Bottom-up modulation of hippocampal function via aberrant amygdalar activity: spotlight on sex-dependent hemispheric lateralization

• Applicant: Gürsel Caliskan, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Biological Psychiatry ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569053334

The improper utilization of contextual information characterizes post-traumatic stress disorder (PTSD). Both human and rodent studies have shown that the hippocampus and amygdala play pivotal roles in forming enduring emotional memories, and disruptions in the circuits within these regions are associated with the pathophysiology of PTSD. While the hippocampus is crucial for encoding and recalling contextual information, the activity level of the amygdala during and after memory formation can determine the emotional intensity of a memory. Elevated amygdalar activity has been linked to heightened emotional processing in individuals with PTSD. Studies in humans have provided evidence for two significant findings: 1) there is a strong sex-dependent vulnerability to PTSD, with women being more likely to develop chronic PTSD, and 2) sex-dependent hemispheric lateralization of amygdalar activity in various human psychiatric disorders, including PTSD. However, the neurobiological basis for these sex-dependent hemispheric asymmetries in disease pathophysiology remains poorly understood. In our proposed project, we will consider both sex and lateralization as central factors to investigate the following overarching hypothesis. We will employ cutting-edge techniques such as chemogenetic and optogenetic circuit interventions, engram labelling, engram-specific single-cell electrophysiology, mesoscopic oscillatory recordings, and fear context discrimination paradigms: "Hyperactivity in the amygdala, leading to an increased emotional burden, triggers abnormal changes in hippocampal memory circuits, ultimately resulting in the formation of aberrant contextual memories." Our analysis will focus on three main objectives: 1) We will use excitatory DREADDs to manipulate the activity of the basolateral amygdala (BLA) unilaterally or bilaterally over the long term. This will help us understand its differential impact on fear context discrimination, which is impaired in PTSD. 2) We will employ engram labelling techniques (RAM: Robust Activity Marking) and assess cellular and circuit-level alterations in the hippocampal dentate gyrus (DG) and CA3 regions using engram-specific chemo- and/or opto-physiology. 3) We will measure in vivo oscillatory activity in the hippocampus and BLA to examine communication within the hippocampus (DG-CA3) and between the hippocampus and amygdala during different phases of fear memory, with lateralized BLA activation. Our functional analysis aims to identify sex differences in lateralization patterns in hippocampal engrams, their plasticity, and oscillatory communication. The outcomes of this project will lay the foundation for future studies that will utilize optogenetic or chemogenetic interventions to target hippocampal engrams in rodent stress models.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Privatdozentin Gabrielle Girardeau, Ph.D.
• Co-Investigator: Sanja Mikulovic, Ph.D.