Gabriele Ronnett - US grants

The rat olfactory system is used as a model in which to study chemosensory transduction. Although the mechanism whereby odorants are encoded has been elusive, an odorant binding protein (OBP) has been purified which demonstrates specific, saturable and physiologically relevant binding to several classes of odorants. Rat olfactory explants in culture and isolated rat olfactory cilia (the chemoreceptive neuronal surface) are used to elucidate the role and regulation of OBP. Conditions for the use of explants of olfactory epithelium to study OBP turnover shall be established. Pulse-chase experiments using (35S) methionine are used to determine synthetic and degradative rates of OBP under different conditions. Quantitation of labelled OBP is done by immunoprecipitation with rabbit anti-rat OBP and gel electrophoresis. Initially, OBP turnover shall be investigated in control or isoproteronol-treated rats and rats with olfactory bulb lesions. A cDNA to OBP shall be identified from a rat olfactory epithelium library using a synthetic oligonucleotide probe to the N-terminal sequence of OBP. This cDNA is then used for in situ hybridization to determine the site of biosynthesis of OBP. The protein sequence for OBP as predicted by the cDNA can be compared to other putative odorant binding proteins. The cDNA is also used to quantitate the mRNA to OBP under conditions previously described. Finally, isolated rat olfactory cilia are used to study the initial events of olfactory signal transduction. It is known that these cilia contain adenylate cyclase whose activity is increased by certain odorants in a GTP-dependent manner. The effects of OBP with or without odorants on cyclase activity shall be studied. In addition, the consequences of cyclase activation with respect to targets for a protein kinase shall be studied.

The overall goal of this project is to characterize the molecular mechanisms of olfactory signal transduction. The olfactory receptor neuron (ORN) is a unique CNS model system. It is capable of regeneration from a maintained population of basal cells. Although it is structurally adapted to perform its chemosensory function at the interface of the environment and the CNS, the ORN utilizes signal transduction proteins found elsewhere in the CNS, and therefore its complex mechanisms for signal transduction should provide insight into transduction elsewhere in the CNS. Two experimental paradigms have been develop for these studies. We have developed a method for primary culture of rat ORN's. To permit direct assay of enzymes such as adenylyl cyclase (AC) and phosphodiesterase (PDE) in relatively intact cells, we have developed a method for primary culture of rat ORN's. To permit direct assay of enzymes such as adenylyl cyclase (AC) and phosphodiesterase (PDE) in relatively intact cells, we have developed a method for a-toxin permeabilization of cells while still in monolayer culture. A second paradigm utilizes rat olfactory cilia isolated by calcium (Ca2) shock in a rapid stop-flow apparatus to assay second messenger responses at rapid time points. The first specific aim will be to characterize the regulation of the cAMP in these two model systems. Two parameters, the free Ca2+ concentration and the effect of phosphorylation, will be determined. The relative contribution of AC activation and PDE activation to the resulting cAMP signal will be determined in isolated cilia a number of specific PDE inhibitors will be utilized. AC and PDE activities can be directly measured in olfactory cultures treated with a-toxin. The second specific aim will investigate the role of the phosphoinositide (PI) system in olfaction. Using the rapid stopflow device to assay changes in InsP in rat cilia, we will determine the generality of this response and its regulation by Ca2+. The ability of odorant or Ca2+ to affect InsP binding to its receptor will also be determined. Using [H]-myoinositol to metabolically primary cultures or a radioassay to detect InsP levels, we will evaluate the ability of a number of odorant to stimulate PI turnover. We will examine the desensitization and resensitization of this response. Subsequent experiments will address the ability of protein kinases and of Ca2+ to modulate this response, thereby clarifying the mechanisms of desensitization. The systems we have adapted represent complementary approaches and present opportunities to study biochemical aspects of olfactory signal transduction, with implications for transduction and desensitization and other G-protein-mediated receptor systems.

