Is the Amygdala a Locus Viewpoint of “ Conditioned Fear ” ?

freezing and FPS (Walker and Davis, 1997; see also Since the publication of Weiskrantz’ seminal paper, widely Davis, 1997, for a review of much of the relevant literainterpreted as suggesting that amygdala lesions impair ture). Therefore, critical additional evidence must be the formation of stimulus–reinforcement associations provided to exclude the very real possibility that the (Weiskrantz, 1956), extensive research in many laboraimpairing effects of L/BL lesions are due simply to an tories has attempted to determine the role(s) of the impaired ability of rats to express freezing or FPS, amygdala in learning and memory. In recent years, many whether it is conditioned or unconditioned. Clearly, until studies have investigated amygdala participation in such evidence is provided, it is premature to conclude Pavlovian “fear conditioning” in rats. The findings of on the basis of results of lesion studies that the L/BL is such studies have suggested that the amygdala may be necessary for the acquisition and expression of condian essential link in a subcortical circuit mediating the tioned fear. formation and permanent (or “indelible”) storage of “condiThe second issue concerns interpretation of the eftioned fear” (reviewed by LeDoux, 1995; Maren and fects of intraamygdala infusions of NMDA antagonists Fanselow, 1996; Davis, 1997). Succinctly put, interpretaon Pavlovian “fear conditioning. ” Several studies have tions of the findings have suggested that “. attaching reported that Pavlovian conditioned freezing or FPS is ‘fear’ to the previously neutral stimulus and rememattenuated by NMDA antagonists infused into the amygbering it is what the amygdala does” (Stevens, 1998). dala (directed at the L/BL) prior to conditioning (see Evidence from many studies is consistent with the hyLeDoux, 1995; Maren and Fanselow, 1996; Davis, 1997). pothesis that the amygdala—in particular, the lateral/ Such findings are consistent with the hypothesis that basolateral (L/BL) nuclei—encodes and permanently induction of NMDA-dependent long-term potentiation stores learned fear. However, there is also evidence that (LTP) within the L/BL may be the neural substrate of challenges this hypothesis. Evaluation of the hypothesis “conditioned fear” (Rogan et al., 1997). However, in and the supporting evidence requires consideration and entertaining this hypothesis, it is essential to provide clarification of several critical issues. evidence that excludes non-mnemonic effects of NMDA The first issue concerns interpretation of the effects antagonists that might disrupt acquisition, such as efof L/BL lesions on the expression of “conditioned fear. ” fects on attentional or motivational processes. FurtherIt is well established that L/BL lesions impair the expresmore, and more importantly, an unambiguous demonsion of conditioned fear, indexed either by “freezing” in stration that intra-L/BL infusions of NMDA antagonists the presence of a cue previously paired with footshock impair learning would not address the critical tenet of or by startle to a tone in the presence of a cue previously the hypothesis that the L/BL is the permanent storage paired with footshock (fear-potentiated startle or FPS) site for “conditioned fear. ” Such findings would be com(LeDoux, 1995; Maren and Fanselow, 1996; Davis, 1997). pletely consistent with the possibility that activation of Indeed, excitotoxic lesions of the L/BL impair freezing NMDA receptors in the L/BL influences short-term memand FPS even when induced 1 month after the conditionory processes within the L/BL and/or alters L/BL activity ing (Lee et al., 1996; Maren et al., 1996). Such impairregulating long-term memory storage in other brain rements are generally interpreted as evidence that L/BL gions (McGaugh et al., 1984; Cahill and McGaugh, 1998). lesions block conditioned fear. However, when using A final issue concerns interpretation of electrophysiolesions to study the role of a brain region in memory, it logical changes in the L/BL associated with “fear condiis absolutely essential to distinguish the lesion’s effects tioning. ” Recent findings suggest, for example, that LTP on memory from other influences on performance (the develops in the L/BL during Pavlovian “fear conditionwell-known “learning/performance” distinction). The coning” (Rogan et al., 1997). However, it is well established clusion that a brain lesion impairs memory requires evithat, within regions of the medial geniculate nucleus dence that the lesion does not simply disrupt the aniknown to project to these same amygdala regions, Pavmal’s ability to make the specific response(s) that are lovian “fear conditioning” induces specific, associative used as evidence of memory. Thus, Richard Thompson changes in neuronal responses to the CS used to induce and colleagues (Thompson et al., 1998), for example, conditioning (for discussion, see Ryugo and Weinbegan their investigation of the role of the deep cerebelberger, 1978; Weinberger, 1998). Additionally, converlar nuclei in Pavlovian eyelid conditioning by demongence of auditory and noxious sensory stimulation is