The goal of this project is to provide the building blocks for an independent research program focused on
the mechanisms by which neural networks incorporate multisensory cues into episodic memories.
Discrimination of different contexts composed of distinct constellations of multisensory cues is a hallmark of
both episodic memory and spatial navigation, two functions ascribed to the mammalian hippocampus. The
Dentate Gyrus of the hippocampus is central to spatial and contextual discrimination; yet the neural
mechanisms by which contextual representations are encoded by principal granule cells has remained a
significant knowledge gap. Preliminary data based on in vivo two photon imaging indicates a novel elevation
of cue-associated activity in the granule cells that correlates with spatial discrimination, both of which
are reduced in mice without adult hippocampal neurogenesis. Thus, this project proposes to test the
hypothesis that specialized cue cells in the dentate gyrus are critical for anchoring contextual
representations and are modulated both by adult neurogenesis and by entorhinal cortical inputs.
These studies represent a number of firsts in linking the physiology and behavioral function of the Dentate Gyrus
during learning of spatial discrimination by investigating 1) the evolution of spatial and cue-associated activity
of granule cells over time in order to support the encoding of contextual representations; 2) the activity of adult
born granule cells and their distinct contributions to cue representations; and 3) the activity of the entorhinal
cortex afferents to the Dentate Gyrus, and the mechanisms by which multisensory information arriving from the
external world generate internal hippocampal representations. To achieve this detailed circuit dissection, I will
use an integrative approach that merges in vivo imaging techniques, genetic-based circuit manipulation
strategies and computational analysis of multi-neuronal activity.
The technical and scientific skills that I will develop during the training period of this project will become
the pillars of an independent research career investigating the function and development of the complex neural
dynamics which support cognitive functions implicated in neuropsychiatric disorders. This training will be
complemented by intense carrier developmental activities and mentorship that will prepare me for the practical
aspects of laboratory management, teaching and fund raising.
Overall, these studies will provide novel insights into how the Dentate Gyrus local and long-range circuits
contribute to cue representations and facilitate contextual discrimination. Since hippocampal damage has been
implicated in the cognitive discrimination impairments associated with Alzheimer’s disease and PTSD,
constructing a dynamic picture of the Dentate Gyrus, an often overlooked hippocampal region, at cellular and
circuit resolutions during the formation of episodic memories may have an important clinical relevance.