The overall goal of this proposal is to determine the role of cGMP in neuronal development using olfactory receptor neurons (ORNs) as a model. Neuronal development and regeneration are complex processes that integrate neuronal proliferation, survival, and differentiation. Our recent data indicate that cGMP has essential roles in olfactory receptor neuronal development and maintenance. We hypothesize that cGMP modulates neuronal proliferation, survival, and maturation. The specific effect that cGMP has depends upon neuronal "status" (age and priming by other factors), and the mechanism and site of cGMP production. Cyclic GMP is produced by two classes of enzymes. [1] cGMP is generated by soluble guanylyl cyclases that are activated by the gaseous messengers NO and CO. [2] cGMP is also produced by receptor guanylyl cyclases activated by calcium and extracellular ligands. Thus, we hypothesize that in the adult olfactory system, CO produced by heme oxygenase (HO) in the olfactory epithelium mediates proliferation and survival signals, while NO produced in the olfactory bulb mediates survival through synaptic integrity. In contrast, receptor guanylyl cyclases located in dendritic membranes regulate long-term responses to stimulus detection through calcium and the ligand, atrial natriuretic peptide (CNP), mediates the maturation and survival of proliferating neuronal precursors. Aim 1will combine in vivo and in vitro approaches using knockout animals and primary cultures of ORNs and biochemical and molecular approaches to test the hypothesis that CO and NO mediate paracrine proliferation/survival or target-derived survival signals for ORNs. Aim 2 will use Western blots, antibodies to signaling cascade proteins, pharmacological agents, dominant negative approaches, biochemical second messenger assays and primary cultures to test the hypothesis that odorant-induced cGMP signaling mediates long-term responses to stimulus detection through the Ras-MAPK pathway. Aim 3 will use biochemical second messenger assays, pharmacological reagents and dominant negative approaches, to test the hypothesis that atrial natriuretic peptide C (CNP) alters cGMP levels to induce maturation and survival of growth factor primed-ORN precursors.

DESCRIPTION (provided by applicant): Rett Syndrome (RTT) is an autism spectrum disorder (ASD) that results in mental retardation, motor dysfunction, seizures, and features of autism. RTT is caused by mutation of methyl-CpG binding protein 2 (MeCP2), a transcription factor. Little is known about the specific neurodevelopmental defects that underlie the complex clinical course of RTT. We have used the olfactory system, human olfactory nasal biopsies, and mouse models of MeCP2 mutation to demonstrate that MeCP2 is expressed with neuronal differentiation, and that MeCP2 mutation mimics the clinical course of RTT, causing distinct developmental and long term phases of compromised neuronal function. Our studies have revealed similarities in the neuronal defects found in RTT patients and mouse models of MeCP2 mutation, validating the olfactory system as a model for RTT. Acutely, Mep2 mutation disrupts neuronal terminal differentiation, axonal targeting, and synaptogenesis, while chronically, MeCP2 mutation affects synaptic organization and function. Our recent data indicate that MeCP2 mutation affects several signaling pathways that are important to synaptogenesis, and that sensory activity actually exacerbates this defect. Our overall hypothesis is that MeCP2 is critical for the establishment and maintenance of connectivity, which includes axonal targeting, synaptogenesis, and synaptic maintenance, including activity-induced synaptic refinement. Developmentally, MeCP2 mutation causes a transient delay of synaptogenesis, which, when overcome, reveals a long-term defects in synaptic structure and function. These defects are non-cell autonomous and are exacerbated by activity. As a consequence, and in an attempt to restore connectivity, neurotransmitter and neurotransmitter receptor expression is altered, resulting in further compromise. This complex course parallels the clinical course seen in RTT. The overall goal of the current proposal is to define the mechanisms that underlie the biological defects incurred by MeCP2 dysfunction to clarify the basis for neuronal compromise. We employ mouse models of MeCP2 mutations, in vivo and in vitro paradigms, and molecular and cell biological approaches. Aim 1 will investigate the non-cell autonomous mechanisms and signaling pathways that underlie the developmental and long term defects in connectivity in MeCP2 mutation. Aim 2 will study how MeCP2 mutation interferes with refinements in connectivity induced by sensory activity. Aim 3 will determine the effect of altering glutamatergic transmission on the acute and chronic neurobiological defects seen with MeCP2 mutation. Understanding the pathobiological mechanisms in RTT is essential to the implementation of therapeutic interventions, and moreover, may contribute to the understanding of the pathogenesis of other neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Rett Syndrome (RTT) is an autism spectrum disorder (ASD) that results in mental retardation, motor dysfunction, seizures, and features of autism. RTT is caused by mutation of MeCP2, a gene that affects brain gene expression, and a type of mutation that may underlie many ASDs. Little is known about the specific neurodevelopmental defects that underlie the complex clinical course of RTT. We use the olfactory system and mouse models of MeCP2 mutation to define the mechanisms that underlie the biological defects incurred by MeCP2 dysfunction to clarify the basis for neuronal compromise in ASDs.

