Cooperate to compete: Identifying a potential role for hippocampal region CA2 in episodic memory formation

To memorize an experience, our brain is replaying associated sequences of neuronal activity in the hippocamus and associated regions. Since we remember only a fraction of our experiences, the brain must have a way to prioritize certain neural activity sequences for replay. This thesis outlines why and how interactions between hippocampal region CA2 and CA3 may play a decisive role in determining which sequences are reactivated. These interactions stand out for two reasons: First, synaptic plasticity at CA3 to CA2 projections is strongly regulated by neuromodulatory substances, which are likely released during emotionally arousing situations. Second, in both directions, excitatory activity in one region suppresses activity in the other region. Connecting these findings, I argue that neuromodulatory release can lead to selective pairing of co-active neural activity sequences across the two regions. Paired sequences may support each others reactivation, while suppressing competing sequences. As shown by neural network simulations, such a pairing mechanism may be particularly beneficial for neural activity sequences comprised of few cells. As the number of recruited cells varies depending on the type of experience, the proposed CA2-CA3 sequence interaction may explain why CA2 is involved in some but not all situations

Degeneracy in epilepsy: multiple routes to hyperexcitable brain circuits and their repair

Abstract Due to its complex and multifaceted nature, developing effective treatments for epilepsy is still a major challenge. To deal with this complexity we introduce the concept of degeneracy to the field of epilepsy research: the ability of disparate elements to cause an analogous function or malfunction. Here, we review examples of epilepsy-related degeneracy at multiple levels of brain organisation, ranging from the cellular to the network and systems level. Based on these insights, we outline new multiscale and population modelling approaches to disentangle the complex web of interactions underlying epilepsy and to design personalised multitarget therapies

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

Inferring causal connectivity from pairwise recordings and optogenetics

To understand the neural mechanisms underlying brain function, neuroscientists aim to quantify causal interactions between neurons, for instance by perturbing the activity of neuron A and measuring the effect on neuron B. Recently, manipulating neuron activity using light-sensitive opsins, optogenetics, has increased the specificity of neural perturbation. However, using widefield optogenetic interventions, multiple neurons are usually perturbed, producing a confound -- any of the stimulated neurons can have affected the postsynaptic neuron making it challenging to discern which neurons produced the causal effect. Here, we show how such confounds produce large biases in interpretations. We explain how confounding can be reduced by combining instrumental variables (IV) and difference in differences (DiD) techniques from econometrics. Combined, these methods can estimate (causal) effective connectivity by exploiting the weak, approximately random signal resulting from the interaction between stimulation and the absolute refractory period of the neuron. In simulated neural networks, we find that estimates using ideas from IV and DiD outperform naive techniques suggesting that methods from causal inference can be useful to disentangle neural interactions in the brain