Fear conditioning

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Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. [1] It is a form of learning in which an aversive stimulus (e.g. an electrical shock) is associated with a particular neutral context (e.g., a room) or neutral stimulus (e.g., a tone), 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 (e.g., an electric shock, loud noise, or unpleasant odor [2] ). 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).

Contents

Fear conditioning apparatus for mice equipped with a sound, a foot shock and an activity sensor with photobeams to measure freezing. Environment context can be changed. This apparatus is also used for PTSD studies. Fear conditioning for mice.jpeg
Fear conditioning apparatus for mice equipped with a sound, a foot shock and an activity sensor with photobeams to measure freezing. Environment context can be changed. This apparatus is also used for PTSD studies.

Fear conditioning has been studied in numerous species, from snails [3] to humans. [4] In humans, conditioned fear is often measured with verbal report and galvanic skin response. In other animals, conditioned fear is often measured with freezing (a period of watchful immobility) or fear potentiated startle (the augmentation of the startle reflex by a fearful stimulus). Changes in heart rate, breathing, and muscle responses via electromyography can also be used to measure conditioned fear. A number of theorists have argued that conditioned fear coincides substantially with the mechanisms, both functional and neural, of clinical anxiety disorders. [5] Research into the acquisition, consolidation and extinction of conditioned fear promises to inform new drug based and psychotherapeutic treatments for an array of pathological conditions such as dissociation, phobias and post-traumatic stress disorder. [6]

Scientists have discovered that there is a set of brain connections that determine how fear memories are stored and recalled. While studying rats' ability to recall fear memories, researchers found a newly identified brain circuit is involved. Initially, the pre-limbic prefrontal cortex (PL) and the basolateral amygdala (BLA) were identified in memory recall. A week later, the central amygdala (CeA) and the paraventricular nucleus of the thalamus (PVT) were identified in memory recall, which are responsible for maintaining fear memories. This study shows how there are shifting circuits between short term recall and long term recall of fear memories. There is no change in behavior or response, only change in where the memory was recalled from. [7]

including medial prefrontal cortex (mPFC) Brain regions in memory formation updated.jpg
including medial prefrontal cortex (mPFC)

In addition to the amygdala, the hippocampus and the anterior cingulate cortex are important in fear conditioning. Fear conditioning in the rat is stored at early times in the hippocampus, with alterations in hippocampal gene expression observed at 1 hour and 24 hours after the event. [8] In the mouse, changed gene expression is also seen in the hippocampus at one hour and 24 hours after fear conditioning. These changes are transient in the hippocampal neurons, and almost none are present in the hippocampus after four weeks. By 4 weeks after the event, the memory of the fear conditioning event is more permanently stored in the anterior cingulate cortex. [9] [10] [11]

Neurobiology

Neuronal gene expression

As shown in the rodent brain, neuronal gene expression is dynamically changed in response to fear conditioning. In particular, the expressions of immediate early genes (IEGs) such as Egr1, c-Fos, and Arc are rapidly and selectively up-regulated in subsets of neurons in specific brain regions associated with learning and memory formation. [12]

A review in 2022 [13] describes multiple steps in up-regulating the IEGs in neurons in the hippocampus during fear conditioning. IEGs are similarly up-regulated in the amygdala during fear conditioning. [14] [15] The multiple steps in up-regulating IEGs [13] include activation of transcription factors, [16] formation of chromatin loops, interaction of enhancers with promoters in chromatin loops and topoisomerase II beta-initiated temporary DNA double-strand breaks.

At least two IEGs up-regulated by fear conditioning, Egr1 and Dnmt3A2 (shown to be an IEG by Oliveira et al. [17] ) affect DNA methylation, and thus expression, of many genes. Up-regulated EGR1 proteins associate with pre-existing nuclear TET1 proteins, and the EGR1 proteins bring TET1 proteins to hundreds of genes, allowing TET1 to initiate DNA demethylation of those genes. [18] DNMT3A2 protein is a de novo DNA methyltransferase, adding methylation to cytosines in DNA. Expression of DNMT3A2 proteins in hippocampus neurons in culture preferentially targeted the addition of new methylation to more than 200 genes involved in synaptic plasticity. [19] Expressions of IEGs are a source of the dynamic changes in subsequent neuronal gene expression in response to fear conditioning.

