Lecture: The Neuroscience of Fear

Introduction

• Presenter: Dr. Kerry Ressler
• Affiliation: McLean Hospital, Harvard Medical School
• Field: Translational Research in Psychiatry
• Expertise: Molecular Neurobiology, Animal Models, Human Genetics, Neuroscience of Fear, Emotion, and Anxiety

Presentation Overview

1. Basic Fear Learning using Animal Models
2. Sensory Systems and Fear Changes
3. Intergenerational Transmission of Fear and Trauma
4. Human Fear Disorders and PTSD
5. Translational Neuroscience Approaches

Basic Fear Learning and Animal Models

• Fear Conditioning: Pavlovian conditioning (tone + foot shock)
• Key Components: Conditioned Stimulus (CS) - neutral cue, Unconditioned Stimulus (US) - shock, Conditioned Response (CR) - fear behavior
• Neural Circuits: Amygdala, Medial Prefrontal Cortex, Hippocampus
• Fear Responses: Fear-potentiated startle, freezing

Amygdala's Role

• Secondary Knowledge: Visual Thalamus to Amygdala (low road); Visual Cortex to Amygdala (high road)
• Critical Pathways: Rapid sensory input, top-down regulation
• Behavioral Responses: Reflexive fear responses, fight or flight

Intergenerational Transmission of Fear and Trauma

• Examples: Grady Trauma Project, Intergenerational cycles of trauma, PTSD, and substance abuse
• Mechanisms: Epigenetic signatures, increased sensory sensitivity
• Studies: Olfactory system - changes in olfactory receptors and neurons post-olfactory fear conditioning

Human Disorders: PTSD

• Definition: Results from exposure to trauma; characterized by re-experiencing, avoidance, mood alterations, and hyper-arousal
• Diagnosis: Requires exposure to life-threatening events or serious injury
• Treatments:
  • Medications: SSRIs (sertraline, paroxetine), prazosin (for nightmares)
  • Therapies: Prolonged exposure therapy, cognitive behavioral therapy (CBT), cognitive processing therapy

How Fear Conditioning Affects Brain Regions

• Brain Imaging: fMRI studies showing amygdala activation in PTSD patients when viewing fearful stimuli
• Key Findings: Increased amygdala activity & decreased top-down regulation
• Biotypes: Different neurobiological subtypes reacting to trauma differently

Extinction of Fear

• Extinction Therapy: Involves repeated exposure without the US leading to decreased CR (fear response)
• Mechanisms: NMDA-dependent plasticity, involvement of hippocampus and prefrontal cortex
• DSC (D-Cycloserine): Enhances extinction by acting on NMDA receptors, varies in effectiveness

Translational Approaches

• Targeted Treatments:
  • Drugs: D-Cycloserine, NMDA agonists, novel targets like neurotensin receptor (NTSR2)
  • Behavioral: Combining cognitive enhancers with precise behavioral interventions
• Genetics and Biomarkers:
  • Genetics: Large-scale GWAS identifying PTSD-associated genes
  • Biomarkers: Physiological and neuroimaging markers to predict PTSD development

Future Directions

• Precision Medicine: Targeting specific molecular pathways involved in fear/extinction
• Cell-Type Specific Approaches: Identifying and targeting fear-on and fear-off cells within the amygdala
• Further Research: Understanding long-term memory consolidation, reconsolidation, and extinction processes

Conclusion

• Vision: Combining molecular, genetic, and circuit-based findings to develop novel PTSD treatments and preventive measures
• Acknowledgements: Collaborative efforts across various institutions and research teams

Q&A Highlights

• Complex PTSD: Requires more of an integrated approach, possibly involving DBT and CBT
• Relation to COVID-19 Anxiety: Similar treatment approaches may be applicable
• Intergenerational Effects: Ongoing work to understand molecular mechanisms, including the role of piRNAs and epigenetic pathways