Fear processing in the brain

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Many experiments have been done to find out how the brain interprets stimuli and how animals develop fear responses. The emotion, fear, has been hard-wired into almost every individual, due to its vital role in the survival of the individual. Researchers have found that fear is established unconsciously and that the amygdala is involved with fear conditioning.

Contents

By understanding how fear is developed within individuals, it may be possible to treat human mental disorders such as anxiety, phobia, and posttraumatic stress disorder.

Neuronal fear pathways

In fear conditioning, the main circuits that are involved are the sensory areas that process the conditioned and unconditioned stimuli, certain regions of the amygdala that undergo plasticity (or long-term potentiation) during learning, and the regions that bear an effect on the expression of specific conditioned responses. These pathways converge in the lateral amygdala. Long-term potentiation (LTP) and synaptic plasticity that enhances the response of lateral amygdala neurons to the conditioned stimulus occurs in the lateral amygdala. As a result, the conditioned stimulus is then able to flow from the lateral amygdala to the central nucleus of the amygdala. The basal and intercalated masses of the amygdala connect the lateral amygdala with the central nucleus of the amygdala directly and indirectly. Pathways from central nucleus of the amygdala to downstream areas then control defensive behavior (freezing) and autonomic and endocrine responses. Recent studies implicate the prelimbic cortex in fear expression as well, possibly by way of its connections to the basal and then to the central nucleus of the amygdala. [1]

Behavioral basis

It has been observed that fear can contribute to behavioral changes. [2] One way this phenomenon has been studied is on the basis of the repeated stress model done by Camp RM et al.(among others). In this particular study, it was examined that the contribution fear conditioning may play a huge role in altering an animal's (Fischer rat's) behavior in a repeated stress paradigm. Behavioral changes that are commonly referred to as depressive-like behaviors resulted from this model of testing. After setting a control and a valid experimental design, Fischer rats were exposed daily to different stressors in a complex environment. After four days of stressor exposure, both exploratory behavior and social interaction were tested on day 5 in either the same environment or a new environment. The rats showed much decreased exploration and social interaction when tested in different contexts compared to control rats. [3] To further make a correlation to the biochemistry (as mentioned below), chronic infusion of propranolol (beta-adrenergic receptor antagonist) prevented the behavioral changes following repeated stressor exposure thus halting long term potentiation. Some physiological changes also occurred including the decrease in body weight gain and adrenal hypertrophy observed in animals exposed to stress. Overall, the conditioned fear responses can contribute to behavioral changes in a repeated stress paradigm. This can be extended to correlate to other animals as well but with varying degrees of responses. [3]

Molecular basis

Molecular mechanisms that have been linked directly to the behavioral expression of conditioning are easier to study in a clinical setting as opposed to mechanisms that underlie long-term potentiation (LTP), in which synaptic plasticity is induced by electrical or chemical stimulation of lateral amygdala circuits. LTP is important for fear processing because it strengthens the synapses in neural circuits. [4] These strengthened synapses are how long-term memory is developed and how fear is developed. [5]

Hebbian synaptic plasticity

Synaptic input can be strengthened when activity in the presynaptic neuron co-occurs with depolarization in the postsynaptic neuron. This is known as Hebbian synaptic plasticity. This hypothesis is especially appealing as an explanation for how simple associative learning, such as that taking place in fear conditioning, might occur. In this model of fear conditioning, strong depolarization of the lateral amygdala elicited by the stimulus leads to the strengthening of temporally and spatially relative conditioned stimulus inputs (that are coactive) onto the same neurons. Experimental data has been shown to support the idea that the plasticity and fear memory formation in the lateral amygdala are triggered by unconditioned stimulus-induced activation of the region's neurons. [1] Thus, unconditioned stimulus-evoked depolarization is necessary for the enhancement of conditioned stimulus-elicited neural responses in this region after conditioned-unconditioned pairing and pairing a conditioned stimulus with direct depolarization of the lateral amygdala's pyramidal neurons as an unconditioned stimulus supports fear conditioning. It is also clear that synaptic plasticity at conditioned stimulus input pathways to the lateral amygdala does occur with fear conditioning. [1]

NMDA-type ionotropic glutamate receptors

Hebian plasticity is believed to involve N-methyl-d-aspartate receptors (NMDARs) and are located on postsynaptic neurons in the lateral amygdala. NMDARs are known to be coincidence detectors of presynaptic activity and postsynaptic depolarization. Auditory inputs are NMDARs in the lateral amygdala and use glutamate as a transmitter. [6] Furthermore, it was tested that when the region's neurons that received auditory inputs also received unconditioned stimulus inputs and broad spectrum NMDAR antagonists in the lateral amygdala resulted in the disruption of the acquisition of fear learning. Therefore, these receptors are crucial to the metabolic pathway of processing and eliciting for the percept of fear. [7]

