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An interview with Joseph LeDoux, who studies brain mechanisms of emotion, memory, and consciousness., (Copyright © 2022.)

Objective: 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: 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: 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: 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.

First characterized in neuronal tissues, the multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key signaling component in several mammalian biological systems. Its unique capacity to integrate various Ca(2+) signals into different specific outcomes is a precious asset to excitable and nonexcitable cells. Numerous studies have reported roles and mechanisms involving CaMKII in brain and heart tissues. However, corresponding functions in vascular cell types (endothelium and vascular smooth muscle cells) remained largely unexplored until recently. Investigation of the intracellular Ca(2+) dynamics, their impact on vascular cell function, the regulatory processes involved and more recently the spatially restricted oscillatory Ca(2+) signals and microdomains triggered significant interest towards proteins like CaMKII. Heteromultimerization of CaMKII isoforms (four isoforms and several splice variants) expands this kinase's peculiar capacity to decipher Ca(2+) signals and initiate specific signaling processes, and thus controlling cellular functions. The physiological functions that rely on CaMKII are unsurprisingly diverse, ranging from regulating contractile state and cellular proliferation to Ca(2+) homeostasis and cellular permeability. This review will focus on emerging evidence of CaMKII as an essential component of the vascular system, with a focus on the kinase isoform/splice variants and cellular system studied., (Copyright © 2016 the American Physiological Society.)

I propose a reconceptualization of key phenomena important in the study of emotion-those phenomena that reflect functions and circuits related to survival, and that are shared by humans and other animals. The approach shifts the focus from questions about whether emotions that humans consciously feel are also present in other animals, and toward questions about the extent to which circuits and corresponding functions that are present in other animals (survival circuits and functions) are also present in humans. Survival circuit functions are not causally related to emotional feelings but obviously contribute to these, at least indirectly. The survival circuit concept integrates ideas about emotion, motivation, reinforcement, and arousal in the effort to understand how organisms survive and thrive by detecting and responding to challenges and opportunities in daily life., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Can we find a way of thinking about the self that is compatible with modern neuroscience? I think we can. First of all, we have to recognize that "the self" is not the same as "the conscious self," since much of who we are as individuals takes place out of conscious awareness. Second, we have to accept that some aspects of the self, especially the unconscious aspects, occur in and can be studied in other species, allowing us to relate these aspects of the self to detailed brain mechanisms. Finally, it also helps to think of the self in terms of memory. Obviously, much of who we are is based on memories learned through personal experience, including both conscious or explicit memories and unconscious or implicit memories. This is particularly important since much progress has been made in relating memory to the cells and synapses of the brain. By viewing the self as a network of memories the effort to relate the self to the brain can build on this progress. Emphasizing memory and experience does not take away from the fact that our genetic history also contributes to who we are. In fact, genes and experience, or nature and nurture, are, in the end, not different things, but different ways of doing the same thing-wiring the synapses of our brain. In many ways, the self is synaptic. This synaptic view of the self is not meant as a challenge to other views, such as spiritual, cultural, or psychological views. It is instead, just a way of understanding how these other aspects of who we are relate, deep down, to the brain.

This article is a transcription of an electronic symposium in which active researchers were invited by the Brazilian Society of Neuroscience and Behavior (SBNeC) to discuss the advances of the last decade in the neurobiology of emotion. Four basic questions were debated: 1) What are the most critical issues/questions in the neurobiology of emotion? 2) What do we know for certain about brain processes involved in emotion and what is controversial? 3) What kinds of research are needed to resolve these controversial issues? 4) What is the relationship between learning, memory and emotion? The focus was on the existence of different neural systems for different emotions and the nature of the neural coding for the emotional states. Is emotion the result of the interaction of different brain regions such as the amygdala, the nucleus accumbens, or the periaqueductal gray matter or is it an emergent property of the whole brain neural network? The relationship between unlearned and learned emotions was also discussed. Are the circuits of the former the underpinnings of the latter? It was pointed out that much of what we know about emotions refers to aversively motivated behaviors, like fear and anxiety. Appetitive emotions should attract much interest in the future. The learning and memory relationship with emotions was also discussed in terms of conditioned and unconditioned stimuli, innate and learned fear, contextual cues inducing emotional states, implicit memory and the property of using this term for animal memories. In a general way it could be said that learning modifies the neural circuits through which emotional responses are expressed.

'Consolidation' has been used to describe distinct but related processes. In considering the implications of our recent findings on the lability of reactivated fear memories, we view consolidation and reconsolidation in terms of molecular events taking place within neurons as opposed to interactions between brain regions. Our findings open up a new dimension in the study of memory consolidation. We argue that consolidation is not a one-time event, but instead is reiterated with subsequent activation of the memories.

The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pinpointed the amygdala as an important component of the system involved in the acquisition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emotion, avoided vague and poorly defined concepts such as "affect," "hedonic tone," or "emotional feelings," and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior.

In recent years, there has been an explosion of interest in the neural basis of emotion. Much of this enthusiasm has been triggered by studies of the amygdala and its contribution to fear. This work has shown that the amygdala detects and organizes responses to natural dangers (like predators) and learns about novel threats and the stimuli that predict their occurrence. The latter process has been studied extensively using a procedure called classical fear conditioning. This article surveys the progress that has been made in understanding the neural basis of fear and its implications for anxiety disorders, as well as the gaps in our knowledge.