Amygdala

Fear conditioning is thought to depend upon an area of the brain called the amygdala. The amygdala is involved in acquisition, storage, and expression of conditioned fear memory. [11] Lesion studies have revealed that lesions drilled into the amygdala before fear conditioning prevent the acquisition of the conditioned response of fear, and lesions drilled in the amygdala after conditioning cause conditioned responses to be forgotten. [20] Electrophysiological recordings from the amygdala have demonstrated that cells in that region undergo long-term potentiation (LTP), a form of synaptic plasticity believed to underlie learning. [21] Pharmacological studies, synaptic studies, and human studies also implicate the amygdala as chiefly responsible for fear learning and memory. [11] Additionally, inhibition of neurons in the amygdala disrupts fear acquisition, while stimulation of those neurons can drive fear-related behaviors, such as freezing behavior in rodents. [22] This indicates that proper function of the amygdala is both necessary for fear conditioning and sufficient to drive fear behaviors. The amygdala is not exclusively the fear center, but also an area for responding to various environmental stimuli. Several studies have shown that when faced with unpredictable neutral stimuli, amygdala activity increases. Therefore, even in situations of uncertainty and not necessarily fear, the amygdala plays a role in alerting other brain regions that encourage safety and survival responses. [23]

In the mid-1950s Lawrence Weiskrantz demonstrated that monkeys with lesions of amygdala failed to avoid an aversive shock while the normal monkeys learned to avoid them. He concluded that a key function of the amygdala was to connect external stimuli with aversive consequences. [24] Following Weiskrantz's discovery many researchers used avoidance conditioning to study neural mechanisms of fear. [25]

Joseph E. LeDoux has been instrumental in elucidating the amygdala's role in fear conditioning. He was one of the first to show that the amygdala undergoes long-term potentiation during fear conditioning, and that ablation of amygdala cells disrupts both learning and expression of fear. [26]

Hippocampus

Some types of fear conditioning (e.g. contextual and trace) also involve the hippocampus, an area of the brain believed to receive affective impulses from the amygdala and to integrate those impulses with previously existing information to make it meaningful. Some theoretical accounts of traumatic experiences suggest that amygdala-based fear bypasses the hippocampus during intense stress and can be stored somatically or as images that can return as physical symptoms or flashbacks without cognitive meaning. [27]

The hippocampus is one of the brain regions that undergoes major alterations in gene expression after contextual fear conditioning. Contextual fear conditioning applied to a rat causes about 500 genes to be up-regulated (possibly due to DNA demethylation of CpG sites) and about 1,000 genes to be down-regulated (observed to be correlated with DNA methylation at CpG sites in promoter regions) (see Regulation of transcription in learning and memory). [8] By 24 hours after the event, 9.17% of the genes in the genomes of rat hippocampus neurons are differentially methylated. The pattern of induced and repressed genes within hippocampal neurons appears to provide a molecular basis for forming the early transient memory of contextual fear conditioning in the hippocampus. [8] When similar contextual fear conditioning was applied to a mouse, one hour after contextual fear conditioning there were 675 demethylated genes and 613 hypermethylated genes in the hippocampus region of the mouse brain. [9] These changes were transient in the hippocampal neurons, and almost none of these DNA methylation alterations were present in the hippocampus after four weeks. However, in mice subjected to contextual fear conditioning, after four weeks there were more than 1,000 differentially methylated genes and more than 1,000 differentially expressed genes in the mouse anterior cingulate cortex [9] where long-term memories are stored.

