Orexin regulation of responses to brain injury

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Principal Investigator: SEEMA  BHATNAGAR
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $220,000
Funding agency: National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY
Traumatic brain injuries (TBI) have devastating consequences for the quality of life of affected individuals.
Mild TBI (mTBI) is extremely common affecting approximately 42 million individuals worldwide (NINDS.gov;
2015). Key symptoms include excessive daytime sleepiness, poor memory and attention and psychiatric
symptoms including anxiety [1, 2]. Recovery from mTBI can be uneven with some individuals developing
long-term symptoms [3]. One factor that could underlie variations between individuals in mTBI severity of
symptoms is stress exposure. Stress exposure is common in environments that lead to TBI [4], stress can
exacerbate mTBI outcomes and result in protracted mTBI outcomes While psychological stress resulting
from mTBI can exacerbate symptoms and lead to psychiatric problems [7], the role of prior stress in
increasing vulnerability to subsequent mTBI is less clear [5]. These results suggest that mitigating the impact
of stress could improve clinical outcomes after mTBI. The objective of this proposal is to determine whether
the neuropeptides orexins are neural substrates through which stress exerts its effects. Orexins have
primarily been studied for their role in regulating behavioral outcomes after injury. However, whether orexins
act during prior stress exposure to regulate outcomes of subsequent mTBI is poorly studied. Based on our
preliminary data, the central hypothesis of this proposal is that orexin neuron activity underlies the
effects of chronic stress on mild lateral fluid percussion injury (LFPI)-induced anxiety-related
behaviors and these actions of orexins are sex-dependent. Two Aims are designed to test this
hypothesis. Experiments in Specific Aim 1 will test the hypothesis that mice susceptible to CSDS will
exhibit sex-specific alterations in glutamatergic regulation of orexin neurons after LFPI. Experiments
in Specific Aim 2 will test the hypothesis that reducing orexin activity during stress will promote
resilience and reduce the effects of LFPI on anxiety outcomes. The proposed experiments will provide
important new information on orexin cell activity as a mechanism to reduce the impact of stress on mTBI-
induced anxiety. The experiments bring together the expertise of the PIs in stress neurobiology and mTBI.
The tools and paradigms proposed for use are well-validated in our labs.

Terms: <Affect><Affective Disorders><Anxiety><Attention><Brain Trauma><Caring><Cell Body><Cells><Chronic><Chronic stress><Clinical><Cognitive><Common Rat Strains><DREADDs><Data><Differences between sexes><Differs between sexes><Direct Expenditure><Environment><Excessive Daytime Sleepiness><Excessive daytime somnolence><Exhibits><Exposure to><Female><Frequencies><Future><Genetic><Glutamates><Goals><Hcrt protein><Hcrt/ORX><Hcrts/ORXs><Health Care Systems><Healthcare Systems><Individual><Injury><L-Glutamate><Lateral><MTBI><Medical><Memory><Mental Health><Mental Hygiene><Mice><Mice Mammals><Modeling><Mood Disorders><Murine><Mus><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neuroendocrine><Neuroendocrine System><Neurons><Neuropeptides><Neurosecretory Systems><Outcome><Patients><Patients with traumatic brain injury><Predisposition><Psychologic Stress><Psychological Health><Psychological Stress><Public Health><QOL><Quality of life><Rat><Rats Mammals><Rattus><Recovery><Regulation><Risk><Role><Services><Severities><Sex Differences><Sexual differences><Site><Source><Stress><Stress and Coping><Subgroup><Susceptibility><Symptoms><Synapses><Synaptic><TBI Patients><Testing><Therapeutic><Translating><Traumatic Brain Injury><Variant><Variation><Woman><Work><anxiety-related behavior><behavior outcome><behavioral outcome><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><brain injury response><build resilience><build resiliency><coping with stress><cost><debilitating symptom><design><designer receptors exclusively activated by designer drugs><designing><develop resilience><develop resiliency><disability><economic analysis><economic assessment><economic evaluation><enhance resilience><enhance resiliency><experience><experiment><experimental research><experimental study><experiments><flexibility><flexible><fluid percussion injury><glutamatergic><hypocretin><hypocretin/orexin><hypocretins/orexins><improve resilience><improve resiliency><improved><increase resilience><increase resiliency><injured><injuries><male><men><mild TBI><mild brain trauma><mild traumatic brain injury><neural><neurobiological><neuronal><orexin><promote resilience><promote resiliency><psychiatric symptom><resilience><resilience development><resilient><response to brain injury><segregation><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><social defeat><social role><stress-related coping><synapse><tool><traumatic brain damage><traumatic brain injury patients>