Faculty Bibliography

Local translation can provide a rapid, spatially targeted supply of new proteins in distal dendrites to support synaptic changes that underlie learning. Learning and memory are especially sensitive to manipulations of translational control mechanisms, particularly those that target the initiation step, and translation initiation at synapses could be a means of maintaining synapse specificity during plasticity. Initiation predominantly occurs via recruitment of ribosomes to the 5' mRNA cap by complexes of eukaryotic initiation factors (eIFs), and the interaction between eIF4E and eIF4G1 is a particularly important target of translational control pathways. Pharmacological inhibition of eIF4E-eIF4G1 binding impairs formation of memory for aversive Pavlovian conditioning as well as the accompanying increase in polyribosomes in the heads of dendritic spines in the lateral amygdala (LA). This is consistent with a role for initiation at synapses in memory formation, but whether eIFs are even present near synapses is unknown. To determine whether dendritic spines contain eIFs and whether eIF distribution is affected by learning, we combined immunolabeling with serial section transmission electron microscopy (ssTEM) volume reconstructions of LA dendrites after Pavlovian conditioning. Labeling for eIF4E, eIF4G1, and eIF2α - another key target of regulation - occurred in roughly half of dendritic spines, but learning effects were only found for eIF4E, which was upregulated in the heads of dendritic spines. Our results support the possibility of regulated translation initiation as a means of synapse-specific protein targeting during learning and are consistent with the model of eIF4E availability as a central point of control. This article is protected by copyright. All rights reserved.

In this My word, Joseph LeDoux explores what the emotional lives of other mammals might be like. He proposes that better understanding of the brain mechanisms of emotional consciousness in humans might shed light on the kinds of conscious capacities that might be possible in non-human primates and non-primate mammals, given the kinds of brains they possess.

While interest in active avoidance has recently been resurgent, many concerns relating to the nature of this form of learning remain unresolved. By separating stimulus and response acquisition, aversive Pavlovian-instrumental transfer can be used to measure the effect of avoidance learning on threat processing with more control than typical avoidance procedures. However, the motivational substrates that contribute to the aversive transfer effect have not been thoroughly examined. In three studies using rodents, the impact of a variety of aversive signals on shock-avoidance responding (i.e., two-way shuttling) was evaluated. Fox urine, as well as a tone paired with the delivery of the predator odor were insufficient modulatory stimuli for the avoidance response. Similarly, a signal for the absence of food did not generate appropriate aversive motivation to enhance shuttling. Only conditioned Pavlovian stimuli that had been paired with unconditioned threats were capable of augmenting shock-avoidance responding. This was true whether the signaled outcome was the same (e.g., shock) or different (e.g., klaxon) from the avoidance outcome (i.e., shock). These findings help to characterize the aversive transfer effect and provide a more thorough analysis of its generalization to warning signals for different kinds of threats. This feature of aversive motivation has not been demonstrated using conventional avoidance procedures and could be potentially useful for applying avoidance in treatment settings.

OBJECTIVE/UNASSIGNED:Trauma-focused cognitive-behavioral therapy (CBT) is an important component of evidence-based treatment for posttraumatic stress disorder (PTSD), but the efficacy of treatment varies from individual to individual. It is hypothesized that some of this variability is derived from interindividual differences in the brain's intrinsic response to trauma-related stimuli and in activity of executive functional regions. The authors sought to characterize these differences using functional MRI (fMRI) in patients about to undergo CBT for PTSD. METHODS/UNASSIGNED:Blood-oxygenation-level-dependent signal was measured in 12 individuals with PTSD related to sexual and/or physical trauma while they read words with positive, neutral, and negative content. Some negative words had PTSD-related themes, while others did not. It was hypothesized that PTSD-related words would evoke emotional processes likely to be engaged by the CBT process and would be most likely to activate brain circuitry important for CBT success. RESULTS/UNASSIGNED:A group-level analysis showed that the rostral dorsomedial prefrontal cortex (rdmPFC) was activated to a greater degree in response to PTSD-related words compared with other word types. This activation was strongest among patients with the best CBT responses, particularly in the latter part of the task, when differences between individuals were most pronounced. CONCLUSIONS/UNASSIGNED:The rdmPFC activation observed in this study may reflect the engagement of neural processes involved in introspection and self-reflection. CBT may be more effective for individuals with a greater ability to engage these processes.