The overall goal of our research is to understand the interaction of signal transduction cascades which mediate neuronal development and survival. Both neurotrophins and neuronal activity induce the transcription of genes crucial for neuronal survival. However, the mechanisms by which these pathways interact to modulate gene expression are unclear. Recent results indicate that cross-talk exists between neurotrophin- and activity- induced cascades. Olfactory receptor neurons (ORNs) are used as a model for these studies: they depend upon both activity and neurotrophins (brain-derived neurotrophic factor, BDNF) for survival ORNs are continually replaced during life from a maintained population of precursors, providing us with an excellent opportunity to study neurogenesis Our data show that both odorants and neurotrophins activate the Ras-MAPK cascade and induce CREB phosphorylation. Odorants increase cAMP, cGMP, inositol phosphates, and intracellular calcium levels. Therefore, any of these pathways may interact with the neurotrophin-induced cascade. We hypothesize that odorant-induced signals modulate neurotrophin-activated cascades to influence neuronal survival. Primary cultures of ORNs in which odorant and neurotrophin signaling is preserved, and genetic models in which activity of neurotrophin signal transduction is interrupted, are utilized in this proposal. In Aim 1, we will use primary cultures and activators/inhibitors of odorant-induced signaling pathways to characterize the interactions of odorant and BDNF-activated cascades. We will determine dose-response curves and time courses for CREB activation by odorants and BDNF; define the role of the odorant-induced cAMP pathway in CREB activation; and identify the role of other odorant-induced signaling pathways in CREB activation. In Aim 2, we will define the steps in the Ras-MAPK pathway through which odorant-activated cascades interact with the neurotrophin pathway. In Aim 3, we will determine which signaling paths are important to ORN survival. Odorants may activate multiple pathways, but not all may be relevant to survival. Genetic models in which either activity (OCNC1 null mice) or BDNF signaling (BDNF null mice) is interrupted are used to define the physiological role of these pathways in survival. Understanding these mechanisms is essential to our ability to manipulate that process.

DESCRIPTION (provided by applicant): Neuronal development and regeneration are complex processes guided by neurotrophic factors, including neuropeptides. The vasoactive intestinal peptide (VIP/pituitary adenylyl cyclase activating polypeptide (PACAP) family of neuropeptides is implicated in many aspects of development. The overall goal of this application is to study the roles of PACAP and its receptors in neuronal proliferation and maturation using olfactory receptor neurons (ORNs) as a model. While their localization during embryogenesis suggests a critical role for PACAP peptides, the mechanisms whereby PACAP mediate these processes is not understood. The olfactory system has several attributes that make it attractive for modeling neuropeptide function. In addition to a developmental program, ORNs regenerate post-natally from maintained precursor cells. Our data demonstrate that ORNs express high levels of PACAP and its receptors during development, making them likely mediators of developmental signals. In addition, PACAP affects ORN proliferation in vitro. The use of partial loss of function knockout models confirms this role in vivo. We hypothesize that PACAP is essential to ORN development and transduces proliferation or differentiation signals through the coupling of PACAP receptors to specific intracellular cascades. Aim I will characterize PACAP and its receptor expression profiles developmentally, during adulthood, during regeneration post-lesioning of the ORN target (the olfactory bulb), and in primary ORN cultures. We will determine which cells types express PACAP and its receptors in different developmental and post-lesioning paradigms and which cell types in the olfactory epithelium express PACAP peptides. Aim II will investigate the roles of PACAP in ORN proliferation, survival and differentiation. We will use PACAP and its antagonist, BrdU/PCNA labeling, TUNEL assays, primary ORN cultures and ORN cell lines as well as adenovirus-mediated gene transfer of antisense RNA to study the roles of PACAP and its receptors in O4RN proliferation and survival in vitro. In Aim Ill, we will use pharmacological reagents and biochemical second messenger assays in ORN primary cultures and cell lines to study the intracellular signaling cascades activated by PACAP during different stages of ORN development. We will determine if PACAP peptides modulate ORN proliferation and differentiation by regulating cyclin-dependent kinases and the inhibitory protein CIP/KIP. These studies will elucidate the function and mechanisms underlying bioactive peptide neurotrophism in the CNS.

