Faculty Bibliography

Functional magnetic resonance imaging in association with an instructed fear/anticipatory anxiety paradigm was used to explore sex differences in the human fear response. During anticipation of mild electrodermal stimulation, women, as compared with men, demonstrated increased activity in the subgenual anterior cingulate cortex and functionally related regions of the insula and brainstem. The subgenual anterior cingulate cortex is a region critical for emotional control implicated in the pathogenesis of psychiatric disease. Present findings suggest a contributory neural substrate for the greater susceptibility of women to anxiety and affective disorders, and emphasize the importance of considering participant sex when designing and interpreting functional neuroimaging studies

Nitric oxide (NO) has been widely implicated in synaptic plasticity and memory formation. In studies of long-term potentiation (LTP), NO is thought to serve as a 'retrograde messenger' that contributes to presynaptic aspects of LTP expression. In this study, we examined the role of NO signaling in Pavlovian fear conditioning. We first show that neuronal nitric oxide synthase is localized in the lateral nucleus of the amygdala (LA), a critical site of plasticity in fear conditioning. We next show that NO signaling is required for LTP at thalamic inputs to the LA and for the long-term consolidation of auditory fear conditioning. Collectively, the findings suggest that NO signaling is an important component of memory formation of auditory fear conditioning, possibly as a retrograde signal that participates in presynaptic aspects of plasticity in the LA

In the present study, we examined the role of the auditory thalamus [medial division of the medial geniculate nucleus and the adjacent posterior intralaminar nucleus (MGm/PIN)] in auditory pavlovian fear conditioning using pharmacological manipulation of intracellular signaling pathways. In the first experiment, rats were given intrathalamic infusions of the MEK (mitogen-activated protein kinase-kinase) inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene (U0126) before fear conditioning. Findings revealed that long-term memory (assessed at 24 h) was impaired, whereas short-term memory (assessed at 1-3 h) of fear conditioning was intact. In the second experiment, rats received immediate posttraining intrathalamic infusion of U0126, the mRNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), or infusion of the protein synthesis inhibitor anisomycin. Posttraining infusion of either U0126 or DRB significantly impaired long-term retention of fear conditioning, whereas infusion of anisomycin had no effect. In the final experiment, rats received intrathalamic infusion of U0126 before long-term potentiation (LTP)-inducing stimulation of thalamic inputs to the lateral nucleus of the amygdala (LA). Findings revealed that thalamic infusion of U0126 impaired LTP in the LA. Together, these results suggest the possibility that MGm/PIN cells that project to the LA contribute to memory formation via ERK (extracellular signal-regulated kinase)-mediated transcription, but that they do so by promoting protein synthesis-dependent plasticity locally in the LA

To elucidate molecular, cellular, and circuit changes that occur in the brain during learning, we investigated the role of a glutamate receptor subtype in fear conditioning. In this form of learning, animals associate two stimuli, such as a tone and a shock. Here we report that fear conditioning drives AMPA-type glutamate receptors into the synapse of a large fraction of postsynaptic neurons in the lateral amygdala, a brain structure essential for this learning process. Furthermore, memory was reduced if AMPA receptor synaptic incorporation was blocked in as few as 10 to 20% of lateral amygdala neurons. Thus, the encoding of memories in the lateral amygdala is mediated by AMPA receptor trafficking, is widely distributed, and displays little redundancy

BACKGROUND: Previous neuroimaging studies have demonstrated exaggerated amygdala responses to negative stimuli in posttraumatic stress disorder (PTSD). The time course of this amygdala response is largely unstudied and is relevant to questions of habituation and sensitization in PTSD exposure therapy. METHODS: We applied blood oxygen level dependent functional magnetic resonance imaging and statistical parametric mapping to study amygdala responses to trauma-related and nontrauma-related emotional words in sexual/physical abuse PTSD and normal control subjects. We examined the time course of this response by separate analysis of early and late epochs. RESULTS: PTSD versus normal control subjects have a relatively increased initial amygdala response to trauma-related negative, but not nontrauma-related negative, versus neutral stimuli. Patients also fail to show the normal patterns of sensitization and habituation to different categories of negative stimuli. These findings correlate with measured PTSD symptom severity. CONCLUSIONS: Our results demonstrate differential time courses and specificity of amygdala response to emotional and control stimuli in PTSD and normal control subjects. This has implications for pathophysiologic models of PTSD and treatment response. The results also extend previous neuroimaging studies demonstrating relatively increased amygdala response in PTSD and expand these results to a largely female patient population probed with emotionally valenced words

Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of amygdala (LA). Recently we have demonstrated that consolidated fear memories, when reactivated, return to a labile state which is sensitive to disruption by the protein synthesis inhibitor anisomycin. The specific molecular mechanisms that underlie this reconsolidation of fear memories are still largely unknown. The activation of extracellular signal-regulated kinase-mitogen-activated protein kinase (ERK-MAPK) pathway in the LA is required for the consolidation of auditory fear memories. In the present study, we examined the role of ERK-MAPK cascade in the LA during reconsolidation of auditory fear conditioning. We show that intra-LA infusions of the MAPK kinase (MEK) inhibitor U0126, a manipulation which inhibits activation of ERK-MAPK, impairs postreactivation long-term memory (PR-LTM) but leaves the postreactivation short-term memory (PR-STM) intact. The same treatment with U0126, in the absence of memory reactivation, has no effect. Furthermore, we verified that reconsolidation requires translation using a second protein synthesis inhibitor, cycloheximide. Post-reactivation infusions of cycloheximide blocked PR-LTM but not PR-STM and, in the absence of reactivation, had no effect. Our data show that activation of ERK-MAPK signalling pathway and protein synthesis in the LA are required for reconsolidation of auditory fear memories

We sought to determine whether contextual fear conditioning, a hippocampal-dependent task, would affect neurogenesis in the dentate gyrus of the hippocampus, and if so, to identify which aspect of the training experience accounts for the change. The immediate shock deficit paradigm was used, together with bromodeoxyuridine immunohistochemistry, to isolate the contribution of different aspects of contextual fear conditioning to neurogenesis. Contextual fear learning caused a 33% decrease in the number of proliferating cells that was anatomically restricted to the dentate gyrus with no change in cell survival or differentiation. This attenuation was not related to exposure to the conditioned stimulus alone, the footshock unconditioned stimulus alone, or the expression of fear to the context after training. Instead, the effect of context conditioning on cell proliferation appears to be specifically due to the formation of an association between the context and shock during training, an amygdala dependent function

The amygdala is critical for acquiring and expressing conditioned fear responses elicited by sensory stimuli that predict future punishment, but there is conflicting evidence about whether the amygdala is necessary for perceiving the aversive qualities of painful or noxious stimuli that inflict primary punishment. To investigate this question, rats were fear conditioned by pairing a sequence of auditory pips (the conditioned stimulus, or CS) with a brief train of shocks to one eyelid (the unconditioned stimulus, or US). Conditioned responding to the CS was assessed by measuring freezing responses during a test session conducted 24 h after training, and unconditioned responding to the US was assessed by measuring head movements evoked by the eyelid shocks during training. We found that pre-training electrolytic lesions of the amygdala's lateral (LA) nucleus blocked acquisition of conditioned freezing to the CS, and also significantly attenuated unconditioned head movements evoked by the US. Similarly, bilateral inactivation of the amygdala with the GABA-A agonist muscimol impaired acquisition of CS-evoked freezing, and also attenuated US-evoked responses during training. However, when amygdala synaptic plasticity was blocked by infusion of the NR2B receptor antagonist ifenprodil, acquisition of conditioned freezing was impaired but shock reactivity was unaffected. These findings indicate that neural activity within the amygdala is important for both predicting and perceiving the aversive qualities of noxious stimuli, and that synaptic plasticity within LA is the mechanism by which the CS becomes associated with the US during fear conditioning