Rapid synaptic potentiation within the anterior cingulate cortex mediates trace fear learning

Long term potentiation (LTP) of central synapses is believed to be the basic mechanism that drives memory storage within the brain [1,2]. Although a critical role for the cerebral cortex in remote fear memory recall has been established [3], little is known regarding immediate cortical contributions to fear memory formation. Much effort instead has focused on the amygdala, where animal studies revealed that associative fear conditioning, which pairs an arbitrary conditioning stimulus (CS) with a noxious one (US), induces changes in excitatory glutamatergic transmission [4-6], and requires postsynaptic GluA2 expression for memory maintenance [7]. Evidence suggests however that in addition to the amygdala, cortical structures also mediate fear learning. In humans, trace fear conditioning, which introduces a time interval between the CS and the US, activates several brain areas including the amygdala, hippocampus, medial prefrontal cortex (mPFC), and the anterior cingulate cortex (ACC) [8,9]. The ACC is involved in the processing of pain, emotion, and threat related stimuli [10,11], and we recently found a trace fear memory enhancement in mice overexpressing Ca2+ ？ calmodulin-dependent protein kinase IV (CaMKIV), that corresponded with enhancements of ACC LTP in layer II/III pyramidal neurons [12]. In rats, trace fear conditioning induces ACC c-fos expression, and visual distraction during the time interval separating the CS and US prevents fear memory and c-fos expression [13].Glutamatergic synapses in the ACC are plastic [14-16], and the N-methyl-D-aspartate (NMDA) receptors are critical for LTP induction within the ACC [17]. The GluN2B subunit in particular has been found to be a critical mediator of pain induced alterations within the ACC [18], and forebrain overexpression of GluN2B in mice enhances contextual and auditory fear memory [19]. We previously showed that LTP induction within the ACC corresponds with postsynaptic upregulation of AMPA receptor GluA1 subun