UC Irvine

The hippocampal formation (HF) and the retrosplenial cortex (RSC) are complex brain regions involved in learning, memory, and cognitive functions, such as spatial navigation and planning. While both regions exhibit diverse circuit connectivity, the organization of these circuits and their impact on behavior remain unclear. To address these knowledge gaps, I have applied viral-genetic mapping techniques to investigating the connectivity of the HF and RSC and their associated behavioral functions. Recent previous studies of the HF identified noncanonical pathways involving the subicular complex and hippocampal subregions CA1, suggesting the existence of extended noncanonical networks involving additional brain regions. For the study described in Chapter 1, I used multiple retrograde and anterograde viral tracers to quantitatively map the circuit connectivity of excitatory neurons in the dorsal hippocampal CA3 subregions. My results reveal significant noncanonical synaptic inputs from ventral CA1, perirhinal cortex, and the subicular complex to dorsal CA3 that follow a proximodistal topographic gradient with regard to CA3 subregions. I confirmed the functional contributions of these pathways: genetic inactivation of the ventral CA1 to dorsal CA3 projection impairs object-related spatial learning and memory. For the study described in Chapter 2, I employed monosynaptic rabies virus tracing to conduct a quantitative examination of the local and global inputs to CA3 inhibitory neurons. Similar to the results of earlier studies of CA3 excitatory tracing, my findings indicate that CA3 inhibitory neurons also receive noncanonical circuit inputs from ventral CA1 and the subiculum complex. Interestingly, my detailed study reveals that these inputs exhibit a topographical gradient along the proximal/distal axes. My study's results provide a new anatomical connectivity basis for studying the function of CA3 excitatory and inhibitory neurons, as well as a circuit foundation to explore their novel roles in hippocampal circuit dynamics and learning and memory behaviors. For my study described in Chapter 3, I employed retrograde and anterograde viral tracers in conjunction with monosynaptic retrograde rabies virus to investigate differential connectivity and functionality among distinct subpopulations of RSC neurons based on their projection patterns. My results reveal notable differences between the secondary motor cortex (M2)-projecting RSC neurons and anterior dorsal thalamus (AD)-projecting RSC neurons. Specifically, M2-projecting neurons exhibit more extensive afferent input from the dorsal subiculum, lateral dorsal and lateral posterior thalamus, as well as sensory cortices, as compared to AD-projecting neurons. Chemogenetic inhibition of M2-projecting RSC neurons leads to impairments in both object location memory and place-action association, whereas the RSC to AD pathway specifically affects object-location memory. These results demonstrate that RSC connectivity and function are organized as a collection of semi-independent circuits. My functional studies show that these semi-independent RSC circuits integrate information from distinct sets of RSC afferents. Together, by elucidating the circuit organization and functional roles of the HF and RSC, my studies shed light on the complex cortico-hippocampal circuit connectivity organization underlying learning and navigation.