Imaging the evolution acute fear: Longitudinal whole brain imaging in living mice of neural activity with MEMRI

Abstract

Life-threatening events cause extreme fear, which evolves in vulnerable people into a debilitating mental illness--post-traumatic stress disorder (PTSD), affecting 6.8% of all Americans. Those who progress to PTSD display both anxiety-related (hyper-arousal) and depressive (avoidance) symptoms. PTSD is accompanied by changes in brain functional anatomy. Some experience relief from selective serotonin reuptake inhibitors (SSRI), some from a1 adrenergic receptor inhibitors, and some respond to combined inhibition of both noradrenergic and serotonergic transporters (NET and SERT), SNRI. Cross-talk between serotonergic and noradrenergic systems (SS and NS) is well known. Both are disturbed in PTSD. Early life adversity is a known risk factor for PTSD. There are no predictive or diagnostic tests, and no reliably effective prevention or intervention for PTSD. Using manganese-enhanced MRI (MEMRI) tract-tracing, we reported that SERT-KO mice have abnormal circuitry in the prelimbic system. To determine whether early life adversity affects this circuit and the behavioral and neural response by fear, SERT-KO and WT mice raised either normally or with maternal deprivation, were exposed to predator stress (PS) in young adulthood, a known naturalistic provocateur of persistent fear in rodents. We use the light-dark box to quantify behavior and Mn²⁺-enhanced MRI (MEMRI) to witness behavior and brain activity. Mn²⁺ increases the relaxation rate of protons in water in T₁-weighted pulse sequences, and thus produces a hyper-intense signal in T₁-weighted MRI. Mn²⁺ is a metabolic contrast agent that reports on neural activity by entering active neurons through voltage-gated Ca²⁺ channels, and is transported along axons tracing multi-synaptic circuitry when injected locally.