Anne Auguste defense thesis - Remote episodic memory in rats: Characteristics, brain networks and role of olfactory and hippocampal adult neurogenesis

Episodic memory reflects the ability to recollect information of a personal event about “what” happened, “where” and “when or in which context”. This memory, complex in terms of multisensory information, makes possible to singularize closed episodes, emerges without training and is long-lasting in time. These essential characteristics have never been used simultaneously in animal models, limiting our understanding of mechanisms that underlie the formation and recall of these particular remote memories. Among mechanisms of plasticity related to learning and memory, adult neurogenesis in the olfactory bulb (OB) and dentate gyrus (DG) of the hippocampus has a major role in different consolidation processes. However, its role in these different brain regions has never been compared for incidental, complex and remote memory, such as episodic memory.
First, we have characterized remote episodic memory in rats using a paradigm recently developed by our team. Rats are exposed to two life episodes during which they form an episodic memory association of olfactory, spatial and contextual information. Despite a high sensibility to interference during recall, this memory is robust since most rats remember episodes over a long period of time, but as in humans, content of the memory varies according to individual. As different memory profiles are stable, reproducible and related to significant behavioural response, we sought their origin. A computational model correlating data of episode encoding with data of recall revealed the critical importance from the first episode of the individual experience of negative value related to odour for a complete episodic memory recollection.
Second, by using cellular imaging of c-Fos and Zif268 in 23 brain regions of rats with different memory profiles, we have determined brain networks which are associated with recall of remote episodic memory according to its content. Incomplete episodic recall of rats with Where profile recruits a restricted brain network including lateral orbitofrontal and anterior retrosplenial cortex, the entire dorsal hippocampus and habenula. In contrast, recall of a complete WWW episodic memory involves a wide brain network encompassing areas of olfactory information processing, a large cortical motif including the orbitofrontal, prefrontal and retrosplenial, a large part of the dorsal hippocampus, the lateral entorhinal cortex and the habenula. The major difference between the complete versus incomplete episodic recollection network is based on the activation of regions involved in emotional information processing (medial orbitofrontal cortex, ventral CA1 and basolateral amygdala), whose recruitment is directly correlated with the accuracy of integrated recollection performance. Using graph theory, we show different brain communication networks depending on whether the memory is complete or not, and depending on brain networks activated during recall reflecting the state of the memory (c-Fos) versus networks inducing synaptic plasticity that would reflect post-recall fate of memory (Zif268).
Thirdly, we determined the role of adult neurogenesis in OB versus DG in the formation and recall of remote episodic memory. By using cellular imaging analysis, we show that newly generated neurons in these different brain areas are differently recruited during the formation versus recall of remote episodic memory. While only dorsal DG newborn neurons are selected during episode encoding for long-term survival, the survival of ventral DG newborn neurons is correlated with the accuracy of memory retention, and new neurons in the OB newborn are specifically recruited during recall of memory.
Finally, by developing a new model of adult neurogenesis suppression with Small Animal Radiation Research Platform (SARRP) system, we show a severe alteration of episodic recollection in all irradiated rats. While adult neurogenesis in the GD is important during recall episodic memory for integrating spatial and olfactory component, adult neurogenesis in the OB has a key role in the meaning of the episodic association, and its alteration compromises the recall of the whole memory.
 

Keywords: remote episodic memory, individual recollection profiles, hippocampo-prefrontal networks, Immediate Early Genes, graph theory, hippocampal adult neurogenesis, olfactory adult neurogenesis, newborn neurons recruitment, SARRP.