Background

The trace fear conditioning (TFC) paradigm differs from standard fear conditioning paradigms (Heise et al., 2017; Segev et al., 2013 and 2015) by the simple insertion of a trace interval between a conditioned stimulus (CS, e.g., tone) and an unconditioned stimulus (US, e.g., electric foot shock), and repeated application of their combination at fixed intervals. The TFC paradigm involves the formation of temporally non-contiguous associations in both natural and pathological conditions, and is considered a complex, hippocampal-dependent paradigm, in contrast to simple cortical-dependent learning paradigms such as taste learning (Stern et al., 2013; Ounallah-Saad et al., 2014; Rappaport et al., 2015; Levitan et al., 2016; Sharma et al., 2018). A remarkable aspect of trace fear conditioning is that it provides a reliable model of attention-dependent associative learning that reflects the complex processing of the hippocampus and alters the circuitry recruited for learning. Several studies have shown that hippocampal lesions before and after training impair the ability of the animal to associate the CS and US stimuli when they are separated by the trace interval (Bangasser et al., 2006; Esclassan et al., 2009). However, animals with hippocampal lesions could associate the CS and US in a delay situation, where no trace interval separates them, but the CS and US co-terminate (McEchron et al., 1998; McEchron et al., 2000; Quinn et al., 2002). Although other brain regions such as the medial prefrontal cortex (Peters et al., 2009; Beeman et al., 2013), the entorhinal and perirhinal cortices (Esclassan et al., 2009; Kent and Brown, 2012), and the amygdala (Pape and Pare, 2010; Gilmartin et al., 2012) are involved in relaying stimulus inputs and response outputs, the hippocampus is selectively involved in trace conditioning rather than general fear learning or expression. Moreover, the acquisition of trace fear conditioning increases intrinsic excitability and facilitates LTP in pyramidal neurons of the hippocampus (Song et al., 2012), which makes trace fear conditioning an ideal paradigm to test hippocampal function in young and aged mice (Sharma et al., 2018).