Endogenous opioid modulation of fear learning circuits in the amygdala

Abstract

The amygdala plays a central role in emotional learning, particularly fear

conditioning, where neutral stimuli are associated with threatening events.

Endogenous opioids have been implicated as fear-inhibiting neuromodulators,

but their specific mechanisms of action within amygdala circuits remain poorly

characterised. This thesis investigates the role of endogenous opioid

signalling in fear related circuits of the amygdala, examining how sensory

inputs can trigger endogenous opioid release and how these opioids

potentially regulate fear learning through multiple mechanisms.

Using a combination of electrophysiology, fibre photometry, and fluorescent

biosensors, I demonstrated that auditory thalamic inputs form strong,

functional glutamatergic synapses onto neurons in the amygdalo-striatal

transition zone, triggering enkephalin release. This enkephalin acts at multiple

sites within the fear circuit, including inhibiting glutamate transmission,

suppressing dopamine release and modulating synaptic plasticity under

specific conditions. Furthermore, in vivo recordings during fear conditioning

revealed dynamic endogenous opioid release patterns, initially occurring in

response to shock before gradually shifting to the conditioned stimulus as

learning progressed.

These findings establish a circuit mechanism by which sensory inputs trigger

opioid release that regulates fear learning through multiple pathways. This

work provides a deeper understanding of how neuromodulator systems can

potentially fine-tune emotional learning, which may inform future approaches

for treating disorders characterised by dysregulated fear responses