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Bridging Molecular and Systems Neuroscience for Hypothalamic Representations of Survival Behaviors.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Bridging Molecular and Systems Neuroscience for Hypothalamic Representations of Survival Behaviors./
Author:	Yang, Hui.
Description:	1 online resource (433 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 84-07, Section: B.
Contained By:	Dissertations Abstracts International84-07B.
Subject:	Neurosciences. -
Online resource:	click for full text (PQDT)
ISBN:	9798368444574

Bridging Molecular and Systems Neuroscience for Hypothalamic Representations of Survival Behaviors.
Yang, Hui.

Bridging Molecular and Systems Neuroscience for Hypothalamic Representations of Survival Behaviors. - 1 online resource (433 pages)

Source: Dissertations Abstracts International, Volume: 84-07, Section: B.

Thesis (Ph.D.)--Albert Einstein College of Medicine, 2024.

Includes bibliographical references

The mammalian hypothalamus controls a variety of behaviors necessary for survival, including eating, drinking, arousal, aggression, defense, and mating. Research interest in the human hypothalamic function is expansive, ranging from longevity, energy metabolism to reproduction, cardiovascular health, etc. In hypothalamus and more broadly in other brain regions, behavioral states can be elicited by perturbation of specific molecularly defined cell types.Among the hypothalamic subregions, the paraventricular hypothalamus (PVH) is an important neural circuit node for need-driven behaviors. PVH receives projections from the brain region that chiefly controls eating and the region that chiefly controls drinking. These projections alone (without collaterals) are sufficient to elicit eating and drinking, respectively. PVH contains neurons that express neuropeptide (hormone) genes, each with specialized influence on behavioral states. These findings indicate a relationship between neuronal gene expression and their influence on the animal's behavioral states. Another reason for evaluating this relationship is that need-driven behaviors can be seen as unfolding in phases, and the brain has evolved designated regions and cell types to control each phase. For example, hunger-driven feeding undergoes the preparatory/appetitive phase, the consummatory phase, and the satiety phase based on neural dynamics. We reasoned that tracking cell-type specific neural dynamics with behavioral phrases may offer an etiologically principled framework to understand PVH function.The first manuscript in this thesis addressed the relationship between PVH genes expression, neuronal function, and behaviors. Considering the natural course of need-driven behaviors and the molecular and functional diversity of PVH, we identified two fundamental questions that have not been adequately addressed for this brain region. First, how similarly or differently did neurons of a molecularly defined cell type respond during different behavior (phases)? Second, how did dynamics in molecularly defined cell types encode behavioral states? There were two types of methods to answer these questions, each with their own limitations. To overcome these limitations, we developed calcium and RNA multiplexed activity (CaRMA) imaging platform. This platform allowed us to obtain neural dynamics at high temporal resolution across 11 behaviors and in all cell types in the PVH. Neuronal gene expression was revealed post hoc.We found that PVH neurons of the same cell type tended to respond similarly. This meant that it might be justified to represent the PVH ensemble as a combinatorial code of cell type activities instead of having to track every individual neuron. To substantiate this idea, we further showed that a 10-neuron ensemble, each from their respective cell type, could accurately decode all 11 behavioral states in our study. Decoding performance decreased if such a 10-neuron ensemble was drawn without regard to cell type. A cell type that responded strongly and similarly (among its members) to a behavior contributed significantly to differentiating that behavior from others.It was noticeable that three cell types responded with similar directionality across behaviors, while a fourth cell type responded oppositely to them under these same set of behaviors. We asked how gene expression might map to and predict functionally classes in the PVH. We found that 3 out of 9 genes, Npy1r. Pdyn, and Crh, showed enrichment for the greatest number of behavioral states. They also segregated into the same functional classes under these behaviors. These findings led us to analyze how well gene expression predicted neuronal function for 11 behaviors. The gene Npy1r was among the most predictive gene sets for all 11 behavioral states. Np1yr was expressed in multiple molecularly defined cell types. Cell types that expressed Npy1r and those lacking Np1yr tended to respond oppositely across multiple behaviors. Neuropeptide Y, which is the ligand of the receptor gene, signals by volume transmission. This signaling mechanism offered a plausible explanation for role of Npy1r in coordinating functional response across several cell types.When we used CaRMA imaging in the PVH study, we identified areas for improvement and developed a newer version termed CaRMA imaging, as described in the second manuscript in this thesis. The newer version achieved 1,000-fold time efficiency improvement in the most critical steps and an increased number of genes (from 12 to 27 or more) for refined molecular classification of neurons. We will soon distribute detailed protocols for both the original and the improved versions of the CaRMA imaging.CaRMA imaging is a discovery tool that bridges molecular and systems neuroscience. It overcomes limitations of stand-alone in vivo neuroimaging or spatial transcriptomics studies. The discoveries made by CaRMA imaging have the potential to be developed into molecular targets and bring the neuropsychiatry discipline closer to precision medicine.