BACKGROUND:The bed nucleus of the stria terminalis (BNST) plays an important role in rodent posttraumatic stress disorder (PTSD), but evidence to support its relevance to human PTSD is limited. We sought to understand the role of the BNST in human PTSD via fMRI, behavioral, and physiological measurements. METHODS:29 patients with PTSD (childhood sexual abuse) and 23 healthy controls (HC) underwent BOLD imaging with an emotional word paradigm. Symptom severity was assessed using the Clinician-Administered PTSD Scale and HPA-axis dysfunction was assessed by measuring the diurnal cortisol amplitude index (DCAI). A data-driven multivariate analysis was used to determine BNST task-based functional co-occurrence (tbFC) across individuals. RESULTS:In the trauma-versus-neutral word contrast, patients showed increased activation compared to HC in the BNST, medial prefrontal cortex (mPFC), posterior cingulate gyrus (PCG), caudate heads, and midbrain, and decreased activation in dorsolateral prefrontal cortex (DLPFC). Symptom severity positively correlated with activity in the BNST, caudate head, amygdala, hippocampus, dorsal anterior cingulate gyrus (dACG), and PCG, and negatively with activity in the medial orbiotofrontal cortex (mOFC) and DLPFC. Patients and HC showed marked differences in the relationship between the DCAI and BOLD activity in the BNST, septal nuclei, dACG, and PCG. Patients showed stronger tbFC between the BNST and closely linked limbic and subcortical regions, and a loss of negative tbFC between the BNST and DLPFC. CONCLUSIONS:Based upon novel data, we present a new model of dysexecutive emotion processing and HPA-axis dysfunction in human PTSD that incorporates the role of the BNST and functionally linked neurocircuitry.

In this My Word, Joseph LeDoux and Hakwan Lau argue that everyday human conscious experiences cannot be understood separately from memory. The authors build on a tripartite model of memory as a way of fractionating consciousness into components that account for wide ranging experiences, from the simplest sensory experience of the color of an apple to a full-blown feeling of fear or other emotions.

In this My Word, Joseph LeDoux describes how his four-decade career exploring how non-conscious processes involving the amygdala detect and respond to danger has contributed to the 'amygdala fear center' meme, a view he does not endorse. The conscious experience of fear, he tells us here, is not wired into the amygdala, but is instead a cognitively assembled understanding that you are in harm's way based on non-conscious memories, schemas, and mental models.

Consciousness is currently a thriving area of research in psychology and neuroscience. While this is often attributed to events that took place in the early 1990s, consciousness studies today are a continuation of research that started in the late 19th century and that continued throughout the 20th century. From the beginning, the effort built on studies of animals to reveal basic principles of brain organization and function, and of human patients to gain clues about consciousness itself. Particularly important and our focus here is research in the 1950s, 1960s, and 1970s involving three groups of patients-amnesia, split brain, and blindsight. Across all three groups, a similar pattern of results was found-the patients could respond appropriately to stimuli that they denied seeing (or in the case of amnesiacs, having seen before). These studies paved the way for the current wave of research on consciousness. The field is, in fact, still grappling with the implications of the findings showing that the ability to consciously know and report the identity of a visual stimulus can be dissociated in the brain from the mechanisms that underlie the ability to behave in a meaningful way to the same stimulus.

In this My Word, Joseph LeDoux describes how his work as a graduate student got him interested in human consciousness. Although he has not studied this topic since 1970s, he never stopped thinking and writing about it during his four-decade career exploring how non-conscious processes involving the amygdala detect and respond to danger. Here, he tells us what is on his mind about consciousness these days.