Mossy cells (MCs) of the dentate gyrus (DG) are glutamatergic neurons that are considered to be important to normal function and their injury has been suggested to contribute to neurological and psychiatric disorders, as well as deficits after traumatic brain injury. Anatomical and slice electrophysiology studies have described MCs in detail, but there is a gap between these studies and understanding how MCs contribute to DG-dependent behavior in vivo. To address this issue, we began with a simple approach: mice were engaged in behaviors related to DG function, and MCs were examined afterwards using the neural activity marker c-fos. We quickly found that simply exploring novel objects led to a large increase in MC c-fos immunoreactivity (ir). Interestingly, most c- fos-ir did not increase in most of the other DG neurons, suggesting preferential activation of MCs by novelty. However, there was one area of the DG where c-fos-ir was consistent: a subset of GCs in dorsal DG. In contrast, the majority of MCs with c-fos-ir were ventral. Because the main projection of ventral MCs is to dorsal GCs, these data suggest that ventral MCs excite dorsal GCs. This circuitry helps explain how normally quiescent GCs become activated in dorsal DG, which is considered essential for cognitive functions of the DG.
In Aim 1 we will use optogenetics to test this hypothesis, taking advantage of new mouse lines that have targeted Cre recombinase to MCs. We will also ask if dorsal MCs have effects analogous to ventral MCs, i.e., dorsal MCs contribute to ventral DG functions.
In Aim 2 the underlying circuitry will be addressed. We suggest that optogenetic excitation of MCs in a normal adult mouse will recapitulate the results with c-fos: MCs excite proximal GCs weakly but distal GCs in a more robust manner. This idea has been supported by data from slices that were cut at an angle to preserve MC axons, and will be tested further in Aim 2 using voltage imaging and microelectrodes.
In Aim 3 we will address the hypothesis that a large number of the distal GCs that are activated by MCs are immature. That hypothesis supports a previously published study showing that MCs are a primary source of afferent input to young GCs that are born in adulthood. This is potentially important because immature GCs are considered central to DG functions. Therefore, we will address the additional hypothesis that MCs activate adult-born GCs primarily in distal locations, leading to stronger excitation of distal GCs than proximal GCs. By providing afferent input to immature GCs, MCs could play a critical role in behaviors associated with adult DG neurogenesis. Together these experiments will significantly advance our understanding of DG circuitry and its contribution to behavior. Because MC injury is associated with several disorders, these experiments will also shed light on impairments in DG functions in those pathological conditions.

Public Health Relevance

This project will address the role of mossy cells (MCs) in the dentate gyrus (DG), a cell type that has been implicated in normal DG function and in pathological conditions ranging from traumatic brain injury and epilepsy to psychiatric illness. We used a marker of neural activity to form hypotheses about the role of MCs in behaviors related to DG function, and now employ optogenetics to selectively activate or silence MCs to establish their role; voltage imaging and patch clamp recordings will be used in a complementary manner. Together the results will significantly advance our understanding of the normal DG, and impairments that develop when MCs are injured or lost in disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ferrante, Michele
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Nathan Kline Institute for Psychiatric Research
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