Abstract
A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA A agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala-independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning.
Highlights
A key finding from studies of Pavlovian fear conditioning is that amygdala function is required to associate neutral conditioned stimuli (CSs) with aversive events
Post-hoc analysis of contextual freezing demonstrated that vehicle-treated mice froze significantly less than sham-treated controls, and muscimol-treated mice froze less to context exposure than vehicle-treated mice or sham controls (Figure 2A). These results demonstrate that perturbation of the dorsal hippocampus (DH) by vehicle infusion produces small deficits in contextual learning during delay fear conditioning, and that inactivation of this brain region with muscimol produces large deficits in contextual learning, confirming that the DH is critical to contextual but not delay fear conditioning
Post-hoc analysis revealed that in both contextual and CS freezing muscimol infused mice froze significantly less than vehicle controls, and that vehicle infusion significantly impaired contextual learning compared to sham controls, while a trend toward a deficit was observed in CS freezing. These results demonstrate that vehicle infusion into the DH disrupts contextual learning, and that inactivation of the DH with muscimol disrupts both contextual and trace-cued fear learning compared to vehicle controls
Summary
A key finding from studies of Pavlovian fear conditioning is that amygdala function is required to associate neutral conditioned stimuli (CSs) with aversive events (unconditioned stimuli; USs). [1,2]), there is general agreement that the amygdala is involved in some aspect of fear learning These models have revealed a great deal about the biochemical, genetic, and epigenetic mechanisms involved in the circuitry that underlies fear learning and memory One possibility is that the hippocampus maintains a representation of the CS during the trace interval and interacts with cortical regions to assign salience and predictive value to that representation It is not yet clear whether amygdala activity is a critical component of this task. It may be that unlike delay and contextual conditioning, activity in the hippocampus and cortex are sufficient to support acquisition of trace fear conditioning
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