Comparison of afferent inputs to the retrosplenial cortex in healthy and pathological conditions using a mouse model of amyloidopathy

Abstract

The retrosplenial cortex (RSC) is a cortical area found in rodents, primates and humans, and is thought to be involved in various cognitive functions including spatial navigation and episodic memory. One of the defining characteristics of the RSC is the high interconnectivity it shares with a range of distal brain regions. This connectivity is likely critical to its function, as reciprocal connections have been anatomically identified with other nodes in the extended memory circuit such as the thalamus and the hippocampal formation. The RSC has also been proposed as a site of covert pathology during Alzheimer’s disease (AD). It exhibits many pathological changes during the early stages of the disease, and is highly susceptible to deafferentation following damage to distally-connected areas. The synaptic strength and specificity of inputs into the RSC are still relatively unknown. Here, the anatomical and functional connectivity of afferent projections into the RSC were examined using a combination of viral anatomical tracing and patch clamp electrophysiology in ex vivo slices. Optogenetic interrogation of projections from the anterior cingulate cortex, the dorsal subiculum and the anterior thalamic nuclei in C57BL/6J mice revealed synaptic connectivity differences between inputs as well as between the granular and dysgranular subdivisions of the RSC. The results also showed that anatomical connectivity does not necessarily predict functional connectivity in RSC. I then investigated whether the anterior thalamic nuclei to RSC projection is disrupted in an amyloidogenic mouse model of AD: the PDGF-APPSw,Ind (J20) transgenic line. While J20 mice exhibited RSC amyloid plaque deposition, there was no change in basal neuronal activity or disruption to synaptic responses. These findings were highly unexpected and speak to the complexity of the RSC and its circuitry. Overall, the work presented in this thesis improves our understanding of the RSC and its circuitry in both healthy and AD conditions. This work increases our knowledge of a brain region that is relatively under-represented in research, but plays a critical role in our cognition by integrating information from all over the brain to help form the complex representations necessary for navigating the world.