Modulation of experience-dependent plasticity in thalamic circuits

Associative learning links sensory, predictive stimuli from the environment with their outcomes and depends on reliable integration of sensory inputs to shape behavioral adaptations and ensure an animal's survival. Several cortical and limbic brain areas have been identified as sites for associative learning. However, the role of thalamic structures that process, relay, and store associative learning-related sensory information remains largely unknown. The medial geniculate body (MGB), or auditory thalamus, is a site of convergence for auditory and somatosensory information. It receives feedforward sensory as well as neuromodulatory input, e.g. acetylcholine - a key component in promoting learning. One prominent cholinergic input to MGB originates in the pedunculopontine tegmental nucleus (PPT). However, the role of brainstem cholinergic inputs to MGB during associative learning remains unknown. In this thesis, I performed tracing experiments to quantify cholinergic projections from PPT to MGB subdivisions and fiber photometry experiments to record physiological calcium activity from cholinergic axon terminals as well as ACh binding in MGB during a fear conditioning paradigm in freely moving mice. In addition, I performed optogenetic experiments to assess the behavioral effect of manipulation of PPT-ACh inputs on learning. Finally, I used deep brain calcium imaging combined with optogenetic manipulation of PPT-ACh inputs in MGB, using a miniaturized microscope approach in freely moving mice, to study modulation of PPT cholinergic inputs on MGB sensory coding and experience-dependent plasticity. I find that PPT sends cholinergic projections to MGB, and particularly to MGBm, which modulate sensory responses of MGB neurons during fear conditioning. In addition, I show that optogenetic manipulation of cholinergic PPT inputs in MGB during fear acquisition affects learning. My project identifies a role for brainstem cholinergic inputs in multi-modal sensory integration during fear conditioning in the auditory thalamus. This will broaden our view on how neuromodulators contribute to associative learning in thalamic areas.