I am a PhD student studying the circuitry of fear and anxiety in the rodent and human brain.
Your brain controls when you feel afraid. Understanding it is not as scary as you think.
The circuit: There is a circuit in your brain, led by the amygdala, that super charges your body to feel what we, as humans, perceive as fear.
The amygdala is responsible for my fear of clowns?: Well, in part. Studies in rodents have shown that the amygdala plays a major role in the fear response. The reaction of freezing, wanting to run away, and having your heart beat of out your chest is spear-headed by the amygdala (Read more) .
But you can't ask a rodent if it feels afraid! You are right, but of the same behaviors elicited by humans, when they feel afraid, are also shown in rodents (see the paper).
So what's this amygdala thing anyway?
I'm glad you asked! The amygdala (named from the Greek word for almond) is an almond-shaped area found in almost all mammalian brains (See the different shapes of the amygdala here).
It connects to many of your sensory and cognitive inputs, so what you see, feel in the environment, and even think about passes through the amygdala.
Even more fascinating, the amygdala can form and retain memories! Rodent studies have shown that fear memories are believed to be stored, at first, within amygdala cells (See the paper).
So why is this important? Well, scientists have discovered that if you find where memories are formed, you can potentially erase memories. Regarding the amygdala, researchers have been able to erase a fear memory (See the paper).
That sounds like science fiction. Believe it or not, rodent and human studies have shown that fear memories can be erased. This has huge potential!
Why? Many people suffer from psychiatric disorders that revolve around traumatic fearful memories. Erasing, or modulating, a fear memory can be a potential way to alleviate debilitating symptoms of fear.
So the next time you feel afraid, you can partially blame your amygdala.
Abstract: 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.
Pub.: 09 Jun '00, Pinned: 22 Apr '17
Abstract: The brain mechanisms of fear have been studied extensively using Pavlovian fear conditioning, a procedure that allows exploration of how the brain learns about and later detects and responds to threats. However, mechanisms that detect and respond to threats are not the same as those that give rise to conscious fear. This is an important distinction because symptoms based on conscious and nonconscious processes may be vulnerable to different predisposing factors and may also be treatable with different approaches in people who suffer from uncontrolled fear or anxiety. A conception of so-called fear conditioning in terms of circuits that operate nonconsciously, but that indirectly contribute to conscious fear, is proposed as way forward.
Pub.: 07 Feb '14, Pinned: 22 Apr '17
Abstract: Tremendous progress has been made in basic neuroscience in recent decades. One area that has been especially successful is research on how the brain detects and responds to threats. Such studies have demonstrated comparable patterns of brain-behavior relationships underlying threat processing across a range of mammalian species, including humans. This would seem to be an ideal body of information for advancing our understanding of disorders in which altered threat processing is a key factor, namely, fear and anxiety disorders. But research on threat processing has not led to significant improvements in clinical practice. The authors propose that in order to take advantage of this progress for clinical gain, a conceptual reframing is needed. Key to this conceptual change is recognition of a distinction between circuits underlying two classes of responses elicited by threats: 1) behavioral responses and accompanying physiological changes in the brain and body and 2) conscious feeling states reflected in self-reports of fear and anxiety. This distinction leads to a "two systems" view of fear and anxiety. The authors argue that failure to recognize and consistently emphasize this distinction has impeded progress in understanding fear and anxiety disorders and hindered attempts to develop more effective pharmaceutical and psychological treatments. The two-system view suggests a new way forward.
Pub.: 10 Sep '16, Pinned: 22 Apr '17
Abstract: In this review, we discuss the usefulness of the distinction between fear and anxiety. The clinical use of the labels is ambiguous, often defining one in terms of the other. We first consider what a useful, objective, and scientifically valid definition would entail and then evaluate several fear/anxiety distinctions that have been made in the neurobiological literature. A strong distinction should specify the difference in conditions that lead to fear versus anxiety. Additionally, fear and anxiety should generate distinct sets of behaviors. Ideally, the two states should be supported by distinguishable neuroanatomical circuits. Such a conceptualization would be consistent with the National Institute of Mental Health's Research Domain Criteria (RDoc). The majority of neurobiological approaches to the fear versus anxiety distinction fail to differentiate the two states in terms of behavior, often using the exact same behavioral measures as indicators. Of the two that do, only Predatory Imminence Theory provides a distinction both in terms of cause and effect. Indeed, that approach provides a ready distinction of anxiety, fear, and panic in terms of both antecedent conditions and response selection rules. Additionally, it appeals to distinct neural circuits to generate these modes of action.