Monoamine neuromodulatory-dependent mechanisms

It is believed that monoamine transmitters such as norepinepherine and dopamine that are released in emotional situations function in regulating glutamatergic transmission and Hebbian plasticity. The modulation of all of the different types of plasticity is called heterosynaptic plasticity. Homosynaptic plasticity is also prevalent which consists solely of the Hebbian plasticity. In a variety of model systems, it has been shown that monoamines modulate plasticity underlying memory formation such as a heightened percept of fear. [8] Neuromodulators also contribute to fear conditioning. [9] The Hebbian mechanisms contribute to plasticity in the lateral amygdala and fear learning. Other modulators apart from the Hebbian mechanisms include serotonin, acetylcholine, endocannabinoids, and various peptides (such as gastrin-releasing peptide, NPY, opiates, and oxytocin) but the role of these compounds are not fully understood.

Norepinephrine

Norepinephrine is a huge player in fear memory formation. Recent studies have demonstrated that the blockade of norepinephrine β-adrenergic receptors (β-ARs) in the lateral nucleus of the amygdala interferes with the acquisition of fear learning when given pretraining stimuli but has no effect when applied posttraining or before memory retrieval. In contrast to effects of β-AR receptor blockade on other forms of learning, this effect is specific to only acquisition, as opposed to the posttraining processing or expression of fear memory. [10] The activation of β-ARs in the lateral amygdala synergistically regulates Hebbian processes to trigger the neuron's associative plasticity and fear learning in the lateral nucleus of the amygdala. One theory suggests that the mechanism of β-AR involvement in the acquisition of fear learning is that they act on GABAergic interneurons to suppress feed-forward inhibition and enhance Hebbian plasticity. β-ARs are found on GABAergic interneurons as well as in the lateral amygdala's pyramidal cells. The process of activation of β-ARs start off by coupling to G protein signaling cascades, which then activate protein kinase A (PKA). This activation can elicits the phosphorylation of NMDARs as well as the ser845 site on GluA1, which could facilitate AMPAR insertion at the synapse.

Dopamine

Dopamine receptor activation (both D1 and D2 receptor subtypes) in the amygdala contributes to the acquisition of fear conditioning. D1 and D2 receptors are G protein coupled and inhibit adenylate cyclase (Gi-coupled) and stimulate adenylate cyclase (Gs-coupled), respectively. Just like β-ARs, dopamine receptors may modulate Hebbian processes directly by reducing feed-forward inhibition. They may also act in a parallel fashion with Hebbian mechanisms to implement synapses in the lateral amygdala and promote plasticity and fear learning through their respective signaling pathways. [11] Accumulating evidence suggests that midbrain dopaminergic innervation of the basolateral amygdala facilitate the formation of fear memories. [12] [13] [14]

Metabotropic glutamate receptor-mediated neuromodulation during

Plasticity and learning can also be modulated by metabotropic glutamate receptors (mGluRs). The proteins mGluRs likely serve a modulatory function and do not participate directly in Hebbian processes. This is because due to the fact these receptors do not contribute to depolarization during synapses. They are also not activated by receptors that participate in Hebbian processes. Finally, they do not detect pre- and postsynaptic neural activity. However, the activation of group I mGluRs in the lateral amygdala and basal nucleus enhances the acquisition, reduction, and amplification of fear conditioning by providing an influx of calcium ions.

Fear circuitry

Fear recognition

Research studies have shown that damage to the bilateral amygdala [15] affects mostly the recognition of fear. In a specific study conducted by Andrew J. Calder and Andrew W. Young, they had subjects classify morphed images of facial expressions ranging from happiness to surprise to fear to sadness to disgust to anger. While control subjects classified these images to the nearest expression, subjects who had damage to the bilateral amygdala had problems with this task, especially with the recognition of facial expressions that show fear. The subjects with the damaged bilateral amygdala had no problems differentiating happiness from sadness, but they could not differentiate the expression of anger from fear. [16]

However, in an experiment conducted by Ralph Adolphs, it elucidated the mechanism of the impaired fear recognition. Adolphs found that his main subject, who had a rare bilateral amygdala damage, could not discern fear expressions because of her inability to look at the eye region of the face. When the subject was instructed to look directly at the eye region of faces with expression, the subject could recognize fear expressions of faces. [17] Although the amygdala does play an important part in the recognition of fear, further research shows that there are alternate pathways that are capable to support fear learning in the absence of a functional amygdala. [18] A study by Kazama also shows that although the amygdala may be damaged, it is still possible for patients to distinguish the difference between safety cues and fear. [19]

