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Neural Circuit and Cellular Signaling Mechanisms by which pappaa and nf1 Regulate Sensory Evoked Behaviors.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Neural Circuit and Cellular Signaling Mechanisms by which pappaa and nf1 Regulate Sensory Evoked Behaviors./
Author:	Miller, Andrew H.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	156 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
Contained By:	Dissertations Abstracts International83-03B.
Subject:	Neurosciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28719335
ISBN:	9798538110025

Neural Circuit and Cellular Signaling Mechanisms by which pappaa and nf1 Regulate Sensory Evoked Behaviors.
Miller, Andrew H.

Neural Circuit and Cellular Signaling Mechanisms by which pappaa and nf1 Regulate Sensory Evoked Behaviors. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 156 p.

Source: Dissertations Abstracts International, Volume: 83-03, Section: B.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2021.

This item must not be sold to any third party vendors.

The nervous system has a remarkable capacity to continuously receive, organize, and adapt to sensory stimuli in order to initiate or suppress behaviors. Neural circuits are specially organized to process various sensory signals and to integrate sensory information with previous experience. Although the synaptic architectures of many sensory circuits have been identified and physiologically characterized, the genes and molecular pathways that establish these sensory circuits remain poorly understood. Identifying genes and characterizing the molecular pathways that contribute to establishing the structure and function of sensory circuits will inform the treatment of sensory-related cognitive dysfunction. The larval zebrafish is a valuable tool for identifying and characterizing genes and molecular pathways that regulate neural circuits for sensory evoked behaviors. Previous work combined high-throughput, automated behavioral tracking with forward genetic screening and gene editing to identify two genes that regulate sensory evoked behaviors. The first, pregnancy-associated plasma protein-aa (pappaa), encodes a secreted metalloprotease known to stimulate insulin-like growth factor (IGF) signaling. The second, neurofibromin 1 (nf1), encodes a Ras-GTPase activating protein (RasGAP) known to inhibit Ras signaling and stimulate cAMP signaling. In this dissertation, I characterize neural circuit and cellular signaling mechanisms by which pappaa and nf1 regulate visually and acoustically evoked behaviors, respectively. Neural circuits coding light increment and decrement are split into parallel retinal pathways via discrete synapses between photoreceptors and distinct bipolar cells. In Chapter 2, I report a novel synaptic role for pappaa in regulating the structure and function of retinal synapses that transmit light decrement information. I demonstrate that Papp-aa regulates cone-to-OFF bipolar cell flat contacts through stimulation of IGF1 receptor signaling to guide motor responses to light decrement. Therefore, Papp-aa is a novel molecular cue that contributes to establishing parallel ON and OFF retinal pathways for guiding motor responses to visual stimuli. Sensory information must also be filtered in neural circuits to allow animals to respond to behaviorally relevant stimuli while ignoring extraneous stimuli. Habituation learning is one sensory filtering mechanism that reduces behavioral responses to repeated, non-harmful sensory stimuli. In Chapter 3, I show that inhibiting chemokine receptor 4 (Cxcr4) signaling in nf1 mutant larval zebrafish rescues habituation learning deficits and increases abnormally low cAMP-PKA signaling. In humans, heterozygous loss of function mutations in NF1 cause the neurogenetic disorder Neurofibromatosis type 1 (NF1), which predisposes patients to peripheral nerve tumors, brain tumors, and cognitive dysfunction. Neurofibromin is known to be a multi-functional protein that regulates various cellular signaling pathways in neural circuits throughout the brain. Therefore, understanding the relationship between neurofibromin and Cxcr4 signaling may inform future treatment of cognitive dysfunction for patients living with NF1. Together this work characterizes how pappaa and nf1 regulate the structure and function of distinct sensory circuits in larval zebrafish and contributes to our understanding of how sensory information is processed to guide behavior.

ISBN: 9798538110025Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

cAMP signaling

Neural Circuit and Cellular Signaling Mechanisms by which pappaa and nf1 Regulate Sensory Evoked Behaviors.
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500 $a Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
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506 $a This item must not be sold to any third party vendors.
520 $a The nervous system has a remarkable capacity to continuously receive, organize, and adapt to sensory stimuli in order to initiate or suppress behaviors. Neural circuits are specially organized to process various sensory signals and to integrate sensory information with previous experience. Although the synaptic architectures of many sensory circuits have been identified and physiologically characterized, the genes and molecular pathways that establish these sensory circuits remain poorly understood. Identifying genes and characterizing the molecular pathways that contribute to establishing the structure and function of sensory circuits will inform the treatment of sensory-related cognitive dysfunction. The larval zebrafish is a valuable tool for identifying and characterizing genes and molecular pathways that regulate neural circuits for sensory evoked behaviors. Previous work combined high-throughput, automated behavioral tracking with forward genetic screening and gene editing to identify two genes that regulate sensory evoked behaviors. The first, pregnancy-associated plasma protein-aa (pappaa), encodes a secreted metalloprotease known to stimulate insulin-like growth factor (IGF) signaling. The second, neurofibromin 1 (nf1), encodes a Ras-GTPase activating protein (RasGAP) known to inhibit Ras signaling and stimulate cAMP signaling. In this dissertation, I characterize neural circuit and cellular signaling mechanisms by which pappaa and nf1 regulate visually and acoustically evoked behaviors, respectively. Neural circuits coding light increment and decrement are split into parallel retinal pathways via discrete synapses between photoreceptors and distinct bipolar cells. In Chapter 2, I report a novel synaptic role for pappaa in regulating the structure and function of retinal synapses that transmit light decrement information. I demonstrate that Papp-aa regulates cone-to-OFF bipolar cell flat contacts through stimulation of IGF1 receptor signaling to guide motor responses to light decrement. Therefore, Papp-aa is a novel molecular cue that contributes to establishing parallel ON and OFF retinal pathways for guiding motor responses to visual stimuli. Sensory information must also be filtered in neural circuits to allow animals to respond to behaviorally relevant stimuli while ignoring extraneous stimuli. Habituation learning is one sensory filtering mechanism that reduces behavioral responses to repeated, non-harmful sensory stimuli. In Chapter 3, I show that inhibiting chemokine receptor 4 (Cxcr4) signaling in nf1 mutant larval zebrafish rescues habituation learning deficits and increases abnormally low cAMP-PKA signaling. In humans, heterozygous loss of function mutations in NF1 cause the neurogenetic disorder Neurofibromatosis type 1 (NF1), which predisposes patients to peripheral nerve tumors, brain tumors, and cognitive dysfunction. Neurofibromin is known to be a multi-functional protein that regulates various cellular signaling pathways in neural circuits throughout the brain. Therefore, understanding the relationship between neurofibromin and Cxcr4 signaling may inform future treatment of cognitive dysfunction for patients living with NF1. Together this work characterizes how pappaa and nf1 regulate the structure and function of distinct sensory circuits in larval zebrafish and contributes to our understanding of how sensory information is processed to guide behavior.
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