A leading model for studying how the brain forms memories about unpleasant experiences is fear conditioning. A cumulative body of work has identified major components of the neural system mediating this form of learning. The pathways involve transmission of sensory information from processing areas in the thalamus and cortex to the amygdala. The amygdala's lateral nucleus receives and integrates the sensory inputs from the thalamic and cortical areas, and the central nucleus provides the interface with motor systems controlling specific fear responses in various modalities (behavioural, autonomic, endocrine). Internal connections within the amygdala allow the lateral and central nuclei to communicate. Recent studies have begun to identify some sites of plasticity in the circuitry and the cellular mechanisms involved in fear conditioning. Through studies of fear conditioning, our understanding of emotional memory is being taken to the level of cells and synapses in the brain. Advances in understanding emotional memory hold out the possibility that emotional disorders may be better defined and treatment improved.

Five healthy male subjects participated in a classical conditioning experiment, and positron emission tomography (PET) was used to compare regional cerebral blood flow before and after conditioning. The subjects participated in three different experimental phases. In the first (habituation) phase they listened to 24 repetitions of a tone with random intervals. In the second (acquisition) phase, the tone was paired with a brief shock to the wrist. In the third (extinction) phase, the tone was presented alone again. 15OPET scans were taken during the habituation and extinction phases. Because the habituation and extinction phases were similar, any difference in blood flow to the tones presented during extinction probably reflected conditioning that occurred during the acquisition phase. Statistical parametric mapping (SPM) analysis of the PET data showed significantly increased activation in the right hemisphere in the orbito-frontal cortex, dorsolateral prefrontal cortex, inferior and superior frontal cortices, and inferior and middle temporal corticies. The only activated areas in the left hemisphere were area 19 and the superior frontal cortex. The results are interpreted as evidence for the involvement of cortical areas in human classical conditioning.

The neural mechanisms of emotion and memory have long been thought to reside side by side, if not in overlapping structures, of the limbic system. However, the limbic system concept is no longer acceptable as an account of the neural basis of memory or emotion and is being replaced with specific circuit accounts of specific emotional and memory processes. Emotional memory, a special category of memory involving the implicit (probably unconscious) learning and storage of information about the emotional significance of events, is modeled in rodent experiments using aversive classical conditioning techniques. The neural system underlying emotional memory critically involves the amygdala and structures with which it is connected. Afferent inputs from sensory processing areas of the thalamus and cortex mediate emotional learning in situations involving specific sensory cues, whereas learning about the emotional significance of more general, contextual cues involves projections to the amygdala from the hippocampal formation. Within the amygdala, the lateral nucleus (AL) is the sensory interface and the central nucleus the linkage with motor systems involved in the control of species-typical emotional behaviors and autonomic responses. Studies of cellular mechanisms in these pathways have focused on the direct relay to the lateral amygdala from the auditory thalamus. These studies show that single cells in AL respond to both conditioned stimulus and unconditioned stimulus inputs, leading to the notion that AL might be a critical site of sensory-sensory integration in emotional learning. The thalamo-amygdala pathway also exhibits long-term potentiation, a form of synaptic plasticity that might underlie the emotional learning functions of the circuit. The thalamo-amygdala pathway contains and uses the amino acid glutamate in synaptic transmission, suggesting the possibility that an amino-acid mediated form of synaptic plasticity is involved in the emotional learning functions of the pathway. We are thus well on the way to a systems level and a cellular understanding of at least one form of emotional learning and memory.

The neural system underlying the conditioning of autonomic and behavioral fear responses to auditory stimuli is now understood in some detail. It involves projections through the auditory system to the medial geniculate body and from there directly to the amygdala. The lateral nucleus is the sensory interface and the central nucleus the motor interface of the amygdala. The lateral nucleus projects to the central nucleus indirectly, by way of the basolateral nucleus. Projections from the amygdala central nucleus to the midbrain central gray region mediate the behavioral responses whereas projections from the amygdala central nucleus to the lateral hypothalamus mediate the autonomic responses. Emotional memories established through such pathways bypass the neocortex and may contribute to the unconscious processing of emotion. Such memories are indelible (highly resistant to extinction). The sensory input pathway exhibits long-term synaptic potentiation and appears to utilize glutamate in synaptic transmission. An excitatory amino acid-mediated form of synaptic plasticity in the lateral amygdala may be responsible in part for emotional learning.

The amygdala appears to play an essential role in many aspects of emotional information processing and behavior. Studies over the past year have begun to clarify the anatomical organization of the amygdala and the contribution of its individual subregions to emotional functions, especially emotional learning and memory. Researchers can now point to plausible circuits involved in the transmission of sensory inputs into the amygdala, between amygdaloid subregions, and to efferent targets in cortical and subcortical regions, for specific emotional learning and memory processes.

Cerebral asymmetry in man has by and large been interpreted in terms of differences at the level of hemispheric organization. The inadequacy of a hemispheric interpretation as a biological account of asymmetry is discussed and a model of the neural mechanisms of cerebral asymmetry is developed. The model focuses on the functional organization of the inferior parietal cortex in human and non-human primates and accounts for the evolution and expression of cerebral asymmetry in man in terms of specific adaptations in select neural systems of ancestral primate brains.

Local cerebral blood flow was measured in rats by the 14C-labeled iodoantipyrine technique with quantitative autoradiography during the processing of environmental stimuli. Presentation of a tone increased blood flow in the auditory but not the visual pathway. When the animal had previously been conditioned to fear the tone, blood flow additionally increased in the hypothalamus and amygdala. Local cerebral blood flow can thus be used to detect patterns of cerebral excitation associated with transient (30- to 40-second) mental events in experimental animals.