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Principal Investigator: Abha K Rajbhandari
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $202,800
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
The fundamental mechanisms by which acute intense stress affects energy homeostasis via brain substrates
and sexual dimorphism of these processes are poorly understood. Environmental stressors induce fight-or-
flight-or-freeze response via the locus coeruleus (LC) in the brainstem, a major sympathetic regulator in
humans and animals that triggers energy metabolism. LC innervates the brown adipose tissue (BAT) and
expresses high levels of PAC1 receptor for the neuropeptide PACAP (pituitary adenylate cyclase activating
peptide). PACAP/PAC1 are critical regulators of stressors of all kinds, fear, appetite, feeding, and energy
metabolism and genetically linked to stress-related disorders like post-traumatic stress (PTSD) in humans.
Intriguingly, women with PTSD showing high blood levels of this neuropeptide and brain PAC1 receptors
regulate fear in a sexually dimorphic manner in animals. To test the importance of PAC1 in acute intense
stress and energy homeostasis, we used the stress-enhanced fear learning (SEFL) behavioral model in mice.
Our preliminary data show that ablation of PAC1 receptors from the LC enhances SEFL expression, energy
metabolism as assessed by indirect calorimetry measurement, and increases metabolic genes like uncoupling
protein 1 in BAT in females than males. Thus, harnessing on the biology of PAC1 receptors, we aim to lay a
mechanistic framework linking acute intense stress and energy metabolism in a systematic and sex-dependent
manner via the LC. We hypothesize that PAC1 receptors in the LC are important for gating stress-associated
metabolic information and BAT functions in a sexually dimorphic manner. Aim 1 will test a SEFL mediated loss
of function of LC-PAC1 on whole body energy expenditure and on BAT functions. For this, we will test if viral
cre-recombinase mediated PAC1 deletion from LC in mice with floxed PAC1 regulates SEFL-associated
energy expenditure and induction of thermogenic genes in BAT in a sex-dependent manner (via transcript
analysis, mitochondrial bioenergetics, and tissue lipolysis). Aim 2 will test if PAC1 expressing LC neurons
project directly to BAT in a sexually dimorphic manner under SEFL. For this, we will use retrograde viral tracing
to determine LC to BAT projecting cell populations combined with in situ hybridization for PAC1 in LC. We
predict that female mice will show enhanced energy expenditure, BAT thermogenesis and increased LC
projection to BAT. Overall, using state-of-the-art tools and techniques and rigorous systems biology approach
of linking acute intense stress and energy metabolism, our studies will lay crucial groundwork for several future
work. This will serve as a premise for studying central sympathetic control of metabolism in chronic stress-
related conditions such as PTSD that are comorbid with metabolic diseases and increasingly prevalent in the
US populations.
Terms: <Ablation><Acute><Adipose tissue><Affect><Anatomic Sites><Anatomic structures><Anatomy><Animals><Appetite><Area><Aujeszky's Disease Virus><Aujeszkys Disease Virus><Autoregulation><BAT uncoupling protein><Behavior><Behavioral><Behavioral Model><Bioenergetics><Biology><Blood><Blood Reticuloendothelial System><Body Tissues><Brain><Brain Nervous System><Brain Stem><Brainstem><Brown Adipose Tissue><Brown Fat><CNS Nervous System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CRE Recombinase><Cell Body><Cells><Central Nervous System><Chemicals><Chronic stress><Data><Desire for food><Differences between sexes><Differs between sexes><Disease><Disorder><Encephalon><Energy Expenditure><Energy Metabolism><Enterobacteria phage P1 Cre recombinase><Experimental Designs><Fatty Tissue><Fear><Female><Freezing><Fright><Future><Gatekeeping><Genes><Genetic Polymorphism><Heat Production><Herpesvirus 1 (alpha), Suid><Herpesvirus Suis><Hibernating Gland><Homeostasis><Human><Hypophysis><Hypophysis Cerebri><In Situ Hybridization><Indirect Calorimetry><Intake><Intermediary Metabolism><Learning><Link><Lipolysis><Locus Coeruleus><LoxP-flanked allele><Measurement><Measures><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolic dysfunction><Metabolism><Mice><Mice Mammals><Mitochondria><Modern Man><Murine><Mus><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neurons><Neuropeptide Receptor><Neuropeptides><Nucleus Pigmentosus Pontis><O element><O2 element><Oxygen><PAC1 receptor><PACAP><PACAP type I receptor><PACAPR-1 protein><Peptides><Physiologic><Physiological><Physiological Homeostasis><Pituitary><Pituitary Gland><Pituitary Nervous System><Population><Process><Pseudorabies virus><Respiration><Respiration Calorimetry><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sex Differences><Sexual differences><Societies><Stress><Suid Herpesvirus 1><Swine Herpesvirus 1><Systems Biology><Techniques><Testing><Thermogenesis><Thesaurismosis><Tissues><Transcript><Viral><Water Intake><Water consumption><Woman><Work><acute stress><adenylate><adipose><bacteriophage P1 recombinase Cre><biological adaptation to stress><blue nucleus><brown adipose tissue uncoupling protein><co-morbid><co-morbidity><comorbidity><comparing females and males><comparing women and men><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><environmental stresses><environmental stressor><feeding><females compared to males><females compared with males><females versus males><females vs males><fighting><floxed><floxed allele><food consumption><gatekeeper><in situ Hybridization Genetics><in situ Hybridization Staining Method><innervation><knock-down><knockdown><locus ceruleus structure><loss of function><mad itch virus><male><metabolism disorder><mitochondrial><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mouse model><murine model><nerve supply><neuronal><new approaches><novel><novel approaches><novel strategies><novel strategy><pituitary adenylate cyclase activating peptide><pituitary adenylate cyclase activating polypeptide><pituitary adenylate cyclase-activating peptide receptor, type I><polymorphism><post-trauma stress><post-traumatic stress><posttrauma stress><posttraumatic stress><programs><reaction; crisis><respiratory mechanism><response><retrograde transport><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><sex based differences><sex dimorphism><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><social role><stress related disorder><stress response><stress; reaction><stressor><thermogenin><tool><transcriptomics><translational model><uncoupling protein 1><viral testing><virus testing><white adipose tissue><women compared to men><women compared with men><women versus men><women vs men><yellow adipose tissue>