DESCRIPTION (provided by applicant): Neuronal development and regeneration are complex processes guided by neurotrophic factors, including neuropeptides. The vasoactive intestinal peptide (VIP/pituitary adenylyl cyclase activating polypeptide (PACAP) family of neuropeptides is implicated in many aspects of development. The overall goal of this application is to study the roles of PACAP and its receptors in neuronal proliferation and maturation using olfactory receptor neurons (ORNs) as a model. While their localization during embryogenesis suggests a critical role for PACAP peptides, the mechanisms whereby PACAP mediate these processes is not understood. The olfactory system has several attributes that make it attractive for modeling neuropeptide function. In addition to a developmental program, ORNs regenerate post-natally from maintained precursor cells. Our data demonstrate that ORNs express high levels of PACAP and its receptors during development, making them likely mediators of developmental signals. In addition, PACAP affects ORN proliferation in vitro. The use of partial loss of function knockout models confirms this role in vivo. We hypothesize that PACAP is essential to ORN development and transduces proliferation or differentiation signals through the coupling of PACAP receptors to specific intracellular cascades. Aim I will characterize PACAP and its receptor expression profiles developmentally, during adulthood, during regeneration post-lesioning of the ORN target (the olfactory bulb), and in primary ORN cultures. We will determine which cells types express PACAP and its receptors in different developmental and post-lesioning paradigms and which cell types in the olfactory epithelium express PACAP peptides. Aim II will investigate the roles of PACAP in ORN proliferation, survival and differentiation. We will use PACAP and its antagonist, BrdU/PCNA labeling, TUNEL assays, primary ORN cultures and ORN cell lines as well as adenovirus-mediated gene transfer of antisense RNA to study the roles of PACAP and its receptors in O4RN proliferation and survival in vitro. In Aim Ill, we will use pharmacological reagents and biochemical second messenger assays in ORN primary cultures and cell lines to study the intracellular signaling cascades activated by PACAP during different stages of ORN development. We will determine if PACAP peptides modulate ORN proliferation and differentiation by regulating cyclin-dependent kinases and the inhibitory protein CIP/KIP. These studies will elucidate the function and mechanisms underlying bioactive peptide neurotrophism in the CNS.

[unreadable] DESCRIPTION (provided by applicant): Obesity and its attended disorders, such as Type II diabetes, have reached epidemic proportions. We previously demonstrated that inhibition of fatty acid synthase (FAS) with C75, a synthetic FAS inhibitor, is anorexogenic and induces significant weight loss. This grant is one of a series of three proposals put forth by our FAS Working Group whose overall goal is to determine how C75 and related classes of compounds mediate their effects. The goal of this proposal is to investigate the cellular mechanisms of actions of C75. FAS catalyzes long chain fatty acid synthesis through a complex seven step condensation reaction that utilizes acetyI-CoA, malonyI-CoA, ATP, and NADPH to generate palmitate. Our hypothesis is that C75 has both central and peripheral actions to modulate body weight. Centrally, C75 alters the metabolisms of neurons including those in hypothalamic feeding pathways to modulate gene expression and influence feeding behavior. Peripherally, C75 acts to increase energy utilization by stimulating carnitine palmitoyl transferase-1 (CPT-1) the enzyme that imports palmitate into the mitochondrion for beta-oxidation. Our hypothesis in this proposal is that C75 alters neuronal metabolism to modulate neuronal signaling pathways, leading to a change in energy perception by the cell. We pose three testable hypotheses regarding the effect of C75 on neuronal metabolism. Specific Aim I will test the hypothesis that FAS inhibition alters neuronal metabolism. We will employ in vitro approaches using primary cultures of cortical neurons, hypothalamic neurons, and the 3T3-L1 cell pre-adipocyte cell line to perform biochemical and molecular assays to understand how FAS inhibition effects neuronal energy flux and enzyme activities. In Aim II we will test the hypothesis that these metabolic changes influence signaling pathways. We will use Western blot analysis and antibodies to signaling cascade proteins, as well pharmacological agents that allow us to selectively modify pathways to determine the effect of FAS inhibition on important cellular substrates such as AMP kinase, uncoupling proteins, and peroxisomes. In Aim III we will test the hypothesis that those pathways are relevant in vivo by modulating these signaling pathways in the presence of C75 and determining which pathways affect feeding and weight loss. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Despite significant advances in our understanding of the consequences of neuronal stress at molecular levels, interventions for neuronal injury, as in stroke, remain elusive. One approach is to identify changes in neuronal metabolism incurred as a consequence of oxidative or metabolic stress that may be neuroprotective, or, alternatively, that may be pro-apoptotic. AMP-activated protein kinase (AMPK) is a known sensor of peripheral energy balance, and is activated when energy sources are low. Peripherally, AMPK acutely regulates cellular metabolism and chronically regulates gene expression. We demonstrated that AMPK in highly expressed in neurons and responds to metabolic challenges by altering neuronal metabolism, suggesting that AMPK may play a physiological role in regulating neuronal energy balance. However, AMPK activation appears to be deleterious in stroke models, in a parallel line of investigation, we have established roles for the fatty acid synthase (FAS) pathway and carnitine palmitoyltransferase (CPT-1) in metabolism and as targets for modulating cellular energy utilization/perception. We have shown that modulation of these pathways by synthetic FAS inhibitors/CPT-1 stimulators that we designed, such as C75, can alter neuronal metabolism. Most recently, we have combined these lines of investigation and shown that C75 inhibits AMPK activation in vitro and in vivo and significantly reduces stroke volume. Our hypothesis is that AMPK plays a role in neuronal energy perception, but its over-activation with metabolic failure is deleterious; furthermore, modulation of the FAS/CPT-1 pathway alters neuronal metabolism to inhibit AMPK and produce neuroprotection under conditions of cellular stress. Aim 1 will use in vitro models to define the regulation of AMPK activity in neurons. Aim 2 will study the role and regulation of AMPK in an ischemia-reperfusion model. Aim 3 will determine the mechanisms by which modulation of the FAS and CPT-1 activities alters AMPK activity and affords neuroprotection.

