Hippocampal-Prefrontal Projections Mediate Sleep-Dependent Spatial Memory Consolidation in Mice

Post by Amanda McFarlan

What's the science?

Research studies have suggested that through the process of memory consolidation, memories are relocated from the hippocampus (where they were initially encoded) to the prefrontal cortex for long-term storage. The process of memory consolidation may rely on the oscillatory rhythms that occur during non-rapid eye movement (non-REM) sleep. The neural pathway that connects hippocampal projection neurons and the medial prefrontal cortex and associated oscillatory neuronal activity has been investigated for its role in working memory. Yet, whether hippocampal-prefrontal projections are important for memory consolidation remains largely unknown. This week in the Journal of Neuroscience, Binder and colleagues investigated the role of monosynaptic projections from the hippocampus to the medial prefrontal cortex in sleep-dependent consolidation of spatial memory.

How did they do it?

The authors bilaterally transduced the ventral and intermediate hippocampus in male mice with iChloC (a chloride-conducting inhibitory Channelrhodopsin) and implanted optic fibers above the infralimbic area of the medial prefrontal cortex to optogenetically target the axon terminals from hippocampal projection neurons forming monosynaptic connections with neurons in the medial prefrontal cortex. They also inserted recording electrodes in the cingulate cortex and the dorsal hippocampus to measure local field potentials in response to optogenetic inhibition. Next, to investigate the role of monosynaptic connections between the hippocampus and the medial prefrontal cortex in sleep-related spatial memory consolidation, the authors trained mice in the Barnes maze test (spatial memory task) during a 4-day period. A baseline measure of electrophysiological activity was recorded in all mice prior to the first test day. On test day 1, the authors placed a mouse in a light-proof box in the middle of a brightly lit maze and then removed the box and observed as the mouse searched the maze for an escape box. Visual cues were set up around the maze to help the mice with spatial orientation. Following the training session in the maze, the authors measured electrophysiological activity for a 3-hour period during which 10 mice received optogenetic inhibition of hippocampal axon terminals during non-REM sleep (inhibition group), 10 mice did not receive any manipulation (control group) and 5 mice received optogenetic inhibition of hippocampal axon terminals during wakefulness and REM sleep (awake-inhibition control group). This entire protocol (training sessions in the maze and electrophysiological recordings) was repeated for 4 days. On test days 5 and 16, the authors removed the escape box from the maze and performed a brief probe trial to test recent and remote memory, respectively.

What did they find?

The authors found that performance levels on the Barnes maze task significantly improved over the 4 test days in both the inhibition and control groups. They also determined that there was an improvement in the use of search strategies across the 4 test days, with a decrease in the random/mixed strategy (disorganized search pattern) and an increase in the serial strategy (mouse visits two or more adjacent holes before reaching the target). Notably, on the 4th test day, the mice in the control group showed a significantly higher incidence of using a direct strategy (mouse goes directly to the target or visits one adjacent hole before reaching the target) compared to the mice in the inhibition group. The mice in the awake-inhibition control group performed similarly to the control group. Additionally, the authors revealed that the mice in the inhibition group had impairments in recent memory (tested on day 5) compared to controls, but not remote memory (tested day 16). Together, these results suggest that optogenetic inhibition of monosynaptic hippocampal-medial prefrontal cortex connections during non-REM sleep does not affect the rate at which mice learn to perform on the Barnes maze task but may impair their spatial memory as indicated by impairments in recent memory and the use of inefficient search strategies. Furthermore, the authors found that after the first day of testing, the inhibition group showed a greater increase in hippocampal sharp-wave ripple density compared to controls. They also determined that mice in the inhibition group showed reduced temporal coupling of sharp-wave ripple activity and sleep spindles as well as sleep spindle activity and neocortical slow oscillations compared to controls, suggesting that optogenetic inhibition of monosynaptic hippocampal-medial prefrontal cortex connections during non-REM sleep disrupts the learning-induced modulation of sleep-associated neuronal activity.


What's the impact?

This is the first study to show that monosynaptic projections from the hippocampus to the medial prefrontal cortex are involved in sleep-dependent consolidation of spatial memory. The authors postulate that these connections are likely important for mediating learning-induced changes in temporal coordination of neuronal activity during sleep. Together, these findings provide insight into the type of information that is consolidated via the hippocampal-prefrontal cortex connections during sleep.

Binder et al. Monosynaptic hippocampal-prefrontal projections contribute to spatial memory consolidation in mice (2019). Access the original scientific publication here.