Détails sur le projet
Description
Project Summary
Human patients with the neurological disorders of Alzheimer’s disease and age-related dementia commonly
show defects in spatial navigation, which correlates strongly with dysfunction in other aspects of cognition such
as episodic memory. During spatial exploration animals form an internal cognitive map of an environment by
integrating online sensory input with information about the animal’s movement through space, a process which
involves the hippocampus. Accordingly, the hippocampus has also been found to exhibit pathological changes
in many disorders of learning and memory. Yet it is still unclear how different subregions of the hippocampus
contribute to the integration of sensory cue and self-motion information in the formation of a spatial map for
navigation, and therefore may underlie the dysfunction in human cognitive disorders. The dentate gyrus (DG) is
the initial stage of the classical ‘trisynaptic circuit’ of the hippocampus, and receives its principal inputs from the
lateral and medial entorhinal cortex (LEC and MEC), which are proposed to carry information about sensory
cues and self-motion, respectively. Thus it has been suggested that the DG integrates cue (“what”) and spatial
(“where”) information to form discrete spatial representations such as those found in place cells elsewhere in the
hippocampus and which are proposed to underlie an animal’s overall map of an environment. We have
documented strong sensory cue responses in dentate granule cells during spatial tasks in head fixed mice, but
it is unknown to what degree cue representations are integrated with purely spatial information in the DG. In this
proposal we will examine the microcircuitry of cue and spatial representations in the dentate gyrus using modern
in vivo population imaging, circuit tracing, and optogenetic technologies combined with precise behaviors
designed to isolate independent cue and spatial influences on dentate granule cell activity. We will leverage
these powerful techniques along with cutting edge analytical tools to test the hypothesis that cue and spatial
representations remain distinct at the level of the dentate gyrus, and thus the DG population consists of separate
classes of “cue cells” driven primarily by the LEC and “place cells” driven by the MEC. Furthermore, we will utilize
the new light-and-activity dependent gene expression system FLiCRE to selectively label and manipulate
functionally distinct cue and place cell populations, in order to determine their inputs and role in spatial behavior.
Together, these experiments will help us better understand the progressive transformation of information within
the hippocampus in the formation of a cognitive map of an environment, and how these processes may be
defective in human cognitive disorders of learning and memory.
Statut | Terminé |
---|---|
Date de début/de fin réelle | 8/1/22 → 7/31/23 |
Financement
- National Institute of Neurological Disorders and Stroke: 321 250,00 $ US
Keywords
- Biología molecular
Empreinte numérique
Explorer les sujets de recherche abordés dans ce projet. Ces étiquettes sont créées en fonction des prix/bourses sous-jacents. Ensemble, ils forment une empreinte numérique unique.