Pub.: 20 Aug '15, Pinned: 22 Apr '17
Abstract: The amygdala has long been associated with emotion and motivation, playing an essential part in processing both fearful and rewarding environmental stimuli. How can a single structure be crucial for such different functions? With recent technological advances that allow for causal investigations of specific neural circuit elements, we can now begin to map the complex anatomical connections of the amygdala onto behavioural function. Understanding how the amygdala contributes to a wide array of behaviours requires the study of distinct amygdala circuits.
Pub.: 17 Jan '15, Pinned: 22 Apr '17
Abstract: Pavlovian fear conditioning is one of the most common and well-understood methods for studying fear learning. However, research is predominantly performed in males. Recently, in a classical Pavlovian fear conditioning paradigm, Gruene and colleagues described an active conditioned fear response ('darting') prevalent in female rats that better maintain an extinction memory.
Pub.: 19 Jan '16, Pinned: 22 Apr '17
Abstract: Broad generalization of negative memories is a potential etiology for anxiety disorders, yet the underlying mechanisms remain unknown. We developed a non-human primate model that replicates behavioral observations in humans and identifies specific changes in tuning properties of amygdala neurons: the width of auditory tuning increases with the distance of its center from the conditioned stimulus. This center-width relationship can account for better detection and at the same time explain the wide stimulus generalization.
Pub.: 23 Dec '14, Pinned: 22 Apr '17
Abstract: We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning.
Pub.: 09 Jun '14, Pinned: 22 Apr '17
Abstract: The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, the mechanism by which CeA contributes to the learning and expression of fear is unclear. We found that fear conditioning in mice induced robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of the CeA (CeL). This experience-dependent plasticity was cell specific, bidirectional and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin-positive neurons impaired fear memory formation. Furthermore, activation of these neurons was necessary for fear memory recall and was sufficient to drive fear responses. Our findings support a model in which fear conditioning-induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output, thereby disinhibiting the medial subdivision of CeA and releasing fear expression.
Pub.: 29 Jan '13, Pinned: 22 Apr '17
Abstract: In Pavlovian fear conditioning, the lateral amygdala (LA) has been highlighted as a key brain site for association between sensory cues and aversive stimuli. However, learning-related changes are also found in upstream sensory regions such as thalamus and cortex. To isolate the essential neural circuit components for fear memory association, we tested whether direct activation of presynaptic sensory inputs in LA, without the participation of upstream activity, is sufficient to form fear memory in mice. Photostimulation of axonal projections from the two main auditory brain regions, the medial geniculate nucleus of the thalamus and the secondary auditory cortex, was paired with aversive footshock. Twenty-four hours later the same photostimulation induced robust conditioned freezing and this fear memory formation was disrupted when glutamatergic synaptic transmission was locally blocked in the LA. Therefore, our results prove for the first time that synapses between sensory input areas and the LA, previously implicated as a crucial brain site for fear memory formation, actually are sufficient to serve as a conditioned stimulus. Our results strongly support the idea that the LA may be sufficient to encode and store associations between neutral cue and aversive stimuli during natural fear conditioning as a critical part of a broad fear memory engram.
