What's the science?
The dentate gyrus and the CA3 are two important regions involved in memory in the hippocampus. The dentate gyrus separates out incoming signals from the cortex and relays patterns of information to the CA3 pyramidal cells via thorny “mossy fiber” projections. Cues can then reactivate this pattern of information in the CA3 cells (also known as pattern completion). The way in which CA3 neurons are able to reactivate the neurons encoding a memory involves recurrent network activity, however the details are not well understood. Understanding differences in cell types within the CA3 of the hippocampus could improve our understanding of this process of reactivating memories. This week in Nature Neuroscience, Hunt and colleagues examine different pyramidal cell types within the CA3 and their activity patterns during sharp waves (i.e. spontaneous reactivation of memory neurons) to understand their role in the “replay” of memory.
How did they do it?
They performed whole-cell patch-clamp on hippocampal tissue slices from mice to assess how the neurons in the CA3 would fire in response to current injection (to cause action potential firing). They then examined the structural and molecular properties of these neurons to see how cell types within the CA3 differed. Next, they used a transgenic mouse line and optogenetics to express light activated channels in mossy fiber axons projecting to CA3 cells from the dentate gyrus. They activated these fibers and measured excitatory post-synaptic currents to map input from dentate gyrus to different pyramidal cells within the CA3. In mice, they measured activity (local field potentials and multi-unit activity) of different labelled pyramidal cells during “sharp wave” events, which are the spontaneous neuron firing events in the CA3, known to be important for memory. The goal was to understand how different pyramidal cells and their firing properties contribute to memory. They used optogenetic activation of cholinergic neurons, which are known to regulate memory in the hippocampus, to test how different pyramidal cell types responded to cholinergic modulation. Lastly, they constructed an “attractor network model” to show how these different cell types contribute to network dynamics in the hippocampus during memory replay.
What did they find?
There were two types of responses from neurons within the CA3 after current injection: neurons that fired in a regular pattern and neurons that fired in a “burst” pattern. The regular firing neurons had thorny spines as expected of CA3 cells, however the burst firing neurons did not have thorny spines (i.e athorny cells). Using a clustering approach, the two cell types were segregated based on their different electrophysiological and structural properties. Using optogenetic activation of mossy fibers, they found that mossy fibers project to regular thorny neurons but not to athorny burst firing neurons in the CA3. However, both thorny and athorny neurons were excited by recurrent activation (i.e. by neurons nearby).
In mice, they measured neuron activity during sharp wave events, which had two phases: an initial ramp phase followed by an exponential increase in firing. They measured properties of firing of the two cell types and found that they behaved differently: thorny cells contribute to initial single spike activity and this spiking peaked during the exponential phase of the sharp wave event, while athorny cells weakly increased their single spike rate during the ramp and exponential phase of the sharp wave event. Athorny neurons contributed more to the complex burst firing (as opposed to single unit firing) component of sharp wave events. Optogenetic activation of cholinergic cells abolished sharp wave events, indicating that sharp waves are regulated by acetylcholine (a neurotransmitter that modulates activity). Further, activation of cholinergic neurons downregulated the burst firing of the athorny pyramidal cells, suggesting that low acetylcholine levels may facilitate the reactivation of pyramidal cells during the “replay” of memory during sharp wave events. Using an “attractor network model” they found that burst firing (driven by athorny cells) were important for evoking sharp wave events, suggesting that these newly defined cells are crucial for memory replay.
What's the impact?
This is the first study to demonstrate that a new “athorny” cell type in the CA3 region of the hippocampus is involved in memory. This new athorny neuron plays a role in burst firing associated with “sharp wave” events that are important for the reactivation of memory (i.e. memory replay). Understanding the cell types involved in memory circuits in the hippocampus is crucial to understanding how memory is encoded and retrieved.
Hunt et al., A novel pyramidal cell type promotes sharp-wave synchronization in the hippocampus. Nature Neuroscience (2018). Access the original scientific publication here.