Distributed neural representations of conditioned threat in the human brain.

Detecting and responding to threat engages several neural nodes including the amygdala, hippocampus, insular cortex, and medial prefrontal cortices. Recent propositions call for the integration of more distributed neural nodes that process sensory and cognitive facets related to threat. Integrative, sensitive, and reproducible distributed neural decoders for the detection and response to threat and safety have yet to be established. We combine functional MRI data across varying threat conditioning and negative affect paradigms from 1465 participants with multivariate pattern analysis to investigate distributed neural representations of threat and safety. The trained decoders sensitively and specifically distinguish between threat and safety cues across multiple datasets. We further show that many neural nodes dynamically shift representations between threat and safety. Our results establish reproducible decoders that integrate neural circuits, merging the well-characterized 'threat circuit' with sensory and cognitive nodes, discriminating threat from safety regardless of experimental designs or data acquisition parameters.

Joseph E. LeDoux.

In an interview with Neuron, Joseph LeDoux outlines his early work on consciousness in split-brain patients, his transition into studying emotional behavior in rodents, and his continued exploration of consciousness in books and other writings. He describes how his research fused with his interest in music, which he pursued though his band, The Amygdaloids, and their unique genre, "heavy mental."

Consciousness, the affectome, and human life.

I have been working on interactions between conscious and non-conscious processes since the late 1970s. In this commentary, I offer a perspective on conscious/non-conscious interactions that might a useful adjunct to the Human Affectome Project as it evolves.

An AAV-CRISPR/Cas9 strategy for gene editing across divergent rodent species: Targeting neural oxytocin receptors as a proof of concept.

A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor (Oxtr) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species (n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.

A generative adversarial model of intrusive imagery in the human brain.

The mechanisms underlying the subjective experiences of mental disorders remain poorly understood. This is partly due to long-standing over-emphasis on behavioral and physiological symptoms and a de-emphasis of the patient's subjective experiences when searching for treatments. Here, we provide a new perspective on the subjective experience of mental disorders based on findings in neuroscience and artificial intelligence (AI). Specifically, we propose the subjective experience that occurs in visual imagination depends on mechanisms similar to generative adversarial networks that have recently been developed in AI. The basic idea is that a generator network fabricates a prediction of the world, and a discriminator network determines whether it is likely real or not. Given that similar adversarial interactions occur in the two major visual pathways of perception in people, we explored whether we could leverage this AI-inspired approach to better understand the intrusive imagery experiences of patients suffering from mental illnesses such as post-traumatic stress disorder (PTSD) and acute stress disorder. In our model, a nonconscious visual pathway generates predictions of the environment that influence the parallel but interacting conscious pathway. We propose that in some patients, an imbalance in these adversarial interactions leads to an overrepresentation of disturbing content relative to current reality, and results in debilitating flashbacks. By situating the subjective experience of intrusive visual imagery in the adversarial interaction of these visual pathways, we propose testable hypotheses on novel mechanisms and clinical applications for controlling and possibly preventing symptoms resulting from intrusive imagery.

The tricky business of defining brain functions.

Neuroscience has a long history of investigating the neural correlates of brain functions. One example is fear, which has been studied intensely in a variety of species. In parallel, unease about definitions of brain functions has existed for over 100 years. Because the translational impact of basic research hinges on how we define these functions, these definitions should be carefully considered.

The day I told Karim Nader, "Don't do the study".

Karim Nader changed the course of memory research by reviving interest in the mostly forgotten topic of post-retrieval manipulations of memory. In this paper I summarize the events leading up to his ground-breaking study in my lab on so-called memory reconsolidation, and the effects of that study on the field.

Temporally and anatomically specific contributions of the human amygdala to threat and safety learning.

Neural plasticity in subareas of the rodent amygdala is widely known to be essential for Pavlovian threat conditioning and safety learning. However, less consistent results have been observed in human neuroimaging studies. Here, we identify and test three important factors that may contribute to these discrepancies: the temporal profile of amygdala response in threat conditioning, the anatomical specificity of amygdala responses during threat conditioning and safety learning, and insufficient power to identify these responses. We combined data across multiple studies using a well-validated human threat conditioning paradigm to examine amygdala involvement during threat conditioning and safety learning. In 601 humans, we show that two amygdala subregions tracked the conditioned stimulus with aversive shock during early conditioning while only one demonstrated delayed responding to a stimulus not paired with shock. Our findings identify cross-species similarities in temporal- and anatomical-specific amygdala contributions to threat and safety learning, affirm human amygdala involvement in associative learning and highlight important factors for future associative learning research in humans.

Putting the "mental" back in "mental disorders": a perspective from research on fear and anxiety.