Molecular mechanisms

Double-strand breaks

More than 100 DNA double-strand breaks occur, both in the hippocampus and in the medial prefrontal cortex (mPFC), in two peaks, at 10 minutes and at 30 minutes after contextual fear conditioning. [28] This appears to be earlier than the DNA methylations and demethylations of neuron DNA in the hippocampus that were measured at one hour and 24 hours after contextual fear conditioning (described above in the section Hippocampus).

The double strand breaks occur at known memory-related immediate early genes (among other genes) in neurons after neuron activation. [29] [28] These double-strand breaks allow the genes to be transcribed and then translated into active proteins.

One immediate early gene newly transcribed after a double-strand break is EGR1. EGR1 is an important transcription factor in memory formation. It has an essential role in brain neuron epigenetic reprogramming. EGR1 recruits the TET1 protein that initiates a pathway of DNA demethylation. Removing DNA methylation marks allows the activation of downstream genes (see Regulation of gene expression#Regulation of transcription in learning and memory. EGR1 brings TET1 to promoter sites of genes that need to be demethylated and activated (transcribed) during memory formation. [30] EGR-1, together with TET1, is employed in programming the distribution of DNA demethylation sites on brain DNA during memory formation and in long-term neuronal plasticity. [30]

DNMT3A2 is another immediate early gene whose expression in neurons can be induced by sustained synaptic activity. [17] DNMTs bind to DNA and methylate cytosines at particular locations in the genome. If this methylation is prevented by DNMT inhibitors, then memories do not form. [31] If DNMT3A2 is over-expressed in the hippocampus of young adult mice it converts a weak learning experience into long-term memory and also enhances fear memory formation. [32]

Intra-amygdala circuit

Neurons in the basolateral amygdala are responsible for the formation of conditioned fear memory. These neurons project to neurons in the central amygdala for the expression of a conditioned fear response. Damage to these areas in the amygdala would result in disruption of the expression of conditioned fear responses. Lesions in the basolateral amygdala have shown severe deficits in the expression of conditioned fear responses. Lesions in the central amygdala have shown mild deficits in the expression of conditioned fear responses. [11]

NMDA receptors and glutamate

One of the major neurotransmitters involved in conditioned fear learning is glutamate. [33] It has been suggested that NMDA receptors (NMDARs) in the amygdala are necessary for fear memory acquisition, because disruption of NMDAR function disrupts development of fear responses in rodents. [33] In addition, the associative nature of fear conditioning is reflected in the role of NMDARs as coincident detectors, where NMDAR activation requires simultaneous depolarization by US inputs combined with concurrent CS activation. [34]

Dopamine

In addition to glutamate, dopamine is involved in fear conditioning and extinction. Dopamine neurons in the ventral tegmental area, substantia nigra pars compacta, and dorsal raphe nucleus play a critical role in forming, consolidating, and retrieving fear-related memories. The amygdala is involved in the initial expression and acquisition of fear, while dopamine receptor activation in the medial prefrontal cortex and striatum works to link fear expression to CS. [35]

Epigenetics

Conditioned fear may be inherited transgenerationally. In one experiment, mice were conditioned to fear an acetophenone odor and then set up to breed subsequent generations of mice. Those subsequent generations of mice also showed a behavioral sensitivity to acetophenone, which was accompanied by neuroanatomical and epigenetic changes that are believed to have been inherited from the parents' gametes. [36]

Across development

The learning involved in conditioned fear, as well as the underlying neurobiology, changes dramatically from infancy, across childhood and adolescence, into adulthood and aging. Specifically, infant animals show an inability to develop fear associations, whereas their adult counterparts develop fear memories much more readily. [37]

Previous research has indicated that adolescents show hampered fear extinction learning compared to children and adults. [38] This finding may have clinical implications, as one of the most widely used treatments for anxiety disorders is exposure based therapy, which builds on the principles of fear extinction. The exact mechanisms underlying the developmental differences in fear extinction learning have not yet been discovered, although it has been suggested that age related differences in connectivity between the amygdala and medial prefrontal cortex can be one of the biological mechanisms underpinning the developmental change in fear extinction learning. [39]

Prior experience with stress

A history of stressors preceding a traumatic event increases the effect of fear conditioning in rodents. [40] This phenomenon, named Stress-Enhanced Fear Learning (SEFL), has been demonstrated in both young (e.g. Poulos et al. 2014 [41] ) and adult (e.g. Rau et al. 2009 [42] ) rodents. Biological mechanisms underpinning SEFL have not yet been made clear, though it has been associated with a rise in corticosterone, the stress hormone, following the initial stressor. [43]

See also

Related Research Articles

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. Epigenetic factors can also lead to cancer.

