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Cellular Mechanisms of Neuromodulation in the Dentate Gyrus.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Cellular Mechanisms of Neuromodulation in the Dentate Gyrus./
Author:	Gulfo, Michelle Christine.
Description:	1 online resource (180 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
Contained By:	Dissertations Abstracts International85-11B.
Subject:	Neurosciences. -
Online resource:	click for full text (PQDT)
ISBN:	9798382612409

Cellular Mechanisms of Neuromodulation in the Dentate Gyrus.
Gulfo, Michelle Christine.

Cellular Mechanisms of Neuromodulation in the Dentate Gyrus. - 1 online resource (180 pages)

Source: Dissertations Abstracts International, Volume: 85-11, Section: B.

Thesis (Ph.D.)--Albert Einstein College of Medicine, 2023.

Includes bibliographical references

The hippocampus is a key player in major physiological and pathological processes within the brain. Uncovering the cellular and molecular bases of these processes is critical for optimal understanding of the brain and disease. The dentate gyrus (DG) of the hippocampus is a primary area of interest as it is the gate to the hippocampus proper and the home of hilar mossy cells (MCs). These poorly understood but highly powerful excitatory neurons alone can modulate hippocampal functions. A central lens through which to study the cellular and molecular bases of brain function is neuromodulation. Neuromodulators are molecules that are released in unique and context-specific manners to shape cellular physiology, circuit function, and ultimately behavior. In this way, neuromodulators link environmental information to the cellular basis of behavioral responses to that information.In particular, dopamine and adenosine are two strong candidate regulators of hippocampal and specifically MC circuitry. Both neuromodulators are implicated in hippocampal and MC-associated processes and conditions including spatial learning, anxiety, and seizures. In addition, dopaminergic fibers are present and functional in the DG, and adenosine is known to be released and synthesized throughout the brain, including in the hippocampus. Finally, there is evidence for the expression of receptors for both dopamine and adenosine on MCs. Expression from the dopamine D2 receptor (D2R) gene promoter is a hallmark feature of MCs, and D2R signal has been demonstrated at the site of MC terminals in cats and humans. The presence of adenosine A1 and A2A receptors (A1Rs and A2ARs, respectively) has also been demonstrated in the hippocampus, with A1Rs particularly localized at glutamatergic terminals. We hypothesized that neuromodulators, namely dopamine and adenosine, critically regulate hilar MC function and are key contributors to MCs' impressive roles in physiology and disease. In this dissertation, I will describe the studies we performed to test this hypothesis.We used a combination of complementary approaches, including a conditional knockout strategy, acute rodent hippocampal slice electrophysiology, pharmacology, immunohistochemistry, and behavioral assessments to test the roles of dopamine and adenosine signaling in MC circuitry and function. In the first and main study of this dissertation (Chapter II), we investigated the function of the hallmark receptor of MCs, D2Rs. We selectively removed the Drd2 gene from MCs in adult mice and found that this manipulation impaired spatial memory, promoted anxiety-like behavior, and increased the severity of and susceptibility to kainic acid-induced seizures. We also found that dopamine negatively regulated the main excitatory output of MCs onto GCs via MC D2Rs in adult mice, while it had no detectable effect on other major properties of MC physiology and circuitry. The MC-GC synapse is a critical locus for regulation of DG and hippocampal function, and thus this may be one mechanism underlying the role of the MC Drd2 gene in behavior. In all, these findings directly revealed for the first time the functional significance of MC D2Rs and provide molecular insight into mossy cell function that may advance understanding and treatment of disease.In the second study (Chapter III), we investigated the role of adenosine/A1R signaling at the MC-GC synapse. Previous work in the Castillo Lab demonstrated that adenosine is the retrograde signal released from GCs to activate MC A2A receptors and mediate MC-GC LTP. We thus hypothesized a potential role for A1R signaling at MC-GC synapses as well. We found that A1R signaling negatively regulated MC-GC transmission and LTP and modulated GC membrane properties. These findings indicated A1Rs as another key negative regulator of the critical MC-GC synapse along with D2Rs. This negative regulation may contribute to the known anticonvulsant and anxiolytic roles of A1Rs.In all, this work has provided mechanistic insights into MC function and the roles of dopamine and adenosine in the DG. In so doing, it has highlighted potential therapeutic targets for brain dysfunction and directions for future study that will hopefully improve understanding of and manipulations targeting the brain in health and disease.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798382612409Subjects--Topical Terms:

