Investigation of a thalamic-hippocampal pathway in contextual fear suppression and extinction

Project Summary Post-traumatic stress disorder (PTSD) is an anxiety disorder that can follow from witnessing or directly experiencing an event involving injury, threat to life, or death. People with PTSD re-experience the traumatic event through flashbacks or nightmares and may feel anxious, numb, or hyperaroused. PTSD can last for years and severely impair day-to-day functioning. The condition exacts an enormous toll on trauma survivors, their families, and society. Moreover, we may be underestimating the individual and societal costs of PTSD, given growing appreciation that PTSD contributes to other chronic and costly physical health problems such as cardiovascular disease. Although treatments for PTSD exist, it remains a difficult and stubborn disorder to treat with many patients resistant to current methods. This issue is in part due to a lack of understanding of the neuronal mechanisms involved in the retrieval of traumatic memories and how they are suppressed or extinguished in normal subjects. It has recently come to light that a subregion of the thalamus called the Nucleus Reuniens (NR) plays a key role in the suppression of fear memories and their extinction – a process in which animals learn that a previously fearful situation is now safe and thus is no longer feared. Understanding how the NR suppresses and extinguishes fear memories is therefore essential for developing effective treatments for PTSD, but this is currently unknown. The hippocampus is a central brain region for the formation, consolidation, and retrieval of contextual fear memories, those that become maladaptive in PTSD patients. NR must therefore interact with the hippocampus to suppress contextual fear memories and support extinction processes. Anatomically, there is a direct connection between NR and the CA1 region of the hippocampus, but physiologically is remains unknown how this pathway interacts with contextual fear memory processing in CA1. To address this, we have developed a new paradigm whereby contextual fear memories can be induced, later retrieved, and eventually extinguished in head-fixed mice exploring virtual reality contexts. This allows us to use 2-photon microscopy (as mice are head fixed) to image the activity of NR inputs directly in CA1 during fear memory retrieval and throughout extinction. We can also manipulate the activity of these inputs using optogenetics and measure the effects on hippocampal population dynamics and single cell activity. It also allows us to image the dendritic activity of CA1 cells during NR input manipulations. Together, this strategy will uncover how NR interacts with hippocampus to suppress fear memory retrieval and promote extinction at the synaptic, single cell, population, and circuit level. These finding will provide new insights that can be used to help develop novel strategies for the treatment of PTSD.