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

Mode of access: World Wide Web

ISBN: 9798368444574Subjects--Topical Terms:

593561
Neurosciences.
Subjects--Index Terms:

Behavioral state codingIndex Terms--Genre/Form:

554714
Electronic books.

Bridging Molecular and Systems Neuroscience for Hypothalamic Representations of Survival Behaviors.
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520 $a The mammalian hypothalamus controls a variety of behaviors necessary for survival, including eating, drinking, arousal, aggression, defense, and mating. Research interest in the human hypothalamic function is expansive, ranging from longevity, energy metabolism to reproduction, cardiovascular health, etc. In hypothalamus and more broadly in other brain regions, behavioral states can be elicited by perturbation of specific molecularly defined cell types.Among the hypothalamic subregions, the paraventricular hypothalamus (PVH) is an important neural circuit node for need-driven behaviors. PVH receives projections from the brain region that chiefly controls eating and the region that chiefly controls drinking. These projections alone (without collaterals) are sufficient to elicit eating and drinking, respectively. PVH contains neurons that express neuropeptide (hormone) genes, each with specialized influence on behavioral states. These findings indicate a relationship between neuronal gene expression and their influence on the animal's behavioral states. Another reason for evaluating this relationship is that need-driven behaviors can be seen as unfolding in phases, and the brain has evolved designated regions and cell types to control each phase. For example, hunger-driven feeding undergoes the preparatory/appetitive phase, the consummatory phase, and the satiety phase based on neural dynamics. We reasoned that tracking cell-type specific neural dynamics with behavioral phrases may offer an etiologically principled framework to understand PVH function.The first manuscript in this thesis addressed the relationship between PVH genes expression, neuronal function, and behaviors. Considering the natural course of need-driven behaviors and the molecular and functional diversity of PVH, we identified two fundamental questions that have not been adequately addressed for this brain region. First, how similarly or differently did neurons of a molecularly defined cell type respond during different behavior (phases)? Second, how did dynamics in molecularly defined cell types encode behavioral states? There were two types of methods to answer these questions, each with their own limitations. To overcome these limitations, we developed calcium and RNA multiplexed activity (CaRMA) imaging platform. This platform allowed us to obtain neural dynamics at high temporal resolution across 11 behaviors and in all cell types in the PVH. Neuronal gene expression was revealed post hoc.We found that PVH neurons of the same cell type tended to respond similarly. This meant that it might be justified to represent the PVH ensemble as a combinatorial code of cell type activities instead of having to track every individual neuron. To substantiate this idea, we further showed that a 10-neuron ensemble, each from their respective cell type, could accurately decode all 11 behavioral states in our study. Decoding performance decreased if such a 10-neuron ensemble was drawn without regard to cell type. A cell type that responded strongly and similarly (among its members) to a behavior contributed significantly to differentiating that behavior from others.It was noticeable that three cell types responded with similar directionality across behaviors, while a fourth cell type responded oppositely to them under these same set of behaviors. We asked how gene expression might map to and predict functionally classes in the PVH. We found that 3 out of 9 genes, Npy1r. Pdyn, and Crh, showed enrichment for the greatest number of behavioral states. They also segregated into the same functional classes under these behaviors. These findings led us to analyze how well gene expression predicted neuronal function for 11 behaviors. The gene Npy1r was among the most predictive gene sets for all 11 behavioral states. Np1yr was expressed in multiple molecularly defined cell types. Cell types that expressed Npy1r and those lacking Np1yr tended to respond oppositely across multiple behaviors. Neuropeptide Y, which is the ligand of the receptor gene, signals by volume transmission. This signaling mechanism offered a plausible explanation for role of Npy1r in coordinating functional response across several cell types.When we used CaRMA imaging in the PVH study, we identified areas for improvement and developed a newer version termed CaRMA imaging, as described in the second manuscript in this thesis. The newer version achieved 1,000-fold time efficiency improvement in the most critical steps and an increased number of genes (from 12 to 27 or more) for refined molecular classification of neurons. We will soon distribute detailed protocols for both the original and the improved versions of the CaRMA imaging.CaRMA imaging is a discovery tool that bridges molecular and systems neuroscience. It overcomes limitations of stand-alone in vivo neuroimaging or spatial transcriptomics studies. The discoveries made by CaRMA imaging have the potential to be developed into molecular targets and bring the neuropsychiatry discipline closer to precision medicine.
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653 $a Eating disorder
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