Silencing hippocampal CA2 reduces behavioral flexibility in spatial learning.

The hippocampus is a key structure involved in learning and remembering spatial information. However, the extent to which hippocampal region CA2 is involved in these processes remains unclear. Here, we show that chronically silencing dorsal CA2 impairs reversal learning in the Morris water maze. After platform relocation, CA2-silenced mice spent more time in the vicinity of the old platform location and less time in the new target quadrant. Accordingly, behavioral strategy analysis revealed increased perseverance in navigating to the old location during the first day and an increased use of non-spatial strategies during the second day of reversal learning. Confirming previous indirect indications, these results demonstrate that CA2 is recruited when mice must flexibly adapt their behavior as task contingencies change. We discuss how these findings can be explained by recent theories of CA2 function and outline testable predictions to understand the underlying neural mechanisms. Demonstrating a direct involvement of CA2 in spatial learning, this work lends further support to the notion that CA2 plays a fundamental role in hippocampal information processing.

Selective neuromodulation and mutual inhibition within the CA3-CA2 system can prioritize sequences for replay.

To make optimal use of previous experiences, important neural activity sequences must be prioritized during hippocampal replay. Integrating insights about the interplay between CA3 and CA2, we propose a conceptual framework that allows the two regions to control which sequences are reactivated. We suggest that neuromodulatory-gated plasticity and mutual inhibition enable discrete assembly sequences in both regions to support each other while suppressing competing sequences. This perspective provides a coherent interpretation for a variety of seemingly disconnected functional properties of CA2 and paves the way for a more general understanding of CA2.

A developmental increase of inhibition promotes the emergence of hippocampal ripples.

Sharp wave-ripples (SPW-Rs) are a hippocampal network phenomenon critical for memory consolidation and planning. SPW-Rs have been extensively studied in the adult brain, yet their developmental trajectory is poorly understood. While SPWs have been recorded in rodents shortly after birth, the time point and mechanisms of ripple emergence are still unclear. Here, we combine in vivo electrophysiology with optogenetics and chemogenetics in 4 to 12-day-old mice to address this knowledge gap. We show that ripples are robustly detected and induced by light stimulation of channelrhodopsin-2-transfected CA1 pyramidal neurons only from postnatal day 10 onwards. Leveraging a spiking neural network model, we mechanistically link the maturation of inhibition and ripple emergence. We corroborate these findings by reducing ripple rate upon chemogenetic silencing of CA1 interneurons. Finally, we show that early SPW-Rs elicit a more robust prefrontal cortex response than SPWs lacking ripples. Thus, development of inhibition promotes ripples emergence.

PymoNNto: A Flexible Modular Toolbox for Designing Brain-Inspired Neural Networks.

The Python Modular Neural Network Toolbox (PymoNNto) provides a versatile and adaptable Python-based framework to develop and investigate brain-inspired neural networks. In contrast to other commonly used simulators such as Brian2 and NEST, PymoNNto imposes only minimal restrictions for implementation and execution. The basic structure of PymoNNto consists of one network class with several neuron- and synapse-groups. The behaviour of each group can be flexibly defined by exchangeable modules. The implementation of these modules is up to the user and only limited by Python itself. Behaviours can be implemented in Python, Numpy, Tensorflow, and other libraries to perform computations on CPUs and GPUs. PymoNNto comes with convenient high level behaviour modules, allowing differential equation-based implementations similar to Brian2, and an adaptable modular Graphical User Interface for real-time observation and modification of the simulated network and its parameters.

CA2 beyond social memory: Evidence for a fundamental role in hippocampal information processing.

Hippocampal region CA2 has received increased attention due to its importance in social recognition memory. While its specific function remains to be identified, there are indications that CA2 plays a major role in a variety of situations, widely extending beyond social memory. In this targeted review, we highlight lines of research which have begun to converge on a more fundamental role for CA2 in hippocampus-dependent memory processing. We discuss recent proposals that speak to the computations CA2 may perform within the hippocampal circuit.