Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation

Abstract

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV ⁺) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV ⁺ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV ⁺ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV ⁺ cells.

eLife digest

Sleep contributes to the strengthening of memories. During non-dreaming sleep, neurons in regions of the brain that form and store memories – such as the hippocampus and prefrontal cortex – fire in rhythmic waves. The neurons in the hippocampus tend to fire during a wave that repeats up to 250 times per second, called sharp-wave ripples. Meanwhile, in the prefrontal cortex, the neurons tend to fire during a lower frequency wave that repeats 12 to 15 times per second, called spindles.

During sleep and quiet wakefulness, hippocampal ripples often synchronize with prefrontal spindles; that is, both waves tend to occur at approximately the same time. Many neuroscientists think this allows the brain regions to better communicate with one another, which in turn should help the brain to strengthen memories. Consistent with this possibility, rodents that learn a new task show more synchrony between ripples and spindles afterwards. But no one had actually tested whether this increase in ripple-spindle synchrony does strengthen the rodent’s memory of the task. It was also unclear how the brain achieves such an increase.

Xia et al. suspected that this process involved a group of inhibitory brain cells called parvalbumin-positive interneurons. These cells act like timekeepers, and help to synchronize the firing of groups of neurons. Xia et al. now show that training mice to associate an environment with a mild electric shock made it more likely that the animals would show ripple-spindle synchrony. Yet, inhibiting the activity of parvalbumin-positive interneurons in either the hippocampus or prefrontal cortex blocked this effect. It also prevented sleep from strengthening the animals’ memory of the link between the environment and the shock.

Patients with Alzheimer’s disease have fewer parvalbumin-positive interneurons. By showing that these neurons help strengthen new memories, these findings may explain why losing them can impair memory. Restoring or replacing interneuron activity could be a promising therapeutic avenue to explore.