Fear Learning & Fear Extinction PDF

Fear learning Assessment of fear conditioning Habituation: no stimulation Conditioning: CS > footshock > UR Testing: CS > CR Conditioned freezing: behavioural features such as immobility, crouched posture with arched spine With footshock: only a few trials are needed for CS-US learning...

Fear learning Assessment of fear conditioning Habituation: no stimulation Conditioning: CS > footshock > UR Testing: CS > CR Conditioned freezing: behavioural features such as immobility, crouched posture with arched spine With footshock: only a few trials are needed for CS-US learning corresponds to the beta value (salience) in Rescorla-Wagner model Fear as part of a defensive behavioural system The fear system orchestrates a variety of adaptive defensive behaviours that ultimately protect the individual from danger (species specific defence responses) Freezing, flight, fight, analgesia, autonomic arousal Which behaviour is expressed has been proposed to depend on the predatory imminence gradient Neurobiology of learned fear What brain areas are involved in learning to predict danger? Thalamus sensory relay center, transmitting sensory information (auditory, visual, and somatosensory) to the amygdala (LA) medial geniculate nucleus (MGN) of the thalamus sends auditory information Direct and indirect pathways to the amygdala Lesion effects Fear Learning: Lesions in sensory thalamic nuclei impair the ability to acquire fear conditioning sensory inputs necessary for CS-US association are disrupted Fear Extinction: disrupting the flow of sensory information to the amygdala harder for the organism to learn that the stimulus is no longer predictive of danger Perirhinal Cortex key role in object recognition and visual information processing integrates complex sensory information interacts with the amygdala and hippocampus to modulate fear responses. FEAR LEARNING Outputs: projects to the BLA, providing detailed sensory input aids in forming associations between complex stimuli (CS) and aversive outcomes (US) FEAR EXTINCTION Projects to hippocampus to process information about the context in which fear learning and extinction occur Helps distinguish between threatening and non-threatening situations based on environmental or object-based cues Projects to amygdala, helping refine the extinction of fear responses when the stimulus no longer predicts danger Lesion effects: Fear Learning: impair the ability to form detailed associations between specific objects or stimuli and aversive events Fear Extinction: interfere with extinction learning, and may fail to appropriately update fear responses when the CS no longer predicts a threat Amygdala central to fear learning processes and stores emotional memories, particularly fear-related stimuli orchestrates fear responses Lateral amygdala (LA): Receives sensory inputs related to conditioned stimuli (CS, such as a tone) and unconditioned stimuli (US, such as a shock) from the thalamus and sensory cortex encodes the CS-US association Basolateral amygdala (BLA): Integrates inputs from the LA and other brain regions (hippocampus and prefrontal cortex) helps modulate emotional responses Central amygdala (CeA): Sends outputs to the hypothalamus and brainstem to trigger fear responses, such as increased heart rate or freezing behaviour projects to regions responsible for autonomic and behavioural fear responses: periaqueductal gray (PAG) for freezing  hypothalamus for hormonal stress responses Lesion effects Lesions of the LA or BLA impair the acquisition and expression of fear learning, meaning animals can't learn or show a conditioned fear response Lesions of the CeA disrupt the expression of fear responses (e.g., freezing), but not necessarily the acquisition of fear memories Prefrontal Cortex (PFC) Inputs: from the amygdala, hippocampus, and thalamus, integrating information about emotional states, context, and sensory inputs Outputs: projects to the amygdala, especially the BLA and intercalated cells (ITC), to modulate fear responses connects to the hypothalamus and PAG for controlling physiological and behavioural fear responses Infralimbic cortex (IL/IF) and prelimbic cortex (PL), plays a key role in the regulation of fear and the process of fear extinction IL: Crucial for fear extinction inhibits amygdala activity and promotes the suppression of conditioned fear responses PL: Facilitates fear expression by maintaining activity in the amygdala during fear conditioning Lesion effects Lesions of the IL/IF prevent fear extinction: animals can't suppress their conditioned fear responses even after repeated exposure to the CS without the US Lesions of the PL impair the expression of conditioned fear, reducing the ability to show fear responses Role of the intercalated cells (ITC) act as "gatekeepers" that control the flow of information within the amygdala (CeA) , determining whether a fear response is expressed or inhibited GABAergic neurons = inhibits other neurons = reduce the expression of fear FEAR EXTINCTION: IL/IF activity increases > stimulate ITCs > inhibit the CeA = suppression of fear response (freezing) Importance: fear CR might persist even when the fear-inducing stimulus is no longer relevant FEAR EXPRESSION PL & BLA activity > reduce ITCs > disinhibition of CeA > expression of fear Importance: allows for the flexible expression of fear, depending on whether the situation requires a fear response or no Hippocampus involved in contextual fear learning and helps modulate fear extinction by providing information about the context in which fear memories were acquired distinguishes between the contexts in which fear is appropriate or not Inputs: It receives sensory and contextual information from various cortical areas, and input from the amygdala about the emotional significance of stimuli Outputs: projects back to the amygdala (particularly the BLA) and the PFC, helping regulate whether a fear response is appropriate in a given context Lesion effects impair contextual fear conditioning: animals have difficulty associating fear responses with specific contexts disrupt contextual fear extinction: animals fail to differentiate between fear-inducing and non-fear-inducing environments, leading to inappropriate fear responses Periaqueductal Gray (PAG) Involvement: The PAG mediates the behavioural and physiological responses associated with fear, such as freezing and changes in autonomic functions (heart rate, breathing) ventrolateral PAG (vlPAG) is involved in fear extinction dorsal PAG (dPAG) is associated with fear expression Inputs: Receives projections from the amygdala (CeA), hypothalamus, and PFC, integrating emotional and autonomic signals Outputs: Projects to the brainstem and spinal cord to control defensive behaviours, such as freezing, fight-or-flight responses, and autonomic regulation Lesion effects Lesions of the vlPAG impair fear extinction: animals fail to reduce fear responses even after repeated extinction trials Lesions of the dPAG can reduce the expression of fear responses, such as freezing, but do not necessarily impair learning of fear Pathways DIRECT PATHWAY Thalamus > Amygdala allow for fast learning, although the pathway carries less information INDIRECT PATHWAY Thalamus > PFC > Amygdala lead to slower learning, but is more refined Discrete neutral stimuli in fear conditioning Aim: Determine whether sensory information about the CS passes through a direct thalamo--amygdalar pathway, or through a thalamocortical pathway Method: disconnection lesions: Lesion auditory thalamus in one hemisphere = remove one hemisphere of thalamus Animals can still learn Lesion medial portion of MG Lesion A1 Lesion in MGm & MGv Brain Areas: Various parts of auditory thalamus: MG - medial geniculate nucleus PIN – posterior intralaminar nucleus SG – suprageniculate nucleus MGm, PIN, SG project directly to the amygdala MGv projects to auditory cortex Results: all groups except for full lesion (MGm & AUx) show high arterial pressure Minimal sympathetic nervous system activation for full lesion **Both pathways are sufficient Only lesioning of both pathways leads to a deficit in fear learning Each pathway is sufficient for learning Neither pathway is necessary Are tones and contexts processed by the same brain areas? Non-legioned: * explicit CS = freezing on the 2nd day (but not to context) * Explicit CS + context = freezing on the 3rd day Amygdala legion: * no learning to CS Cortex lesion: Hippocampus: * learn freezing to CS * Cannot learn about context When CS-US associations are formed, CR are orchestrated by the central nucleus of the amygdala Sensory information converges on the lateral and basal nuclei of the amygdala where association formation takes place Once associations are formed, conditioned responses are orchestrated via the central nucleus and its output to the midbrain (PAG) opioid-mediated modulation of learning Fear extinction Fear extinction: Extinction leads to a reduction in the conditioned response Distinct populations of BA neurons encode fear conditioning and extinction Day 1: Habituation, no fear conditioning neither fear no extinction neurons are strongly activated by the tone Day 2: First day of extinction – (they can’t record during fear conditioning (FC) fear neurons show response to tone extinction neurons don’t show response Day 3: Full extinction Fear neurons don’t show responses Extinction neurons do show responses Basal amygdala: fear learning and extinction measures in Connections to infralimbic cortex: * pre-limbic: fear acquisition * Infra-limbic: fear extinction Connections to central nucleus Spontaneous recovery after extinction - long interval: rebound in freezing to CS - Short interval: small rebound in freezing Evidence that extinction is new learning, not forgetting EVIDENCE FOR NEW LEARNING Spontaneous recovery: the memory re-emerges later Renewal: after extinction occurs, when the animal switches to a new context freezing re-emerges Reinstatement: simply providing a footshock (not following the CS) will immediately lead to freezing following the CS Neural circuits of Fear Extinction The CS-noUS association results in the development of new connections that suppress the expression of the original CS- US association by the central nucleus of the amygdala Black lines = safety cues Red lines = danger cues The context and CS regulate extinction neurons in the basal nucleus and the infralimbic cortex, which in turn switch ON ITCb cells thus inhibiting the central nucleus Neural circuits of Fear Extinction: Hippocampus Hippocampus is important for renewal of fear - same context of extinction learning = low response - Different context of extinction learning = Two hypothesis for spontaneous recovery 1. Perceived features of the context change as time passes 2. The extinction learning is forgotten 1. Acquisition memory dominates over extinction memory Fear Extinction: the NMDA receptor There are two binding sites on the NMDA receptor 1) glutamate 2) glycine interfering with NMDA receptor in the infra limbic cortex functioning at the glutamate binding site (with AP5 or ifenprodil) blocks extinction learning - increased level of freezing because freezing is blocked