Document text
Principal Investigator: SEEMA BHATNAGAR
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $220,000
Funding agency: National Institute of Mental Health
SUMMARY
Habituation is the progressive decline in responses to repeated exposure to the same, homotypic stressor. It
is highly conserved and observed in species ranging from humans to rodents. Habituation is adaptive because
it allows animals to filter out irrelevant stimuli and focus selectively on important stimuli, thereby facilitating
optimal responding in a complex and changing environment. The ability to habituate to repeated cognitive
stressors is disrupted in several psychiatric disorders including post-traumatic stress disorder post-traumatic
stress disorder (PTSD). In previous work, we identified sex differences in habituation in adult rats. While male
rats habituate to 5 days of 30min restraint/day, as indicated by reductions in hypothalamic-pituitary-adrenal
(HPA) activity and behavior on the 5th compared to the 1st day, female rats do not habituate to 5 days of
restraint. We showed that elevations in orexinergic expression and activity in adult females compared to adult
males contribute to this disrupted habituation in females. The elevations in orexin mRNA in adult females are
dependent on glucocorticoid receptor (GR) binding at the prepro-orexin promoter. However, little is known
about orexin functions in adolescence. In preliminary data, we show that adolescent male and female rats
do not habituate to 5 days of repeated restraint and that male adolescents exhibit higher basal circulating
glucocorticoids than adult males. They also exhibit higher orexin expression that do adult males. Together,
the findings in adult and adolescent rats suggest that higher orexin expression and activity in adolescent
males and females may be promoted by elevated glucocorticoids and lead to disrupted habituation. The
posterior paraventricular thalamus (pPVT) is an important site mediating habituation, is densely innervated
by orexins and orexins act in the pPVT to regulate responses to chronic stress such as facilitation. These
data lead to the central hypothesis that elevations in orexin expression and activity in both adolescent
males and females are promoted by glucocorticoids and that elevations in orexin neurotransmission
in the pPVT disrupt habituation in adolescence. Specific Aim 1 will test the hypothesis that increased GR
binding at the prepro-orexin promoter in adolescent males and females elevates orexin expression. Specific
Aim 2 will test the hypothesis that elevations in orexin activity in the pPVT of adolescent male and female
rats disrupt neuroendocrine and behavioral habituation. Experiments will use DREADDs or virally-mediated
knockdown of orexin receptors to inhibit orexin activity in the pPVT. We expect that inhibition of orexin activity
in the pPVT will promote habituation in both male and female adolescent rats. Together, the experiments will
provide the first information on orexin activity and functions during adolescence and provide
mechanistic insights as to why habituation is not observed in adolescence.
Terms: <12-20 years old><21+ years old><ATP-Dependent RNA Helicase p54 Gene><Adolescence><Adolescent><Adolescent Youth><Adrenal Glands><Adrenals><Adult><Adult Human><Adult females><Adult women><Animals><Behavior><Causality><Cell Body><Cell Density><Cells><Chronic stress><Cognitive><Common Rat Strains><Complex><Corticosterone><DDX6 gene><DEAD/H Box 6 Gene><DREADDs><Data><Differences between sexes><Differs between sexes><Environment><Etiology><Exhibits><Exposure to><Female><Female Adolescents><Females in adulthood><Genetic><Glucocorticoid Receptor><Glucocorticoids><HLR2><HTS1><Hcrt protein><Hcrt/ORX><Hcrts/ORXs><Helicase, RNA, Nuclear 2 Gene><Human><Hypophysis><Hypophysis Cerebri><Hypothalamic structure><Hypothalamus><Lead><Male Adolescents><Mediating><Mental disorders><Mental health disorders><Messenger RNA><Modeling><Modern Man><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neuroendocrine><Neuroendocrine System><Neuronal Transmission><Neurons><Neurosecretory Systems><P126><P70><P82><PTSD><Pb element><Pituitary><Pituitary Gland><Pituitary Nervous System><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Prevention><Psychiatric Disease><Psychiatric Disorder><Rat><Rats Mammals><Rattus><Receptor Protein><Regulation><Rodent><Rodentia><Rodents Mammals><Role><ST5><ST5 gene><Sex Differences><Sexual differences><Short interfering RNA><Site><Small Interfering RNA><Stimulus><Stress><Suppression of Tumorigenicity 5><Technology><Testing><Thalamic structure><Thalamus><Viral><Women in adulthood><Work><acute stress><adolescence (12-20)><adolescent boy><adolescent girl><adulthood><age associated difference><age based difference><age dependent difference><age dependent variation><age difference><age related difference><age related variation><age specific difference><axon signaling><axon-glial signaling><axonal signaling><base><bases><behavioral habituation><causation><designer receptors exclusively activated by designer drugs><differ by age><difference across age><difference in age><disease causation><experiment><experimental research><experimental study><experiments><glia signaling><glial signaling><habituation><heavy metal Pb><heavy metal lead><hypocretin><hypocretin/orexin><hypocretins/orexins><hypothalamic><improved><insight><juvenile><juvenile human><knock-down><knockdown><mRNA><male><mental illness><nerve signaling><neural signaling><neurobiological><neuronal><neuronal signaling><neurotransmission><orexin><orexin 1 receptor><p54><post-trauma stress disorder><posttrauma stress disorder><prepro-hypocretin><prepro-orexin><promoter><promotor><psychiatric illness><psychological disorder><receptor><receptor binding><receptor bound><response><restraint><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><siRNA><social role><stressor><suprarenal gland><thalamic><traumatic neurosis><variation by age>