Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2011.Cataloged from PDF version of thesis.Includes bibliographical references (p. 190-212).Declarative memory requires the integration and association of multiple input streams within the medial temporal lobe. Understanding the role each neuronal circuit and projection plays in learning and memory is essential to understanding how declarative and episodic-like memories are formed. This work here addresses the role of the medial entorhinal cortex layer III (MEC-III) to CA1 projections in episodic-like memory formation and recall. This circuit is addressed with a triple transgenic mouse which allows for the expression of tetanus toxin, an enzyme that disrupts synaptic vesicle fusion, specifically in MEC-III neurons. Utilizing this triple transgenic mouse model, which allows for the specific and reversible ablation of synaptic transmission only in medial entorhinal cortex layer III excitatory neurons, the function of this pathway in various learning and memory tasks is tested. Synaptic output from the medial entorhinal cortex layer III neurons is necessary for acquisition, but not recall of tone and contextual fear memories in trace fear conditioning, and not in delay conditioning. This is the first demonstration that acquisition and recall of the same memory engram do not require the exact same anatomy. Additionally, this pathway is necessary for performance in a delayed nonmatch-to-place working memory task, in which the animal must utilize memory from the previous trial to successfully complete the following trial. Both the trace and working memory paradigm require the integration of information across a delay, which we propose is supported by known persistent activity in entorhinal neurons. CAl receives input from both entorhinal layer III and CA3. We show that synaptic transmission from CA3 is not required for tone fear memory in the trace paradigm and not required for working memory in the same delayed nonmatch-to-place paradigm, further isolating the necessity for MEC-III inputs in both of these behaviors. Functional MEC-III synaptic transmission is also necessary for pattern-completion contextual recall in the pre-exposure contextual fear conditioning paradigm. Contrary to previous literature, the MEC-II to CAl pathway is not necessary for consolidation of spatial memories and anatomical tracings using this mouse line demonstrate that the MEC-III projects to CA1 and not CA3. The MEC-II pathway however, does project via two pathways to the same target in CA1, the perforant and alvear pathways. The alvear pathway has not been reported before in mice. Recent advances in mouse genetic tools have allowed for circuit studies of the medial temporal lobe. We have used these tools and elucidated some of the specific circuits involved with temporal and working memory.by Alexander Jay Rivest.Ph.D.