Grant: Discovery Grants Program - Individual

Keeping memories distinctwhere you parked your car today, for example, as opposed to where you parked yesterdayis a critical faculty without which we would be utterly lost in the world (1,2). The major objective of the work proposed here is to develop an understanding of mechanisms underlying this essential memory process known as pattern separation (PS). To achieve this goal, we will combine cutting-edge behavioural and neurobiological techniques to answer mechanistic questions that have to this point been impossible to address. Substantial evidence now exists to show that adult born neurons (ABNs) in the dentate gyrus region of the hippocampus (DG) play an essential functional role in PS (2,3). Our preliminary data suggestperhaps surprisinglythat astrocytes are also essential. These glial cells have traditionally been assumed to act only in a supporting role to neurons (4). However, with the development of more sophisticated molecular techniques, evidence is now accumulating to show that these cells respond to neuronal activation and release molecules that can modulate synaptic plasticity (5,6,7), and so may play an essential part in cognition. Aim 1 of this proposal is to determine whether and how astrocytes contribute to keeping memories distinct. Our hypothesis is that is that astrocyte signalling is critical for PS. We also expect that astrocytes interact with ABNsvia specific molecular mechanisms that we will testin the service of PS. An additional intriguing mechanistic consideration is that if ABNs are helpful for memory, memory may be helpful for ABNs: the simple act of learning and/or remembering may grow new neurons or promote their survival and integration into hippocampal networks. If this is the case, this mechanism could help to explain why cognitive or “brain” training sometimes improves performance on subsequent cognitive tests, and sometimes does not (9,10,11). Our preliminary data indicate that simply looking at objects placed close together is enough to spur the production and/or survival of ABNs, and mice that have had this experience show improved performance on subsequent cognitive tests. Aim 2 of this proposal is to test our hypothesis that experience that promotes PS will increase neurogenesis and result in experience-induced cognitive facilitation. We predict that the effect of such experience will be relatively specific: training on cognitive tests that challenge PS will generalize only to other cognitive tests that feature a major PS component. Aim 3 is to investigate the specific brain mechanisms that underlie such experience-induced facilitation, guided by our findings under Aim 1. The program of work proposed here will deliver a mechanistic understanding of how PS is achieved, which is essential to a complete understanding of memory. In the long term, this work will lead to a more fundamental understanding of how neurons and glial cells may interact in the service of cognition.