Epigenetics

This project stems from a puzzling finding we obtained in the course of our work on the cellular and molecular mechanisms underlying the ability to generalize from previous experience, termed 'rule learning' or 'learning how to learn'. Much to our surprise, it became apparent that offspring of rats who acquired rule-learning are much better learners than rats whose parents were not trained for such a rule. Accordingly, the main hypothesis we test is that rats and mice trained in a complex task until they acquire rule-learning pass on trans-generationally to their offspring superb learning capabilities.

We suggest that inheritance of superb learning capabilities results from receiving a modified epigenome from parents. At the cellular level, superb learning capabilities manifest in changes in multiple neuronal traits. More specifically, increase in intrinsic excitability, enhanced synaptic release and reduced postsynaptic excitatory and inhibitory conductances. This collection of synaptic and cellular changes is commonly observed in the formation of engram cells, and thereby suggest that offspring neurons are primed for becoming memory cells. At the systems level, these traits serve to maintain the relevant neuronal networks in a 'learning-mode' state, during which new memories can be acquired more easily and efficiently. Thus, this project does not only shed light on this unique memory-transference mechanism, but  also expands our basic understandings of the biological basis of learning and memory. These will likely have significant social implications.

The biological basis of epigenetic inheritance, and its behavioral consequences, have been under intense scrutiny.

However, our model system goes beyond previous studies by three key elements:

1. It describes the inheritance of complex behavior (rule-learning), rather than simple forms of learning.

2. It is generalized beyond a specific stimulation, modality or learning paradigm.

3. At the cellular biophysical level, transferred modifications are expressed in both intrinsic neuronal excitability, and synaptic connectivity and transmission.

To unravel the mechanisms underlying this novel phenomenon, we apply an integrative multi-level approach, together with our colleagues at the Technion, the Hebrew University, and Charite University Berlin.  We undertake a top-down-bottom-up approach to elucidate the mechanism(s) behind epigenetic inheritance of learning capabilities.