Conditioned stimuli

There has been a substantial amount of research done on conditioned stimuli, where a neutral stimulus, such as a flash of light, is paired with a shock is given to a rat. The result of this conditioned stimulus is to provoke the unconditioned response, fear. The once neutral stimulus is given again to see if the rat would show the responses of fear. However, because fear responses involve many behaviors, it is important to see which behaviors are exhibited when the conditioned stimulus is given. [2]

Visual and auditory stimuli

Initially, the visual stimuli is first received by the visual thalamus and relayed to the amygdala for potential danger. The visual thalamus also relays the information to the visual cortex and is processed to see if the stimuli poses a potential threat. If so, this information is relayed to the amygdala and the muscle contraction, increased heart rate and blood pressure begins, thus activating the sympathetic neuronal pathway. A presentation of a neutral visual stimuli has been shown to intensify the percept of fear or suspense induced by a different channel of information, such as audition. [20] [21] From Le Doux's research, it shows that sound stimuli are not directly relayed from the auditory thalamus to the central nucleus. [15]

Perception

The perception of fear is elicited by many different stimuli and involves the process described above in biochemical terms. Neural correlates of the interaction between language and visual information has been studied by Roel Willems et al. [22] The study consisted of observing how visual and linguistic information interact in the perception of emotion. A common phenomenon from film theory was borrowed which states that the presentation of a neutral visual scene intensifies the percept of fear or suspense induced by a different channel of information, such as language. This principle has been applied in a way in which the percept of fear was present and amplified in the presence of a neutral visual stimuli. The main idea is that the visual stimuli intensify the fearful content of the stimuli (i.e. language) by subtly implying and concretizing what is described in the context (i.e. sentence). Activation levels in the right anterior temporal pole were selectively increased and is believed to serve as a binding function of emotional information across domains such as visual and linguistic information. [23]

Exposure to different types of emotion and levels of arousal also appear to influence pain through an interaction known as the valence-by-arousal interaction. During this reaction, negative emotions experienced by an individual with low levels of arousal tend to cause enhanced pain while negative valenced emotions with higher levels of arousal have been observed to decrease the perception of pain. Low levels of arousal would include reactive emotions such as anxiety while higher levels of arousal include emotions such as fear. [24]

Related Research Articles

<span class="mw-page-title-main">Amygdala</span> Each of two small structures deep within the temporal lobe of complex vertebrates

The amygdala is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex vertebrates, including humans. Shown to perform a primary role in the processing of memory, decision making, and emotional responses, the amygdalae are considered part of the limbic system. The term "amygdala" was first introduced by Karl Friedrich Burdach in 1822.

<span class="mw-page-title-main">Long-term potentiation</span> Persistent strengthening of synapses based on recent patterns of activity

In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.

Hebbian theory is a neuroscientific theory claiming that an increase in synaptic efficacy arises from a presynaptic cell's repeated and persistent stimulation of a postsynaptic cell. It is an attempt to explain synaptic plasticity, the adaptation of brain neurons during the learning process. It was introduced by Donald Hebb in his 1949 book The Organization of Behavior. The theory is also called Hebb's rule, Hebb's postulate, and cell assembly theory. Hebb states it as follows:

Let us assume that the persistence or repetition of a reverberatory activity tends to induce lasting cellular changes that add to its stability. ... When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

<span class="mw-page-title-main">Fear conditioning</span> Behavioral paradigm in which organisms learn to predict aversive events

Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus is associated with a particular neutral context or neutral stimulus, resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus. Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).

In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

Spike-timing-dependent plasticity (STDP) is a biological process that adjusts the strength of connections between neurons in the brain. The process adjusts the connection strengths based on the relative timing of a particular neuron's output and input action potentials. The STDP process partially explains the activity-dependent development of nervous systems, especially with regard to long-term potentiation and long-term depression.

<span class="mw-page-title-main">AP5</span> Chemical compound

AP5 is a chemical compound used as a biochemical tool to study various cellular processes. It is a selective NMDA receptor antagonist that competitively inhibits the ligand (glutamate) binding site of NMDA receptors. AP5 blocks NMDA receptors in micromolar concentrations.

An avoidance response is a natural adaptive behavior performed in response to danger. Excessive avoidance has been suggested to contribute to anxiety disorders, leading psychologists and neuroscientists to study how avoidance behaviors are learned using rat or mouse models. Avoidance learning is a type of operant conditioning.

