Catecholaminergic control of hippocampal-prefrontal networks during contextual fear memory encoding, maturation and extinction

• Applicant: Privatdozent Dr. Georg Köhr
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565977806

Fear and trauma can generate extremely long-lasting memories that are difficult to extinguish, which explains the susceptibility to relapse. This is true in both humans and animals. However, the vast majority of animal studies examine the encoding of recent fear memory (1 day old) and its extinction already one day later, because remote fear memory (4 weeks old) is nearly impossible to extinguish. This resistance is likely due to a distinct storage mechanism compared with recent fear memory. The proposed project aims to identify neural circuits and molecularly defined pathways in mice involved in contextual fear memory maturation as well as in extinction. To causally target neuromodulatory mechanisms underlying aversive and extinction learning in mice, fiber photometry will monitor the activity of two critical neuromodulatory hubs, i.e., locus coeruleus and ventral tegmental area. Simultaneously, the release of the neurotransmitters norepinephrine and dopamine will be monitored by selective sensors in dorsal subregions of the hippocampal-prefrontal circuitry (CA1-prelimbic cortex), known to have distinct and complementary roles in fear memories. Emerging spatiotemporal dynamics of transmitter release will next be corroborated by optogenetics during contextual fear conditioning. Activation or inhibition of transmitter release, either globally or locally in their target areas, will reveal how encoding and retrieval of remote fear memory differ from recent memory. In addition, single-unit and local field potential recordings aim to identify distinct physiological signatures of recent and remote fear memory, whose modifications will be examined during extinction. The context will either be extinguished during reconsolidation-updating, the period of memory malleability instigated by prior memory retrieval, or outside the reconsolidation window, the period of increased memory stability one day after memory retrieval. The extinction of stable, likely more generalized fear is of particular translational relevance concerning remote fear memory. We will optimize our extinction protocol by optogenetics to reach robust and long-lasting extinction. Parallel electrophysiological recordings will address whether extinction generates a new fear extinction memory or reorganizes the original fear memory storage network. Successful prevention of fear relapse will be tested 30 days later by spontaneous fear recovery in the conditioned context. Together, this project examines the potential of neuromodulation to enhance the selectivity of neural interventions and thus therapeutic efficacy for anxiety disorders. In the long-term, the project may help to refine treatment strategies for anxiety disorders in humans.

• DFG Programme: Research Grants