The prefrontal cortex regulates the expression of fear based on previously learned information. facilitates fear memory through integration of sensory and emotional signals and through coordination of memory storage in an amygdala-based network. in this network in addition to regulating the subsequent of fear. In the next section we discuss findings from trace and contextual fear conditioning which provide an avenue for studying the role of the PFC in fear memory formation. Trace and contextual fear conditioning Dorsal regions of the PFC are necessary for associative fear learning when temporal or contextual complexity is usually introduced. In trace fear conditioning a cue predicts the occurrence of an aversive shock that will occur many seconds later. The association of the cue and shock cannot be supported by simultaneous sensory activation converging on amygdala neurons as can be the case for delay conditioning. Thus additional circuitry is usually recruited to process this temporal component including the prefrontal cortex hippocampus and entorhinal and perirhinal cortices [11 17 28 The precise role of each structure is largely unknown but it is usually thought that activity in one or more of these structures may support trace conditioning by providing a bridging transmission between representations of the CS and UCS. While some computational models suggest that the hippocampus might provide a bridging transmission [34 35 neither CA1 nor DG areas exhibit firing patterns consistent with providing this transmission . More recently the PFC has emerged as a strong candidate for this function. Cue-initiated prolonged firing lasting several seconds had been well documented in studies of working memory in primates. Recording studies in Rabbit polyclonal to Shc.Shc1 IS an adaptor protein containing a SH2 domain and a PID domain within a PH domain-like fold.Three isoforms(p66, p52 and p46), produced by alternative initiation, variously regulate growth factor signaling, oncogenesis and apoptosis.. trace fear conditioning showed that models in PFC maintain firing past CS-offset into the trace interval for both short 2-sec  and long 20-sec intervals  (Physique 1A). These “bridging” cells are observed in the dorsal prelimbic (PL) area but not the ventral infralimbic (IL) area . Similar results have been obtained in rabbits performing trace eyeblink conditioning with prolonged firing neurons located primarily in deep output layers of dorsal PL and anterior cingulate cortex (ACC) [38-40]. This anatomical position is usually in line with a model where PL provides a bridging transmission allowing CS-activated networks to coincide with UCS delivery. Elegant work out of the Mauk lab has provided physiological support for such a model. Electrical activation of cortical input to cerebellum during the CS and trace interval was sufficient to support acquisition of eyeblink CRs in the absence of a functioning PFC . Additional lines of Epothilone D evidence provide indirect support for any bridging role for the PFC in associative fear learning. Molecular mechanisms important for prolonged firing of cortical cells such as activation of NR2B-containing NMDA receptors and muscarinic acetylcholinergic (mACh) receptors are important for trace fear conditioning [18 42 We recently directly tested the requirement of prefrontal trace interval bridging activity to learning using optogenetic silencing of prelimbic neurons during the trace interval . Silencing PL activity during the 20-sec trace interval but not during the CS or inter-trial interval prevented the development of fear to the CS (Physique 1). This obtaining showed for the first time that prefrontal cortical activity is likely to link discrete events in memory. The next challenge is usually to determine the information content of this bridging activity. It is unlikely to be sensory processing per se a function that may be supported by prolonged firing in perirhinal cortex [30 43 Instead it Epothilone D may reflect the Epothilone D maintenance of attentional resources during the CS-UCS interval and/or the coordination of associative encoding downstream in amygdala and rhinal cortices. Whether this activity contributes to local storage of the association in the PFC is also a question of current interest (Box 1). Physique 1 Bridging activity in the PL PFC is necessary for trace fear conditioning. (A) Rats were trained with trace fear conditioning and unit activity in PFC or hippocampus was recorded during training. Prelimbic but not hippocampal neurons exhibit sustained … Box 1. Role of the prefrontal cortex in memory storage Activity in the prefrontal cortex is critical for the acquisition of trace and contextual Epothilone D fear memories but whether the PFC also serves as a storage site for these remembrances is usually a matter of some argument. In trace.