Mental health problems often involve clusters of symptoms that include subjective (conscious) experiences as well as behavioral and/or physiological responses. Because the bodily responses are readily measured objectively, these have come to be emphasized when developing treatments and assessing their effectiveness. On the other hand, the subjective experience of the patient reported during a clinical interview is often viewed as a weak correlate of psychopathology. To the extent that subjective symptoms are related to the underlying problem, it is often assumed that they will be taken care of if the more objective behavioral and physiological symptoms are properly treated. Decades of research on anxiety disorders, however, show that behavioral and physiological symptoms do not correlate as strongly with subjective experiences as is typically assumed. Further, the treatments developed using more objective symptoms as a marker of psychopathology have mostly been disappointing in effectiveness. Given that "mental" disorders are named for, and defined by, their subjective mental qualities, it is perhaps not surprising, in retrospect, that treatments that have sidelined mental qualities have not been especially effective. These negative attitudes about subjective experience took root in psychiatry and allied fields decades ago when there were few avenues for scientifically studying subjective experience. Today, however, cognitive neuroscience research on consciousness is thriving, and offers a viable and novel scientific approach that could help achieve a deeper understanding of mental disorders and their treatment.

As soon as there was life, there was danger: the deep history of survival behaviours and the shallower history of consciousness.

It is often said that fear is a universal innate emotion that we humans have inherited from our mammalian ancestors by virtue of having inherited conserved features of their nervous systems. Contrary to this common sense-based scientific point of view, I have argued that what we have inherited from our mammalian ancestors, and they from their distal vertebrate ancestors, and they from their chordate ancestors, and so forth, is not a fear circuit. It is, instead, a defensive survival circuit that detects threats, and in response, initiates defensive survival behaviours and supporting physiological adjustments. Seen in this light, the defensive survival circuits of humans and other mammals can be conceptualized as manifestations of an ancient survival function-the ability to detect danger and respond to it-that may in fact predate animals and their nervous systems, and perhaps may go back to the beginning of life. Fear, on the other hand, from my perspective, is a product of cortical cognitive circuits. This conception is not just of academic interest. It also has practical implications, offering clues as to why efforts to treat problems related to fear and anxiety are not more effective, and what might make them better. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

Human threat learning is associated with gut microbiota composition.

The ability to learn about threat and safety is critical for survival. Studies in rodent models have shown that the gut microbiota can modulate such behaviors. In humans, evidence showing an association with threat or extinction learning is lacking. Here, we tested whether individual variability in threat and extinction learning was related to gut microbiota composition in healthy adults. We found that threat, but not extinction learning, varies with individuals' microbiome composition. Our results provide evidence that the gut microbiota is associated with excitatory threat learning across species.

Conditional Control of Instrumental Avoidance by Context Following Extinction.

Using rodents, three training arrangements (i.e., ABB vs. ABA, AAA vs. AAB and ABB vs. ABC) explored whether extinction influences the expression of avoidance in a manner controlled by context. Retention testing following extinction showed that more avoidance responding (i.e., renewal) was observed when extinguished cues were tested outside of the context where they had undergone extinction. In contrast, response rates were significantly lower when stimuli were tested within the context where extinction learning had occurred. These findings add to the emerging literature assessing the role of Pavlovian extinction processes in the development of instrumental avoidance responding by demonstrating conditional control over extinguished responding by context. This study was conducted using a within-subjects approach that minimized the potential for context-outcome associations to bias responding, and thus, reflects hierarchical control over behavior based on the specific associative status of each tested cue in each training context.

What emotions might be like in other animals.

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.

Observation of others' threat reactions recovers memories previously shaped by firsthand experiences.

Information about dangers can spread effectively by observation of others' threat responses. Yet, it is unclear if such observational threat information interacts with associative memories that are shaped by the individual's direct, firsthand experiences. Here, we show in humans and rats that the mere observation of a conspecific's threat reactions reinstates previously learned and extinguished threat responses in the observer. In two experiments, human participants displayed elevated physiological responses to threat-conditioned cues after observational reinstatement in a context-specific manner. The elevation of physiological responses (arousal) was further specific to the context that was observed as dangerous. An analogous experiment in rats provided converging results by demonstrating reinstatement of defensive behavior after observing another rat's threat reactions. Taken together, our findings provide cross-species evidence that observation of others' threat reactions can recover associations previously shaped by direct, firsthand aversive experiences. Our study offers a perspective on how retrieval of threat memories draws from associative mechanisms that might underlie both observations of others' and firsthand experiences.

The bed nucleus of the stria terminalis and functionally linked neurocircuitry modulate emotion processing and HPA axis dysfunction in posttraumatic stress disorder.

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.

Motivational factors underlying aversive Pavlovian-instrumental transfer.

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.

Seeing consciousness through the lens of memory.

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.

Thoughtful feelings.

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.

How does the non-conscious become conscious?

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.