DESCRIPTION (provided by applicant): Olfaction is critical for survival, and in humans, diminished olfactory capacity as seen with aging, injury, or disease may compromise health and quality of life. Olfactory sensory neurons (OSNs) serve as the initial site of olfactory signaling, and thus they are critical for olfactory function. The development of OSNs is a complex process that must integrate neuronal proliferation, differentiation, and survival. While progress has been made on the mechanisms that mediate odor detection in OSNs, relatively little is know regarding the factors that are critical for their homeostasis. We demonstrated that cyclic GMP (cGMP) plays a role in the proliferation, differentiation, synapse formation, and neuroprotection of OSNs. cGMP is generated by soluble guanylyl cyclases (GCs) which are activated by the gaseous messengers NO (made by nitric oxide synthase (NOS)) and CO (made by heme oxygenase (HO)). cGMP is also produced by receptor GCs which are activated by extracellular ligands and Ca2+. Our overall hypothesis is that cGMP plays a role in regulating OSN proliferation, differentiation, and survival, and in the protection of OSNs from stress. The specific effect that cGMP has depends upon neuronal }status} (age and priming by other factors), and the mechanism, timing, and site of cGMP production. The goal of this proposal is to delineate the mechanisms that mediate these actions. We employ molecular and cell biological approaches using in vitro and in vivo models to investigate testable hypotheses. Aim 1 will utilize in vitro cultures, in vivo sensory stimulation and deprivation models, and biochemical and genetic approaches to investigate the regulation of the MEK/Erk and PI3K/Akt signaling pathways by cGMP to contribute to OSN survival. Aim 2 will use these models to study the role of cGMP in OSN differentiation and synaptogenesis. Aim 3 will utilize in vitro and in vivo models of sensory stimulation and deprivation, and biochemical and genetic approaches to study the role of cGMP in remediating the effects of stress on OSN survival. The rationale for these studies is that understanding the factors that regulate the survival of OSNs is essential for strategies aimed at preserving olfactory function. PUBLIC HEALTH RELEVANCE: The olfactory system is critical for survival, and in humans, diminished sensory capacity seen with aging, injury, or disease compromises health and quality of life. Olfactory sensory neurons (OSNs) serve as the initial site of olfactory signaling, and thus their survival is critical for olfactory function. Our studies have demonstrated that the second messenger cyclic GMP (cGMP) plays critical roles in the development and survival of OSNs, and in their response to stress. In this proposal, we study the mechanisms of these effects to evaluate the role that cGMP plays in the survival of these neurons. These findings have the potential to provide the basis for the development of therapeutic agent(s) to rescue neurons from death in response to injury.

