Epigenetic engrams in planarians

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

ABSTRACT Although selective synaptic remodeling within neural circuits is widely accepted as the molecular substrate for storage of memories in the brain—the so called “engram”—evidence exists in different model organisms that memories and behaviors can be encoded, and possibly transmitted, by RNA, suggesting that acquired neural states can propagate to molecular species outside the nervous system. There are also rare examples of this information being inherited through the germline in a transgenerational fashion. Such findings have often been accompanied by heavy skepticism, arguably because the precise molecular species encoding the memories have not been identified and the pathways responsible for their biogenesis, movement, and function in the nervous system are not known. Here, I propose to utilize the model planarian Schmidtea mediterranea to define the nature of these molecular memories. Planarians are flatworms with the remarkable ability to regenerate their entire brain after amputation of the head. A largely forgotten and highly controversial body of work from the 1960’s reported that planarians could be trained to associate neutral stimuli with punishment and that the effects of training were maintained after complete brain regeneration. The mechanistic insight of these early studies was limited by the lack of molecular genetic tools to characterize the phenomenon and precisely manipulate the animals. In the intervening years, the field of planarian regeneration has experienced a molecular and genomic renaissance thanks to concerted efforts to develop S. mediterranea as a molecular model system. Many experimental and genomic tools are now available in this species. I will leverage these tools as well as modern neuroscience approaches coupled with automated behavioral tracking to uncover the molecular mechanisms of trans-(re)-generational memory. Toward this end, we have established new behavioral paradigms in S. mediterranea. Our preliminary data is consistent with the original observations that associative memories are retained even after decapitation and complete brain regeneration. We also have extensive expertise in cloning, sequencing, and characterizing the function of various classes of noncoding RNAs in traditional (mammalian cells) and non-traditional (ant) model systems and we will deploy this knowledge to identify the RNAs that mediate trans-regenerational memories in planarians as well as the molecular pathways that regulate their biogenesis, movement, and function. Trans-regenerational memory recall might share common molecular mechanisms with transgenerational inheritance of acquired behaviors. Our studies will foster a deeper understanding of neuroepigenetics in animals with more complex brains, including humans.