Prelimbic prefrontal neurons drive fear expression: a clue for extinction--reconsolidation interactions.

Learning associations between cues in the environment gives organisms the ability to predict impending danger. The last few decades of research have established that these stimulus– danger or fear associations are formed in the amygdala (LeDoux, 2000). This type of learning is modeled in the laboratory by presenting a neutral sensory stimulus (such as a tone) with an aversive stimulus (such as a shock) in close temporal contiguity. As a result, organisms learn to fear the previously neutral stimulus. The convergence of afferent inputs signaling the neutral stimulus (termed the conditioned stimulus or CS) and the aversive stimulus (unconditioned stimulus or US) onto neurons in the lateral amygdala (LA) leads to the long-term potentiation (LTP) of CS input synapses, such that when the CS subsequently occurs on its own, these inputs are now strong enough to drive outputs from the LA to trigger the fear response. The fear response is mediated through the major output structure of the amygdala, the central nucleus, and comprises a wide repertoire of behavioral and physiological reactions including behavioral freezing, changes in heart rate and blood pressure, and release of stress hormones. But whereas CS-evoked fear reactions, such as freezing, are long lasting and slow to dissipate (lasting at least as long as the CS, that is, a few seconds to several minutes, and in some cases longer), LA neural responses during the CS are brief and phasic ( 50–500 ms) (Quirk et al., 1995). Thus, while the association of the CS and US are formed in the LA (and possibly elsewhere) and neural output from the LA is required to initiate the fear response, the expression and maintenance of the fear response to the CS is sustained somewhere else. Though individual brain regions have been identified that participate as output structures for specific reactions to fearful stimuli (such as the midbrain periaqueductal gray for conditioned freezing and analgesia), the specific mechanisms by which these fearconditioned responses are maintained are not well understood. This has prompted recent studies examining possible brain regions that function to sustain the fear response throughout the CS, and has led to the discovery of the prelimbic cortex (PL) as a likely candidate for this role. Previous studies showed that inactivation of PL reduced conditioned fear responses, whereas stimulation of PL enhanced fear responses (Corcoran and Quirk, 2007; Vidal-Gonzalez et al., 2006). Additional evidence that directly linked PL activation and sustained conditioned fear was reported recently in The Journal of Neuroscience by Burgos-Robles et al. (2009). Using multichannel unit recordings in behaving rats, the authors characterized the firing profile of PL neurons throughout fear conditioning and extinction. They reported three key findings: (1) PL neurons showed conditioninginduced enhancement of neural firing rate in response to the CS that diminished with extinction; (2) These conditioned responses were sustained throughout the presentation of the conditioned stimuli (a 30 s tone) and correlated with the expression of CS-induced freezing behavior; (3) The magnitude of CS-induced PL responses during fear conditioning corresponded with the ability to successfully recall extinction memory 24 h later. Together, these findings provide striking support for the idea that PL neurons drive the expression of conditioned fear. The PL is well situated for this role because it receives inputs from the hippocampus and sensory cortex, and it is the target of neuromodulators such as norepinephrine and dopamine that are released in response to frightening stimuli and might participate in the maintenance of the fear response. PL also sends outputs to the basal nucleus of the amygdala, as well as to other regions mediating not only conditioned freezing (periaqueductal gray) but also conditioned instrumental responses (ventral striatum) such as active avoidance. Based on this architecture, Burgos-Robles et al. (2009) proposed a model (their Fig. 7) wherein PL converts phasic inputs from the amygdala into sustained outputs.