593561
Neurosciences.
Subjects--Index Terms:

AnxietyIndex Terms--Genre/Form:

554714
Electronic books.

Cellular Mechanisms of Neuromodulation in the Dentate Gyrus.
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520 $a The hippocampus is a key player in major physiological and pathological processes within the brain. Uncovering the cellular and molecular bases of these processes is critical for optimal understanding of the brain and disease. The dentate gyrus (DG) of the hippocampus is a primary area of interest as it is the gate to the hippocampus proper and the home of hilar mossy cells (MCs). These poorly understood but highly powerful excitatory neurons alone can modulate hippocampal functions. A central lens through which to study the cellular and molecular bases of brain function is neuromodulation. Neuromodulators are molecules that are released in unique and context-specific manners to shape cellular physiology, circuit function, and ultimately behavior. In this way, neuromodulators link environmental information to the cellular basis of behavioral responses to that information.In particular, dopamine and adenosine are two strong candidate regulators of hippocampal and specifically MC circuitry. Both neuromodulators are implicated in hippocampal and MC-associated processes and conditions including spatial learning, anxiety, and seizures. In addition, dopaminergic fibers are present and functional in the DG, and adenosine is known to be released and synthesized throughout the brain, including in the hippocampus. Finally, there is evidence for the expression of receptors for both dopamine and adenosine on MCs. Expression from the dopamine D2 receptor (D2R) gene promoter is a hallmark feature of MCs, and D2R signal has been demonstrated at the site of MC terminals in cats and humans. The presence of adenosine A1 and A2A receptors (A1Rs and A2ARs, respectively) has also been demonstrated in the hippocampus, with A1Rs particularly localized at glutamatergic terminals. We hypothesized that neuromodulators, namely dopamine and adenosine, critically regulate hilar MC function and are key contributors to MCs' impressive roles in physiology and disease. In this dissertation, I will describe the studies we performed to test this hypothesis.We used a combination of complementary approaches, including a conditional knockout strategy, acute rodent hippocampal slice electrophysiology, pharmacology, immunohistochemistry, and behavioral assessments to test the roles of dopamine and adenosine signaling in MC circuitry and function. In the first and main study of this dissertation (Chapter II), we investigated the function of the hallmark receptor of MCs, D2Rs. We selectively removed the Drd2 gene from MCs in adult mice and found that this manipulation impaired spatial memory, promoted anxiety-like behavior, and increased the severity of and susceptibility to kainic acid-induced seizures. We also found that dopamine negatively regulated the main excitatory output of MCs onto GCs via MC D2Rs in adult mice, while it had no detectable effect on other major properties of MC physiology and circuitry. The MC-GC synapse is a critical locus for regulation of DG and hippocampal function, and thus this may be one mechanism underlying the role of the MC Drd2 gene in behavior. In all, these findings directly revealed for the first time the functional significance of MC D2Rs and provide molecular insight into mossy cell function that may advance understanding and treatment of disease.In the second study (Chapter III), we investigated the role of adenosine/A1R signaling at the MC-GC synapse. Previous work in the Castillo Lab demonstrated that adenosine is the retrograde signal released from GCs to activate MC A2A receptors and mediate MC-GC LTP. We thus hypothesized a potential role for A1R signaling at MC-GC synapses as well. We found that A1R signaling negatively regulated MC-GC transmission and LTP and modulated GC membrane properties. These findings indicated A1Rs as another key negative regulator of the critical MC-GC synapse along with D2Rs. This negative regulation may contribute to the known anticonvulsant and anxiolytic roles of A1Rs.In all, this work has provided mechanistic insights into MC function and the roles of dopamine and adenosine in the DG. In so doing, it has highlighted potential therapeutic targets for brain dysfunction and directions for future study that will hopefully improve understanding of and manipulations targeting the brain in health and disease.
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