Adam Ramsaran, The Hospital for Sick Children
Winner of the Marlene Reimer Brain Star of the Year Award, as the number one ranked winner of 2023
Scientific publication
Ramsaran AI, Wang Y, Golbabaei A, Aleshin S, De Snoo ML, Yeung BA, Rashid AJ, Awasthi A, Lau J, Tran LM, Ko SY, Abegg A, Duan LC, McKenzie C, Gallucci J, Ahmed M, Kaushik R, Dityatev A, Josselyn SA, & Frankland PW. (2023). A shift in the mechanisms controlling hippocampal engram formation during brain maturation. Science, 380(6644), 543-551.
Mechanisms controlling memory formation shift as the juvenile brain matures.
The capacity for episodic memory (memories for personally experienced events, including their setting, or context) develops during childhood. It is thought that the development of episodic memory in human children, and episodic-like memory in animals, reflects the functional maturation of the hippocampus, which is a critical structure in the brain’s episodic memory network. Yet, the neurobiological mechanisms of episodic-like memory development in the hippocampus have largely remained unstudied. In this study, Adam Ramsaran and colleagues found that, in mice, episodic-like memory (i.e., remembering not only what happened, but where it happened) develops between postnatal days 20 and 24, caused by several age-dependent cellular and molecular changes that affect how memories are represented in the hippocampus.
An engram is physical trace of a memory localized in the brain, typically referring to a specific population of neurons, or neuronal ensemble, that encodes a given memory. Consistent with previous research, Ramsaran found that episodic-like memories in older (>P24) mice were encoded by sparse engram neuronal ensembles in the CA1 region of the hippocampus, whereas spatially imprecise pre-episodic memories in younger mice were encoded by dense engrams. They demonstrated that this shift in hippocampal engram formation is supported by the maturation of extracellular perineuronal nets around inhibitory parvalbumin-expressing interneurons. That is, they could reinstate dense engram and spatially-imprecise memory formation in adult mice by inhibiting the activity of parvalbumin interneurons or interfering with perineuronal net stability in CA1. Moreover, they could cause early emergence of sparse engram and episodic-like memory formation in younger mice by accelerating the maturation of perineuronal nets around interneurons in CA1.
The publication identifies several novel phenomena related to the development of memory.
First, although it was believed that the development of episodic and episodic-like memory reflected the onset of hippocampal memory function, this study demonstrated that hippocampal memory function precedes the development of episodic-like memory. In other words, the immature hippocampus supports various types of memory in early life and does not “come online” to support episodic-like memory, as was previously believed.
Second, this study is the first to identify age-dependent differences in the way memory engrams are formed in the brain. They identified cellular and molecular mechanisms underlying these differences, which may be targeted to potentially reverse episodic-like memory impairments in animals affected by aging or neurodevelopmental disorders.
Third, the researchers identified a developmental rise in inhibition as a key driver of episodic-like memory development. This rise in inhibition is supported by maturation of hippocampal perineuronal nets in the extracellular matrix. Perineuronal net maturation in the brain cortex is known to drive developmental changes in sensation and perception. Therefore, similar neurobiological mechanisms are responsible for the development of memory and sensory systems. Maturation of the extracellular matrix and circuit inhibition may be a brain-wide mechanisms for brain and behavioral development.
About Adam Ramsaran
Adam Ramsaran performed this research as part of his PhD thesis in the laboratory of Paul Frankland at the Hospital for Sick Children, Associated with the University of Toronto. As first author of this publication, he developed the ideas for the study, designed and performed most experiments, analyzed data, generated illustrations, and wrote the paper. Supervisors and collaborators from the Sheena Josselyn (Hospital for Sick Children) and Alexander Dityatev (Otto von Guericke University, Germany) labs were involved in most stages of the study. Many co-authors are undergraduate and master’s student trainees under his supervision, who made publication-quality contributions to the study.
Sources of funding
This study was funded by Brain Canada, the Canadian Institutes of Health Research (CIHR), University of Toronto, SickKids Research Institute, German Research Foundation, German Center for Neurodegenerative Diseases (DZNE), National Institutes of Health (NIH), Natural Sciences and Engineering Research Council of Canada (NSERC), Ontario Graduate Scholarship program, Ontario Trillium Scholarship program and the Vector Institute.
