Venue : Centre Broca
Thesis defense in french
Team : Neurogenesis and pathophysiology
Thesis directed by Muriel Koehl
Involvement of adult hippocampal neurogenesis and prenatal stress in vulnerability to develop memory disturbances associated with post-traumatic stress disorder in a mouse model
Post-Traumatic Stress Disorder (PTSD) is a neuropsychiatric condition that can develop after a traumatic experience. While PTSD is classically associated with an excessive intensification of the traumatic memory, patients actually exhibit a unique memory profile where both an emotional hypermnesia for salient sensory cues and a declarative amnesia for the context surrounding the event coexist. This memory profile appears central to the pathology, and recent studies suggest that the contextual amnesia might be at the core of traumatic memory. However, the neurobiological mechanisms underlying this traumatic memory remain largely unexplored.
Neurons generated throughout adulthood in the hippocampus (Adult Hippocampal Neurogenesis, AHN) play a crucial role in contextual memory, pattern separation, and stress resilience. These functions suggest a potential role for these neurons in PTSD-like memory. Therefore, we tested the hypothesis according to which the activity of these adult-born neurons is involved in the formation of traumatic memory. Using optogenetics combined with a mouse model that differentiates the development of normal adaptive fear memory from that of pathological PTSD-like fear memory, we demonstrated that activating or inhibiting these neurons prevented or induced PTSD-like memory development, respectively.
In humans, not all individuals exposed to traumatic events develop PTSD, highlighting the existence of risk factors. Early life experiences, including those encountered in utero, have a lasting impact on brain development and functions. Notably, it has been suggested that early life stress might increase vulnerability to different neuropsychiatric disorders, but again the underlying mechanisms remain poorly known. Interestingly, exposure to prenatal stress reduces AHN in mice. Taken together with our findings on the role of AHN in traumatic memory, that led us to postulate on one hand that prenatal stress could heighten susceptibility to traumatic memory, and on the other hand that disturbances of AHN could be involved in such a vulnerability. We first validated the presence of behavioral changes linked to functions underpinned by AHN in mice subjected to prenatal stress using two pattern separation behavioral tasks. Subsequently, using our PTSD-like memory model, we found that these mice exhibited a mnemonic profile typical of PTSD, and that optogenetic activation of hippocampal adult-born neurons could prevent the development of this profile in favor of a normal and adaptive fear memory.
In conclusion, this thesis work highlights the pivotal role of hippocampal neurons generated in adulthood in PTSD-like memory and suggests that they are a core neurobiological mechanism that could explain the increased vulnerability to PTSD induced by prenatal stress, thereby opening new preventive and therapeutic targets for PTSD.
Adult neurogenesis, PTSD, fear memory, prenatal stress, hippocampus, behavior
Muriel Koehl (thesis director)
Aline Desmedt (invited)
Nora Abrous (invited)