The coding of stimulus context in the sensory thalamus

• Applicant: Dr. Ricardo Paricio Montesinos
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528405672

Many stimuli in our ever-changing multisensory environment are neither aversive or appealing in nature, but may be interpreted as such depending on the context. For example, in a football match, we may get excited to hear the whistle that concedes our team a penalty kick, but we may be afraid of hearing the same whistle when it signals a penalty for our rival. Similarly, a soft noise may not trigger a large behavior change in a mouse that is hiding in safety, but could elicit an escape response if the mouse is exploring an open area. Therefore, animals can interpret and react to stimuli depending on the context at which they appear, but the neural mechanisms underlying stimulus contextualization are unknown. For the correct contextualization of stimuli, both perception and memory functions are required. Therefore, brain areas like cortex, thalamus, amygdala or hippocampus could play a role. Because existing evidence shows that sensory thalamus connects with both cortex and amygdala, modifies its sensory responses upon learning, is required for fear conditioning and encodes high order cognitive features in mice, I hypothesize that sensory thalamus is a major center for stimulus contextualization. In this project, therefore, I aim to investigate the mechanisms that underlie stimulus contextualization in the sensory thalamus. To do this, I have divided the project in three parts. In Work Package 1, I plan to develop a behavioral task where mice perform contextualization of stimuli, and learn to report an auditory cue, when present in a specific multisensory context. In Work Package 2, I will investigate the calcium responses of sensory thalamus neurons while mice perform the contextualization behavior. Finally, in Work Package 3, I will inhibit two major projections of sensory thalamus – those targeting cortex and amygdala –, to link different populations of thalamic neurons to specific behavioral stages of stimulus contextualization. To complement this, and to relate these findings to a prevalent human disease where stimulus contextualization and one of these output regions (amygdala) is impaired, I will test a mouse model of Alzheimer’s disease (APP/PS1 model). In this mouse model (like in the human disease) the temporal lobe, including amygdala, is particularly impaired. Therefore, I will investigate how mice contextualize stimuli under this disease, as well as the underlying neural activity in auditory thalamus, which could help identify impaired mechanisms that underlie cognitive symptoms in Alzheimer’s disease. Together, with the proposed experiments I aim to understand the mechanisms of contextualization of stimuli in the auditory thalamus. These will help explain how animals can identify relevant situations and respond with behaviors that are appropriate in each context.

• DFG Programme: WBP Position