Project Details
Projekt
Corticofugal mechanisms of naturalistic threat memory
Applicant
Professor Johannes Letzkus, Ph.D.
Subject Area
Cognitive, Systems and Behavioural Neurobiology
Experimental and Theoretical Network Neuroscience
Experimental and Theoretical Network Neuroscience
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 520215880
Threat (or fear) memory is critical for survival, and a leading model for dissecting how sensory input is linked to adaptive behavior by learning. Moreover, dysfunctions of threat perception such as excessive fear or chronic anxiety can lead to human anxiety disorders and depression, highly prevalent conditions causing enormous personal and societal cost. In consequence, decades of work have investigated the neuronal mechanisms of auditory threat memory. However, the lion’s share of this research has so far used very simple and reductionist auditory conditioned stimuli (CSs), for which perception is not a challenge. In addition, this work was strongly focused on subcortical pathways and mechanisms. We recently discovered that the auditory cortex plays a critical role for the acquisition and expression of threat memory when complex, naturalistic CSs are used. In contrast, conditioning to simple auditory CSs does not require auditory cortex function. These results provide new entry points on the question how threat memories are formed in the brain, raising the possibility that corticofugal feed-back projections emanating from the auditory cortex may play a key role for threat memory under naturalistic conditions. To test this hypothesis, we aim to use a combination of general and pathway-specific optogenetic inactivation, high-density in vivo extracellular recordings and discriminative auditory threat conditioning in mice. We propose to focus on two key candidate output pathways of the auditory cortex. First, the projection to the lateral amygdala has long been implicated in memory, but how this pathway affects CS encoding in the amygdala, and how threat conditioning changes this influence is not understood, in particular for the complex, perceptually challenging CSs we investigate. Second, the higher-order auditory thalamus also has a key role for threat memory, but was so far largely investigated as a source of feed-forward information transmitted to the lateral amygdala and the auditory cortex. However, the higher-order thalamic nuclei also receive strong feed-back projections from the auditory cortex, which may therefore play a key role for complex CS threat memory. In addition to dissecting the brain-wide mechanisms and coding principles of naturalistic threat memory, we aim to link our work to the overwhelming majority of studies which have used simple pure tone CSs by performing analogous experiments in a side-by-side fashion. We expect that our results will reveal so far little understood mechanisms by which the auditory cortex contributes to the processing of behaviorally relevant stimuli and to memory in subcortical brain regions. In addition to thus expanding our understanding of the brain-wide circuitry underlying associative threat memory, we expect that the use of naturalistic rather than simple CSs will furthermore generate insights with greater relevance for human experiences leading to adaptive or maladaptive outcomes.
DFG Programme
Priority Programmes
