In mammals, long-term memory induced by Pavlovian fear conditioning has been shown to be dependent on the amygdala during a protein and mRNA synthesis-dependent phase of memory consolidation. We have used genes identified in a kainic acid model of synaptic plasticity as in situ hybridization probes during the consolidation period after fear conditioning. We found that these genes were transcriptionally regulated in several brain areas only when stimuli were presented in a manner that supported behavioral learning and not after unpaired presentations or footshocks alone. Immediate early genes and neurofilament mRNA peaked approximately 30 min after conditioning, as expected. Interestingly, nurr-1, alpha-actinin, and 16c8 increased approximately 2-4 hr later, whereas neurogranin and gephyrin decreased during that time. Our results suggest that fear memory consolidation occurs within a broad neural circuit that includes, but is not limited to, the amygdala. Together, a broad array of transcriptionally regulated genes, encoding transcription factors, cytoskeletal proteins, adhesion molecules, and receptor stabilization molecules, appear to mediate the neural plasticity underlying specific forms of long-term memory in mammals.

The basolateral amygdala's involvement in fear acquisition and expression to visual and auditory stimuli is well known. The involvement of the basolateral and other amygdala areas in fear acquisition and expression to stimuli of other modalities is less certain. We evaluated the contribution of the basolateral and medial amygdala to olfactory and to context fear and fear conditioning by infusing into these areas the NMDA receptor antagonist AP5, the AMPA/kainate receptor antagonist NBQX, or vehicle prior to either odor-shock pairings or fear-potentiated startle testing. Pre-training AP5 infusions into the basolateral amygdala disrupted fear conditioning to the odor but not the context conditioned stimulus (CS). Pre-test NBQX infusions disrupted fear-potentiated startle to the odor but not context CS. Neither compound blocked fear conditioning when infused into the medial amygdala prior to training, but pre-test NBQX infusions did block fear-potentiated startle. The results confirm and extend recent findings suggesting a role for the basolateral amygdala in olfactory fear and fear conditioning, reveal an unexpected dissociation of the basolateral amygdala's involvement in discrete cue versus context fear and fear conditioning, and implicate for the first time the medial amygdala in fear-potentiated startle.For auditory and visual stimuli, the amygdala plays a key role in fear conditioning and fear expression as assessed with several behavioral measures (cf., Fendt and Fanselow 1999;Davis 2000;LeDoux 2000). We have found, for example, that pre-test infusions into the basolateral amygdala (i.e., the lateral, basolateral, and basomedial nuclei) of ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonists block fear-potentiated startle to visual and auditory conditioned fear stimuli (CSs), and that pre-training (i.e., light-shock or toneshock) infusions of either N-methyl-D-aspartate (NMDA) receptor antagonists or AMPA/kainate receptor antagonists block fear conditioning (cf., Walker and Davis 2002b). In most (e.g., Miserendino et al. 1990;Campeau et al. 1992;Gewirtz and Davis 1997), but not all (e.g., Fendt 2001; see also Lee et al. 2001) cases, pre-test intra-amygdala infusions of NMDA receptor antagonists have not been found to disrupt fear expression to auditory and visual CSs. Similar results have been obtained from other laboratories using different treatments and other fear-related behaviors (e.g., LeDoux et al. 1990;Muller et al. 1997;Groenink et al. 2000;Rodrigues et al. 2001).Visual and auditory information reach the basolateral amygdala indirectly via intermediary structures such as auditory and visual thalamus and perirhinal cortex. Olfactory information also reaches the basolateral amygdala indirectly. Uniquely, however, the main and accessory olfactory bulbs also send direct projections to several amygdala areas including the medial and cortical nuclei, the nucleus of the lateral olfactory tract, and the periamygdaloid cortex (cf., Alheid et al. 1995;McDonald 1998;Pitkanen...

Key PointsQuestionDoes provision of pharmacogenomic testing for drug-gene interactions affect selection of antidepressant medication and response of depressive symptoms in patients with major depressive disorder (MDD)?FindingsIn this randomized clinical trial that included 1944 patients with MDD, provision of pharmacogenomic tests for drug interactions compared with usual care resulted in prescriptions with no predicted drug-gene interactions in 45% vs 18%, respectively, a difference that was statistically significant. Remission of symptoms reached a maximum difference of 16.5% vs 11.2% at 12 weeks but was not significantly different at 24 weeks.MeaningPharmacogenomic testing for drug-gene interactions in MDD reduced prescription of medications with predicted drug-gene interactions but had small and nonpersistent effects on symptom remission.

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Recently, R. Richardson, A. Vishney, and J. Lee (1999) reported that ambient odor cues that were previously paired with footshock potentiate the acoustic startle response in rats. The authors of the present study extend those findings by using a discrete 4-s amyl acetate odor paired with footshock to address several parametric issues that might be important for using odorants as conditioned stimuli (CSs) in this paradigm. Amyl acetate (5%) had no significant effect on startle in untrained rats but did potentiate startle in rats that received 1, 2, 5, or 10 odor-shock pairings. Fear-potentiated startle decreased but was still significant up to 40 days after conditioning and could be measured in test trials separated by as little as 30 s. The magnitude of potentiated startle decreased with decreasing concentrations of amyl acetate (5%-5 x 10-9%). The anxiolytic compound buspirone (10 mg/kg) significantly attenuated olfactory-mediated fear-potentiated startle.