Metaplasticity is a term originally coined by W.C. Abraham and M.F. Bear to refer to the plasticity of synaptic plasticity. Until that time synaptic plasticity had referred to the plastic nature of individual synapses. However this new form referred to the plasticity of the plasticity itself, thus the term meta-plasticity. The idea is that the synapse's previous history of activity determines its current plasticity. This may play a role in some of the underlying mechanisms thought to be important in memory and learning such as long-term potentiation (LTP), long-term depression (LTD) and so forth. These mechanisms depend on current synaptic "state", as set by ongoing extrinsic influences such as the level of synaptic inhibition, the activity of modulatory afferents such as catecholamines, and the pool of hormones affecting the synapses under study. Recently, it has become clear that the prior history of synaptic activity is an additional variable that influences the synaptic state, and thereby the degree, of LTP or LTD produced by a given experimental protocol. In a sense, then, synaptic plasticity is governed by an activity-dependent plasticity of the synaptic state; such plasticity of synaptic plasticity has been termed metaplasticity. There is little known about metaplasticity, and there is much research currently underway on the subject, despite its difficulty of study, because of its theoretical importance in brain and cognitive science. Most research of this type is done via cultured hippocampus cells or hippocampal slices.

<span class="mw-page-title-main">Reward system</span> Group of neural structures responsible for motivation and desire

The reward system is a group of neural structures responsible for incentive salience, associative learning, and positively-valenced emotions, particularly ones involving pleasure as a core component. Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.

<span class="mw-page-title-main">Basolateral amygdala</span>

The basolateral amygdala, or basolateral complex, consists of the lateral, basal and accessory-basal nuclei of the amygdala. The lateral nuclei receives the majority of sensory information, which arrives directly from the temporal lobe structures, including the hippocampus and primary auditory cortex. The basolateral amygdala also receives dense neuromodulatory inputs from ventral tegmental area (VTA), locus coeruleus (LC), and basal forebrain, whose integrity are important for associative learning. The information is then processed by the basolateral complex and is sent as output to the central nucleus of the amygdala. This is how most emotional arousal is formed in mammals.

Coincidence detection in the context of neurobiology is a process by which a neuron or a neural circuit can encode information by detecting the occurrence of temporally close but spatially distributed input signals. Coincidence detectors influence neuronal information processing by reducing temporal jitter, reducing spontaneous activity, and forming associations between separate neural events. This concept has led to a greater understanding of neural processes and the formation of computational maps in the brain.

Activity-dependent plasticity is a form of functional and structural neuroplasticity that arises from the use of cognitive functions and personal experience; hence, it is the biological basis for learning and the formation of new memories. Activity-dependent plasticity is a form of neuroplasticity that arises from intrinsic or endogenous activity, as opposed to forms of neuroplasticity that arise from extrinsic or exogenous factors, such as electrical brain stimulation- or drug-induced neuroplasticity. The brain's ability to remodel itself forms the basis of the brain's capacity to retain memories, improve motor function, and enhance comprehension and speech amongst other things. It is this trait to retain and form memories that is associated with neural plasticity and therefore many of the functions individuals perform on a daily basis. This plasticity occurs as a result of changes in gene expression which are triggered by signaling cascades that are activated by various signaling molecules during increased neuronal activity.

<span class="mw-page-title-main">Nonsynaptic plasticity</span> Form of neuroplasticity

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

Memory allocation is a process that determines which specific synapses and neurons in a neural network will store a given memory. Although multiple neurons can receive a stimulus, only a subset of the neurons will induce the necessary plasticity for memory encoding. The selection of this subset of neurons is termed neuronal allocation. Similarly, multiple synapses can be activated by a given set of inputs, but specific mechanisms determine which synapses actually go on to encode the memory, and this process is referred to as synaptic allocation. Memory allocation was first discovered in the lateral amygdala by Sheena Josselyn and colleagues in Alcino J. Silva's laboratory.

<span class="mw-page-title-main">Heterosynaptic plasticity</span>

Synaptic plasticity refers to a chemical synapse's ability to undergo changes in strength. Synaptic plasticity is typically input-specific, meaning that the activity in a particular neuron alters the efficacy of a synaptic connection between that neuron and its target. However, in the case of heterosynaptic plasticity, the activity of a particular neuron leads to input unspecific changes in the strength of synaptic connections from other unactivated neurons. A number of distinct forms of heterosynaptic plasticity have been found in a variety of brain regions and organisms. These different forms of heterosynaptic plasticity contribute to a variety of neural processes including associative learning, the development of neural circuits, and homeostasis of synaptic input.

Early long-term potentiation (E-LTP) is the first phase of long-term potentiation (LTP), a well-studied form of synaptic plasticity, and consists of an increase in synaptic strength. LTP could be produced by repetitive stimulation of the presynaptic terminals, and it is believed to play a role in memory function in the hippocampus, amygdala and other cortical brain structures in mammals.

References

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