Pub.: 18 Oct '14, Pinned: 22 Apr '17
Abstract: The amygdala's historical role in processing stimuli related to threat and fear is being modified to suggest a role that is broader and more abstract. Amygdala lesions impair the ability to seek out and make use of the eye region of faces, resulting in impaired fear perception. Other studies in rats and humans revive earlier proposals that the amygdala is important not only for fear perception as such, but also for detecting saliency and biological relevance. Debates about some features of this processing now suggest that while the amygdala can process fearful facial expressions in the absence of conscious perception, and while there is some degree of preattentive processing, this depends on the context and is not necessarily more rapid than cortical processing routes. A large current research effort extends the amygdala's putative role to a number of psychiatric illnesses.
Pub.: 29 Jul '08, Pinned: 22 Apr '17
Abstract: Organisms tend to respond similarly to stimuli that are perceptually close to an event that predicts adversity, a phenomenon known as fear generalization. Greater dissimilarity yields weaker behavioral responses, forming a fear-tuning profile. The perceptual model of fear generalization assumes that behavioral fear tuning results from perceptual similarities, suggesting that brain responses should also exhibit the same fear-tuning profile. Using fMRI and a circular fear-generalization procedure, we tested this prediction. In contrast with the perceptual model, insula responses showed less generalization than behavioral responses and encoded the aversive quality of the conditioned stimulus, as shown by high pattern similarity between the conditioned stimulus and the shock. Also inconsistent with the perceptual model, object-sensitive visual areas responded to ambiguity-related outcome uncertainty. Together these results indicate that fear generalization is not passively driven by perception, but is an active process integrating threat identification and ambiguity-based uncertainty to orchestrate a flexible, adaptive fear response.
Pub.: 17 Nov '15, Pinned: 22 Apr '17
Abstract: Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias.
Pub.: 01 Nov '11, Pinned: 22 Apr '17
Abstract: Learning to contend with threats in the environment is essential to survival, but dysregulation of memories for traumatic events can lead to disabling psychopathology. Recent years have witnessed an impressive growth in our understanding of the neural systems and synaptic mechanisms underlying emotional memory formation. As a consequence, interest has emerged in developing strategies for suppressing, if not eliminating, fear memories. Here, I review recent work employing sophisticated behavioral, pharmacological, and molecular tools to target fear memories, placing these memories firmly behind the crosshairs of neurobiologically informed interventions.
Pub.: 11 Jun '11, Pinned: 22 Apr '17
Abstract: Fear learning is a rapid and persistent process that promotes defense against threats and reduces the need to relearn about danger. However, it is also important to flexibly readjust fear behavior when circumstances change. Indeed, a failure to adjust to changing conditions may contribute to anxiety disorders. A central, yet neglected aspect of fear modulation is the ability to flexibly shift fear responses from one stimulus to another if a once-threatening stimulus becomes safe or a once-safe stimulus becomes threatening. In these situations, the inhibition of fear and the development of fear reactions co-occur but are directed at different targets, requiring accurate responding under continuous stress. To date, research on fear modulation has focused mainly on the shift from fear to safety by using paradigms such as extinction, resulting in a reduction of fear. The aim of the present study was to track the dynamic shifts from fear to safety and from safety to fear when these transitions occur simultaneously. We used functional neuroimaging in conjunction with a fear-conditioning reversal paradigm. Our results reveal a unique dissociation within the ventromedial prefrontal cortex between a safe stimulus that previously predicted danger and a "naive" safe stimulus. We show that amygdala and striatal responses tracked the fear-predictive stimuli, flexibly flipping their responses from one predictive stimulus to another. Moreover, prediction errors associated with reversal learning correlated with striatal activation. These results elucidate how fear is readjusted to appropriately track environmental changes, and the brain mechanisms underlying the flexible control of fear.
Pub.: 07 Nov '08, Pinned: 22 Apr '17
Abstract: Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after a traumatic experience such as domestic violence, natural disasters or combat-related trauma. The cost of such disorders on society and the individual can be tremendous. In this article, we review how the neural circuitry implicated in PTSD in humans is related to the neural circuitry of fear. We then discuss how fear conditioning is a suitable model for studying the molecular mechanisms of the fear components that underlie PTSD, and the biology of fear conditioning with a particular focus on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB), GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches might help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD.
Pub.: 30 Jul '11, Pinned: 22 Apr '17
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