic mild stress may produce individual differences or have no effect on HPA axis responses [19], [20], [21]. We examined this issue here using a repeated CORT paradigm that reliably increases depression-like behavior and amygdala-dependent fear memory, and alters amygdalar and hippocampal plasticity [10], [22], [23], [24], [25], [26], [27]. We examined the effects of repeated CORT administration on freezing behavior after three different trace fear conditioning training paradigms. Given previous findings in our lab, we expected to see an increase in trace fear memory in CORT treated animals [10]. Considering that we have also previously demonstrated that the effects of CORT on fear memory are dependent on the training paradigm [10], we also anticipated that these enhancements in fear will be dependent on the intensity of the trace fear conditioning protocol.
Section snippets
Animals
Three separate experiments used 18 (experiment 1), 19 (experiment 2), and 18 (experiment 3) adult male Long-Evans rats (purchased from Charles River, Canada). Rats were housed individually in standard polyproplylene cages maintained on a 12 h light/dark cycle (lights on at 07:00 h) in a room maintained at 21 °C. Rats had free access to water and Purina rat chow. All experimental procedures were conducted during the light phase under an animal care protocol approved by the University of
Body weight
Animals from experiments 1, 2, and 3 had similar changes in body weight over the course of treatment; therefore, the experiments were combined for statistical analysis. As shown in Fig. 1, CORT prevented the normal increase in body weight over time. A significant within-subjects main effect of day (F(1.49,75.78) = 160.31, p < 0.001) suggests that all animals gained weight over time. However, a significant Day by Treatment interaction (F(1.49,75.78) = 181.80, p < 0.001) indicated that the CORT and
Discussion
Two general conclusions can be drawn from the data in these experiments. First, repeated CORT exposure significantly enhances acquisition and recall of trace fear associations. Second, observable enhancements in fear behavior during recall of trace associations produced by CORT exposure are largely dependent on the intensity of the protocol used during training.
Our conclusion that CORT can enhance the acquisition of fear learning in a trace conditioning paradigm is evidenced by a significant
Acknowledgements
This work was supported by funding from the Natural Sciences and Engineering Research Council of Canada (NSERC) to LEK [grant number 222912]. The authors declare no conflicts of interest.
References (48)
- et al.
Glucocorticoid receptor antagonists in the hippocampus modify the negative feedback following neural stimuli
Brain Res.
(1999) - et al.
Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: an immunohistochemical and in situ hybridization study
Neurosci. Res.
(1996) - et al.
Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement
Neuroscience
(2000) - et al.
Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons
Brain Res.
(1992) - et al.
Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons
Brain Res.
(1990) - et al.
Repeated stress causes reversible impairments of spatial memory performance
Brain Res.
(1994) - et al.
Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala
Neuroscience
(2006) - et al.
The effect of chronic corticosterone on fear learning and memory depends on dose and the testing protocol
Neuroscience
(2015) - et al.
Bridging the interval: theory and neurobiology of trace conditioning
Behav. Process.
(2014) - et al.
Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule, its polysialylation, and L1
Neuroscience
(2001)