Repeated corticosterone enhances the acquisition and recall of trace fear conditioning

Highlights

• The effects of chronic corticosterone (CORT) on trace fear conditioning are unknown.

• Long-Evans rats received vehicle or CORT (40 mg/kg) injections for 21 days.

• CORT increased both the acquisition and recall of trace conditioned fear.

• Enhanced recall in CORT rats was dependent on the intensity of training.

Abstract

Repeated exposure to high levels of stress hormones can enhance contextual and discrete fear conditioning in rats. A common belief is that this enhanced fear memory is largely mediated by the amygdala because both contextual and discrete fear conditioning are dependent on an intact amygdala. However, trace fear conditioning is thought to be amygdala independent, and therefore, it is not clear what impact stress would have on this form of fear learning. Here, we examined whether the stress hormone corticosterone (CORT) would enhance memory in a hippocampal-dependent trace fear conditioning test. Male Long-Evans rats received either 40 mg/kg of CORT or vehicle injections for 21 consecutive days. On day 22, rats received either 1, 2, or 5 tone-trace-shock pairings. On day 23, the rats were tested for behavior to the conditioned tone cues in a novel context. We found that CORT significantly increased the acquisition of trace conditioned fear. We also found that CORT significantly increased recall of trace conditioned cues, but only when a 2 trace-pairing protocol was used during training. These results suggest that CORT can enhance non-amygdala forms of fear learning and memory and that high levels of stress hormones modify the physiological substrates that mediate emotionally driven behavior in tasks that are less dependent on amygdala functioning.

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.