Hypothesis

We propose that the age-related decline in amygdala-ventral prefrontal cortex (vmPFC) structural connectivity reduces glutamatergic input to central amygdala (CeA) CRF neurons, leading to sustained CREB downregulation and enhanced fear extinction, thereby decreasing trait anxiety. In pathological aging, focal amygdalar tau accumulation disrupts this plasticity, restoring hyperreactivity through impaired extinction.

Mechanistic Reasoning

The traditional model holds that stronger amygdala-vmPFC connectivity enables top-down inhibition of threat responses, reducing anxiety. Yet, aging presents a paradox: decreased structural connectivity correlates with lower trait anxiety PMC4087066. This suggests a shift in control from prefrontal regulation to intrinsic amygdala circuits, particularly CRF neurons in the CeA, which are critical for fear extinction ouci.dntb.gov.ua.

• CREB as a molecular switch: CREB downregulation in CeA CRF neurons promotes extinction, while overexpression blocks it ouci.dntb.gov.ua. Age-related disconnection likely reduces glutamatergic drive from vmPFC, lowering NMDA receptor (Grin1) activation in CRF neurons ouci.dntb.gov.ua, leading to sustained CREB suppression and facilitated extinction.
• Stress modulation: Under stress, locus coeruleus-norepinephrine activation biases amygdala-prefrontal circuits toward fear consolidation Frontiers in Systems Neuroscience 2022. In aging, reduced connectivity might buffer this bias, or compensatory changes in noradrenergic systems could alter CRF neuron sensitivity.
• Pathological aging: Focal amygdalar tau in preclinical Alzheimer's disease associates with anxiety and altered connectivity doi:10.1101/2024.06.03.597160. Tau accumulation may disrupt synaptic function, impairing CREB dynamics and extinction despite disconnection, leading to hyperreactivity.
• Therapeutic insights: Successful pharmacotherapy in elderly GAD increases prefrontal connectivity during reappraisal Argo Pitt 2021. Our hypothesis suggests that in healthy aging, therapy might optimize a new equilibrium by fine-tuning CRF neuron plasticity rather than restoring youthful connectivity.

Testable Predictions

1. Aged animal models: Mice with age-related reductions in vmPFC-CeA connectivity will show lower CREB phosphorylation in CeA CRF neurons and enhanced fear extinction compared to young controls, measurable via immunohistochemistry and behavioral assays.
2. Glutamatergic intervention: In young mice, chemogenetic inhibition of vmPFC-to-CeA projections or Grin1 deletion in CRF neurons will mimic age-related anxiety reduction and CREB downregulation.
3. Tau pathology interaction: In tauopathy models (e.g., P301S mice), despite structural disconnection, fear extinction will be impaired, and CREB activity in CRF neurons will be elevated, correlating with anxiety-like behavior.
4. Pharmacological testing: CREB inhibitors (e.g., 666-15) microinfused into CeA will reduce anxiety in aged mice with low connectivity but not in young mice or tauopathy models.
5. Human biomarkers: In older adults, diffusion MRI for amygdala-vmPFC connectivity combined with CSF p-tau and anxiety assessments will reveal that low tau individuals show the connectivity-anxiety paradox, while high tau individuals exhibit anxiety despite disconnection.

Implications

This hypothesis reconciles the anxiety-connectivity paradox by proposing a mechanistic shift from top-down regulation to CRF neuron plasticity in aging. It highlights CREB as a key target for age-related anxiety disorders and underscores the divergence between healthy and pathological aging. Testing these predictions could inform precision therapeutics for anxiety in late life.