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Aversively-motivated associative learning allows animals to avoid harm and thus ensures survival. Aversive learning can be studied by the fear learning paradigm, in which an innocuous sensory stimulus like a tone (conditioned stimulus, CS), acquires a negative emotional valence after pairing with an aversive outcome, such as a mild footshock (unconditioned stimulus, US). Canonically, the amygdala is thought to be the primary brain region showing plasticity of CS-responses during fear learning. The posterior insular cortex (pInsCx) is a multimodal sensory area, involved in the processing of auditory, somatosensory-nociceptive, and interoceptive information, and has been shown to project to the amygdala. Thus, in my PhD thesis, I have investigated the possible plasticity of auditory representations in the pInsCx, the synaptic mechanisms underlying this plasticity, and its role in the retrieval of fear memories. I first employed in-vivo single-unit recordings in the pInsCx of mice undergoing fear learning, to study the neuronal responses to relevant sensory modalities. A substantial subpopulation of neurons responded to footshocks (~30%) and a smaller subpopulation (~10%) acquired a response to the tone (CS) following fear learning ("tone learners"). Furthermore, a partially overlapping neuronal population showed a response to the movement onset following aversively-mediated freezing of the mice; this response also increased with fear learning. This data suggests associative, aversively-motivated plasticity of both the CS-representation, and of movement-ON responses in the pInsCx following fear learning. I next investigated the origin and possible plasticity of long-range synaptic inputs that carry auditory information to the pInsCx. Using anatomical and functional connectivity assays, I found that both auditory thalamus (MGm) and primary auditory cortex (A1) send excitatory long-range connections to the pInsCx. Optogenetically-evoked EPSCs at the A1 to pInsCx connection showed robust signs of long-term potentiation after fear learning, whereas the ones from the MGm did not. Optogenetic silencing of A1 axons in the pInsCx led to a bi-directional modulation of learned tone responses during fear memory recall, indicating opposing, but plastic influences via direct excitation, and feedforward inhibition of pInsCx principal neurons after fear learning. Anterograde tracing of neurons in the pInsCx that receive input from A1 revealed that these neuorns project to the ventral tail striatum, but not to the lateral amygdala. Finally, I employed optogenetic silencing during CS presentations, to investigate the behavioral role of CS processing in the pInsCx during fear memory recall. The results did not reveal a significant change of the freezing response of mice during fear memory recall, indicating that the CS-evoked activity in the pInsCx might not be necessary for the retrieval of a basic form of auditory-cued fear memory. This study shows that neurons in the pInsCx undergo associative plasticity of auditory representations during fear learning, mediated by long-term potentiation of a novel synaptic pathway from A1 to pInsCx. The role of the plastic changes of auditory representations in the pInsCx for the formation of aversive memories however needs further investigation, either through additional specificity of the targeted neuronal populations, or through more complex behavior paradigms.
Henry Markram, Rodrigo de Campos Perin
Dimitri Nestor Alice Van De Ville, Thomas William Arthur Bolton, Farnaz Delavari, Nada Kojovic