DESCRIPTION (provided by applicant): Metabolic dysfunction is both causative and the final common pathway responsible for the morbidity and mortality of many diseases. For example, obesity and its attendant disorders, such as Type 2 Diabetes and Cardiovascular Disease, have reached epidemic proportions globally. Understanding how genetic and environmental factors affect metabolism, and how therapeutic interventions may remediate these metabolic alterations, is critical to disease treatment and prevention. Investigations of metabolic dysregulation require the capability to assess whole animal physiology, including food intake, energy expenditure, the relative use of fuel sources, exercise tolerance, and activity. No such integrative facility currently exists at The Johns Hopkins University School of Medicine or nearby Institutions. Our goal is to acquire a Comprehensive Lab Animal Monitor System (CLAMS) to permit the continuous and simultaneous monitoring and assessment of indirect calorimetry (VO2, RER), food intake, physical activity, and voluntary and stimulus-driven exercise. The Johns Hopkins Medical Institution (JHMI), specifically the Institute for Basic Biomedical Sciences (IBBS), has provided infrastructure and financial resources to the Center for Metabolism and Obesity Research (CMOR) to permit investigator and technical support for the CLAMS. Since its inception this year, CMOR has served as a foundation for the study and support of integrative research in the field of metabolism and systems biology to advance our understanding of the biological mechanisms that regulate metabolism and how they are dysregulated in disease. CMOR's goals are to provide an infrastructure for scientific interactions among faculty and community, to integrate research using model organisms and metabolic profiling, to develop service and technological resources, to enhance the education of trainees, and to foster interactions between the center and others organizations that support research in metabolism. The acquisition and support of the CLAMS is central to these goals. The experiments that will be enabled by the CLAMS will provide comprehensive evaluation of metabolic parameters for the exploration of the cellular mechanisms critical to the development of therapeutic interventions.

DESCRIPTION (provided by applicant): The olfactory system is critical for survival, and in humans, diminished sensory capacity seen with aging, injury, or degenerative diseases compromises health and the quality of life. Olfactory sensory neurons (OSNs) are the initial site of odorant detection, and thus their survival is critical for olfactory function. While progress has been made regarding the mechanisms that mediate odorant detection in OSNs, less is known about the factors that are critical for OSN survival. Our studies demonstrate that, in addition to the rapid signaling for odor detection, sensory stimulation induces long-term responses that may support neuronal survival. Our recent data suggest that odorant detection and sensory stimulation-driven survival proceed by parallel pathways. Furthermore, we found that sensory stimulation evokes cellular stress, which is exacerbated when sensory stimulation-activated pathways are inhibited. Our overall hypothesis is that sensory stimulation activates multiple signal transduction cascades in parallel to those that serve stimulus detection to promote neuronal survival and to respond to activity-induced cellular stress. Loss of these responses to sensory stimulation exacerbates activity- related stress, leading to progressive cell damage and ultimately neuronal death. The overall goal of this proposal is to delineate the signal transduction pathways that mediate sensory stimulation driven survival and stress responses. We employ molecular and cell biological approaches using in vitro and in vivo models to investigate testable hypotheses. Aim 1 will utilize in vitro cultures, in vivo sensory stimulation and deprivation models, and biochemical and genetic approaches to delineate the mechanisms of the MEK/Erk and PI3K/Akt signaling pathways that contribute to sensory stimulus-dependent OSN survival. Aim 2 will use these models to study the divergence of odorant detection pathways and activity-dependent OSN survival. Aim 3 will utilize in vitro and in vivo models of sensory stimulation and deprivation, and biochemical and genetic approaches to study the effects of sensory-induced stress on OSN survival and the pathways that are involved. The rationale for these studies is that understanding the factors that regulate the survival of OSNs is essential for strategies aimed at preserving olfactory function. These findings have the potential to provide a basis for the development of therapeutic strategies to rescue neurons from death in response to injury and thus preserve olfactory function. PUBLIC HEALTH RELEVANCE: The olfactory system is critical for survival, and in humans, diminished sensory capacity of seen with aging, injury, or degenerative diseases compromises health. Olfactory sensory neurons (OSNs) serve as the initial site of olfactory signaling, and thus their survival is critical for preserving olfactory function. Our studies evaluate the roles that sensory input and activity play in the survival of these neurons. These findings may have the potential to provide a basis for the development of therapeutic strategies to rescue neurons from death in response to injury and thus preserve olfactory function.