The survival of stable place cells is predictive of a good cognitive outcome after stroke

This is a summary of Heiser, H., Kiessler, F., Roggenbach, A. et al. ‘Brain-wide microstrokes affect the stability of memory circuits in the hippocampus’ published in Nature Communications 16, 3462 (2025). https://doi.org/10.1038/s41467-025-58688-4

The challenge

More than 70% of stroke survivors develop forms of cognitive decline, yet the corresponding mechanisms are poorly understood, and specific treatment options are therefore unavailable. We know that the accumulation of smaller ischemic events does not result in acute cognitive impairment but that this decline develops in the months and years after these events. The hippocampus is particularly susceptible to these events. Furthermore, previous studies have demonstrated the importance of ‘place cells’ – cells that respond to the animal's current location and contain a representation of contextual, sensory, and episodic experiences of an environment – for memory formation and maintenance. Due to technical limitations it was not possible before to study the fate of the same individual nerve cells in the hippocampus in the healthy and post-stroke condition in active animals in a relevant cognitive task. With our study, we present a new experimental paradigm that allows revealing the role of individual nerve cells within a neuronal population involved in spatial memory in health and disease.

Our approach

We established aa novel mouse model to measure the loss of spatial memory and mimic key features of small vessel disease using chronic 2-photon calcium imaging in the hippocampus. Mice were trained to perform a cognitive task in a virtual reality environment before and after brain-wide microstrokes during the recordings. Our approach allowed to track the fate of individual nerve cells in the hippocampus for several weeks before and after stroke. 

Our findings

We found that, under normal conditions, hippocampal neurons exhibit varying degrees of stability in their coding of spatial memory. However, this stability was disrupted by microstrokes, which resulted in cognitive impairments. We discovered that cognitive outcomes were linked to the preservation of a functional subclass of place cells with stable coding for spatial information, as well as the overall stability, precision, and persistence of the hippocampal network. Mice that exhibited more synchronous activity in their place cells near important locations demonstrated recovery from cognitive impairment. This shows that the survival of place cells with stable coding can be a strong predictor of positive cognitive outcomes following a stroke. The synchronous activity of place cells helps them survive and re-stabilize the rewiring network after a stroke.

The implications

The well-known concept of Hebbian learning of “neurons that fire together wire together” also applies to a rewiring network after brain injury. This has implications for the development of novel pharmacological and stimulation strategies: novel strategies could aim to induce the co-activation of neurons in networks to stabilize and enhance reorganizing circuits in the brain after stroke.

Creating SyNergies

The study was led by SyNergy member Anna-Sophia Wahl who was joined by our member Julijana Gjorgjieva. Anna-Sophia and Julijana used their “SyNergies” to gain a deeper understanding of neuronal encoding in the hippocampus in health and disease: While the Wahl lab performed the experiments, the Gjorgjieva lab provided help in mathematically describing the complex hippocampal network reactions after stroke.