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

The amygdala is a paired nuclear complex present in the cerebral hemispheres of vertebrates. It is considered part of the limbic system. In primates, it is located medially within the temporal lobes. It consists of many nuclei, each made up of further subnuclei. The subdivision most commonly made is into the basolateral, central, cortical, and medial nuclei together with the intercalated cell clusters. The amygdala has a primary role in the processing of memory, decision-making, and emotional responses. The amygdala was first identified and named by Karl Friedrich Burdach in 1822.

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

Immediate early genes (IEGs) are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized. IEGs are distinct from "late response" genes, which can only be activated later, following the synthesis of early response gene products. Thus IEGs have been called the "gateway to the genomic response". The term can describe viral regulatory proteins that are synthesized following viral infection of a host cell, or cellular proteins that are made immediately following stimulation of a resting cell by extracellular signals.

<span class="mw-page-title-main">EGR1</span> Protein-coding gene in the species Homo sapiens

EGR-1 or NGFI-A is a protein that in humans is encoded by the EGR1 gene.

Extinction is a behavioral phenomenon observed in both operantly conditioned and classically conditioned behavior, which manifests itself by fading of non-reinforced conditioned response over time. When operant behavior that has been previously reinforced no longer produces reinforcing consequences, the behavior gradually returns to operant levels. In classical conditioning, when a conditioned stimulus is presented alone, so that it no longer predicts the coming of the unconditioned stimulus, conditioned responding gradually stops. For example, after Pavlov's dog was conditioned to salivate at the sound of a metronome, it eventually stopped salivating to the metronome after the metronome had been sounded repeatedly but no food came. Many anxiety disorders such as post-traumatic stress disorder are believed to reflect, at least in part, a failure to extinguish conditioned fear.

In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones.

<span class="mw-page-title-main">DNA demethylation</span> Removal of a methyl group from one or more nucleotides within a DNA molecule.

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<span class="mw-page-title-main">8-Oxo-2'-deoxyguanosine</span> Chemical compound

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<span class="mw-page-title-main">Activity-regulated cytoskeleton-associated protein</span> Protein-coding gene in the species Homo sapiens

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The cellular transcription factor CREB helps learning and the stabilization and retrieval of fear-based, long-term memories. This is done mainly through its expression in the hippocampus and the amygdala. Studies supporting the role of CREB in cognition include those that knock out the gene, reduce its expression, or overexpress it.

<span class="mw-page-title-main">Memory</span> Faculty of mind to store and retrieve data

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Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal and human behavior. It seeks to explain how nurture shapes nature, where nature refers to biological heredity and nurture refers to virtually everything that occurs during the life-span. Behavioral epigenetics attempts to provide a framework for understanding how the expression of genes is influenced by experiences and the environment to produce individual differences in behaviour, cognition, personality, and mental health.

Daniela Schiller is a neuroscientist who leads the Affective Neuroscience Lab at the Mount Sinai School of Medicine. She is best known for her work on memory reconsolidation, and on modification of emotional learning and memory.

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<span class="mw-page-title-main">Stephen Maren</span>

Stephen Andrew Maren is an American behavioral neuroscientist investigating the brain mechanisms of emotional memory, particularly the role context plays in the behavioral expression of fear. He has discovered brain circuits regulating context-dependent memory, including mapping functional connections between the hippocampus, prefrontal cortex, and amygdala that are involved in the expression and extinction of learned fear responses.

<span class="mw-page-title-main">TET enzymes</span> Family of translocation methylcytosine dioxygenases

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