A Novel Pathway Underlying Hippocampal-Neocortical Interactions
Post by Shireen Parimoo
What's the science?
Interactions between the hippocampus and the neocortex are crucial for learning and forming memories. These interactions are thought to occur via bursts of high-frequency oscillatory activity known as sharp-wave ripples in the hippocampus. For example, hippocampal sharp wave ripples modulate neuronal firing in anatomically connected regions like the prefrontal cortex. However, it is not known how ripples facilitate communication with other regions that don’t have direct connections to the hippocampus. One possibility is through coupling with the granular retrosplenial cortex (gRSC), which is structurally connected to the hippocampus via the subiculum and also has dense connections to the rest of the brain. This week in Nature Communications, Nitzan and colleagues investigated the role of the subiculum and gRSC in mediating hippocampal communication through sharp wave ripples.
How did they do it?
The authors obtained both in vivo and in vitro electrophysiological recordings from the CA1 region of the hippocampus, the subiculum region of the hippocampus, and the gRSC. Using these recordings, they characterized the pattern of oscillatory activity in these regions. First, they assessed whether the time course and strength of hippocampal sharp wave ripples were coupled to ripple activity in the deep and superficial layers of the gRSC. Then, they optogenetically stimulated neurons in the dorsal CA1 and the subiculum to directly observe the effect of hippocampal input on activity in the subiculum and gRSC. They also investigated whether hippocampal-gRSC coupling was modulated by cortical state, which includes neuronal synchronization and desynchronization. During cortical synchronization, the activity of the underlying neuronal population rhythmically alternates between bursts of firing and inactivity. They evaluated whether the relationship between hippocampal ripples and gRSC ripples was altered during periods of synchronization and desynchronization in the gRSC. Finally, to assess whether the effect of hippocampal SWRs on gRSC activity was mediated by the subiculum, they recorded ripple activity in the gRSC while inhibiting subicular axons.
What did they find?
Neurons in the gRSC exhibited ripple-like activity, particularly in superficial layers, which were coupled with hippocampal sharp wave ripples. Specifically, hippocampal ripples were immediately followed by the increased firing of neurons, as well as greater ripple activity in the gRSC. Moreover, the strength of hippocampal ripples was positively correlated with the strength of gRSC ripples. Optogenetic stimulation of the subiculum elicited ripple activity in the superficial layers of the gRSC but suppressed neurons in deeper layers. Hippocampal-retrosplenial coupling was also greater during periods of synchronization in the gRSC, but nearly absent during neuronal desynchronization. Thus, hippocampal sharp wave ripples have a differential effect on neurons in the deep and superficial layers of the gRSC, and this effect is modulated by the cortical state of the gRSC.
Hippocampal ripples also activated bursting neurons in the subiculum. In turn, these bursting subicular neurons modulated activity in the gRSC. Stimulating subicular induced excitatory responses in the superficial gRSC, while non-bursting neurons had little effect on gRSC activity. Additionally, optogenetically inhibiting the subicular neurons reduced ripple activity in the gRSC, even in the presence of hippocampal ripples. This shows that bursting neurons in the subiculum directly mediate the coupling between hippocampal and retrosplenial ripples.
What's the impact?
This study identified a novel mechanistic pathway through which hippocampal sharp wave ripples transmit information to the neocortex, particularly to regions that don’t have direct anatomical connections to the hippocampus. These results pave the way for future research to determine how the interactions between the retrosplenial cortex and other regions of the brain support learning and memory.
Nitzan et al. Propagation of hippocampal ripples to the neocortex by way of a subiculum-retrosplenial pathway. Nature Communications (2020). Access the original scientific publication here.