Fear Learning and Extinction

Fear Learning

• Assessment of Fear Conditioning:
  • Habituation: Absence of stimulation
  • Conditioning: Conditioned Stimulus (CS) paired with Unconditioned Stimulus (US), leading to Unconditioned Response (UR)
  • Testing: CS presented, eliciting Conditioned Response (CR)
• Conditioned Freezing: Immobility, crouched posture with arched spine.
  • Footshock: Few trials needed for CS-US association
  • Rescorla-Wagner Model: Corresponds to the beta value (salience)
• Fear as a Defensive System:
  • Orchestrates adaptive behaviours for protection.
  • Species-specific Defence Responses: Freezing, flight, fight, analgesia, autonomic arousal
  • Predatory Imminence Gradient: Determines which behaviour is expressed based on perceived threat level.

Neurobiology of Fear Learning

• Brain Areas:
  • Thalamus: Sensory relay center, transmitting sensory information (auditory, visual, somatosensory) to the amygdala.
    • Medial Geniculate Nucleus (MGN): Sends auditory information.
    • Direct and Indirect Pathways to the Amygdala:
      • Direct: Thalamus directly to amygdala.
      • Indirect: Thalamus to prefrontal cortex to amygdala.
• Lesion Effects:
  • Fear Learning: Lesions in sensory thalamic nuclei impair fear conditioning.
    • Disruption of sensory inputs essential for CS-US association.
  • Fear Extinction: Disrupting sensory flow to amygdala hampers learning that the stimulus is no longer predictive of danger.

Perirhinal Cortex

• Role: Object recognition, visual information processing, integrates complex sensory information.
• Interaction: With amygdala and hippocampus to modulate fear responses.
• Outputs:
  • Projects to basolateral amygdala (BLA), providing detailed sensory input.
    • Aids in associating complex stimuli (CS) with aversive outcomes (US).
  • Projects to hippocampus, processing information about the context of fear learning and extinction.
    • Distinguishes between threatening and non-threatening contexts.
  • Projects to amygdala, refining fear response extinction when the stimulus no longer predicts danger.
• Lesion Effects:
  • Fear Learning: Impairs forming detailed associations between specific objects or stimuli and aversive events.
  • Fear Extinction: Interferes with extinction learning, failing to update fear responses appropriately when the CS no longer predicts a threat.

Amygdala

• Central to fear learning: Processes and stores emotional memories, particularly fear-related stimuli.
• Lateral Amygdala (LA): Receives sensory inputs related to CS and US from the thalamus and sensory cortex.
  • Encodes the CS-US association.
• Basolateral Amygdala (BLA): Integrates inputs from LA and other brain regions (hippocampus and prefrontal cortex).
  • Modulates emotional responses.
• Central Amygdala (CeA): Sends outputs to the hypothalamus and brainstem to trigger fear responses (e.g., increased heart rate, freezing).
  • Projects to regions responsible for autonomic and behavioral fear responses:
    • Periaqueductal Gray (PAG): Freezing.
    • Hypothalamus: Hormonal stress responses.
• Lesion Effects:
  • LA or BLA Lesions: Impair acquisition and expression of fear learning.
  • CeA Lesions: Disrupt expression of fear responses (e.g., freezing), but not necessarily the acquisition of fear memories.

Prefrontal Cortex (PFC)

• Inputs: Amygdala, hippocampus, and thalamus.
  • Integrates information about emotional states, context, and sensory inputs.
• Outputs:
  • Projects to the amygdala (BLA and intercalated cells (ITC)), modulating fear responses.
  • Connects to the hypothalamus and PAG, controlling physiological and behavioral fear responses.
• Infralimbic Cortex (IL/IF) and Prelimbic Cortex (PL): Key role in fear regulation and fear extinction.
  • IL: Crucial for fear extinction.
    • Inhibits amygdala activity and suppresses conditioned fear responses.
  • PL: Facilitates fear expression by maintaining amygdala activity during fear conditioning.
• Lesion Effects:
  • IL/IF Lesions: Prevent fear extinction.
  • PL Lesions: Impair conditioned fear expression.

Intercalated Cells (ITC)

• Gatekeepers: Control information flow within the amygdala (CeA).
• GABAergic neurons: Inhibit other neurons, reducing fear expression.
• Fear Extinction: IL/IF activity increases, stimulating ITCs, inhibiting CeA, and suppressing the fear response.
• Fear Expression: PL and BLA activity reduce ITCs, disinhibiting CeA and expressing fear.

Hippocampus

• Contextual Fear Learning: Helps modulate fear extinction by providing information about the context of fear memory acquisition.
  • Distinguishes between contexts where fear is appropriate or not.
• Inputs: Receives sensory, contextual information from cortical areas and amygdala.
• Outputs: Projects back to amygdala (BLA) and PFC, regulating appropriate fear responses in context.
• Lesion Effects:
  • Impair contextual fear conditioning: Difficulty associating fear responses with specific contexts.
  • Disrupt contextual fear extinction: Fail to differentiate between fear-inducing and non-fear-inducing environments.

Periaqueductal Gray (PAG)

• Involvement: Mediates behavioral and physiological fear responses (e.g., freezing, autonomic changes).
  • Ventrolateral PAG (vlPAG): Fear extinction.
  • Dorsal PAG (dPAG): Fear expression.
• Inputs: Amygdala (CeA), hypothalamus, and PFC.
• Outputs: Brainstem and spinal cord, controlling defensive behaviors (freezing, fight-or-flight) and autonomic regulation.
• Lesion Effects:
  • vlPAG Lesions: Impair fear extinction.
  • dPAG Lesions: Can reduce fear response expression (freezing) but may not impair learning of fear.

Pathways

• Direct Pathway: Thalamus to Amygdala.
  • Fast learning but carries less information.
• Indirect Pathway: Thalamus to PFC to Amygdala.
  • Slower learning but more refined.

Discrete Neutral Stimuli in Fear Conditioning

• Aim: Determine if sensory information about the CS travels via a direct thalamic-amygdalar pathway or a thalamocortical pathway.
• Method: Disconnection lesions.
  • Lesion auditory thalamus in one hemisphere.
  • Lesion medial portion of MG.
  • Lesion A1.
  • Lesion in MGm and MGv.
• Brain Areas:
  • MG - medial geniculate nucleus.
  • PIN – posterior intralaminar nucleus.
  • SG – suprageniculate nucleus.
  • MGm, PIN, SG project directly to 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 for learning.
  • Neither pathway is necessary.

Tone and Context Processing

• Non-legioned:
  • Explicit CS: Freezing on the second day, but not to context.
  • Explicit CS + Context: Freezing on the third day.
• Amygdala legion: No learning to CS.
• Cortex lesion:
  • Hippocampus:
    • Learn freezing to CS.
    • Cannot learn about context.

Amygdala and Fear Responses

• When CS-US associations are formed, conditioned responses 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

• Extinction: Reduction in Conditioned Response (CR) over time.
• Distinct Neuron Populations: BA neurons encode fear conditioning and extinction.
  • Day 1 (Habituation): Neither fear nor extinction neurons are strongly activated by the tone.
  • Day 2 (First day of extinction): Fear neurons respond to the tone; extinction neurons do not.
  • Day 3 (Full extinction): Fear neurons do not respond; extinction neurons do.
• Basal Amygdala: Fear learning and extinction measures.
• Connections to Infralimbic Cortex:
  • Prelimbic: Fear acquisition.
  • Infralimbic: Fear extinction.
• Connections to Central Nucleus:

Spontaneous Recovery

• Long interval: Rebound in freezing to CS.
• Short interval: Small rebound in freezing.
• Evidence for new learning: Extinction is not forgetting but new learning.
  • Spontaneous recovery: Memory re-emerges later.
  • Renewal: Freezing re-emerges when the animal switches to a new context, even after extinction.
  • Reinstatement: Providing a footshock (not following the CS), immediately leads to freezing after the CS.

Neural Circuits of Fear Extinction

• CS-noUS Association: New connections develop that suppress expression of the original CS-US association by the central nucleus of the amygdala.
• Context and CS: Regulate extinction neurons in the basal nucleus and infralimbic cortex, switching ON ITCb cells and inhibiting the central nucleus.

Hippocampus and Fear Extinction

• Important for Renewal:
  • Same Context: Low response.
  • Different Context: High response.

Two Spontaneous Recovery Hypotheses

• First Hypothesis:

• Second Hypothesis: