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Principal Investigator: Staci D Bilbo
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $395,625
Funding agency: National Institute on Drug Abuse
The dopaminergic “reward” circuitry undergoes significant developmental plasticity during
adolescence, including the refinement of dopamine D1 and D2 (D1/D2r) receptors within the
nucleus accumbens (NAc). We have recently demonstrated in male rats that microglia – the
primary immune cells of the CNS that also play a role in sculpting developing circuits – engulf and
eliminate D1rs during a precise window of adolescent NAc development in response to receptor
“tagging” by complement protein C3; and that this developmental pruning of D1rs by microglia is
critical for the development of normal reward-driven behavior (social play). Moreover, rats that
receive repeated morphine during adolescence (but not young adulthood) show persistent
changes in microglial function and increased reinstatement to morphine as adults; and, pre-
treatment with a glial modulator during adolescent morphine exposure prevents this increased
reinstatement, implicating a critical role for microglia. Microglia refine synapses based on
changes in neural activity, leading us to hypothesize that, in males (1) microglia sculpt NAc D1rs
during normal adolescence as a consequence of altered dopamine (DA) activity which leads to
receptor tagging by the “eat me” signal C3; and (2) factors that significantly impact DA signaling
within the NAc during adolescence could persistently alter reward processing - including addiction
liability - by changing microglial pruning of D1rs. We will use 3 aims to test the hypothesis that
dopaminergic input to the NAc leads to complement C3 “tagging” of D1r and phagocytosis by
microglia and that disruptions of this normal input (e.g. by social isolation stress) will lead to
dysregulated long-term reward-driven behaviors. Importantly, D1r refinement occurs via
unknown mechanisms in females, independent of microglia-C3 interaction, and the implications
for addiction have not been assessed. To explore putative mechanisms in females we will
additionally assess changes in D2r, and examine additional putative molecular tags/ “eat-me”
signals.
Terms: <12-20 years old><12th grade><21+ years old><Abscission><Acute><Adolescence><Adolescent><Adolescent Youth><Adult><Adult Human><Age><Alcohol Drinking><Alcohol consumption><Behavior><Brain><Brain 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><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Common Rat Strains><Complement><Complement Proteins><Death><Development><Disease><Disorder><Dopamine><Dopamine Receptor><Drug Exposure><Drug abuse><Drug usage><Drugs><Eating><Encephalon><EtOH drinking><EtOH use><Excision><Extirpation><Female><Food Intake><Genetic><Hortega cell><Human><Hydroxytyramine><Immune><Immunes><Inflammatory><Infumorph><Intracellular Communication and Signaling><Kadian><Life><MS Contin><MSir><Mediating><Medication><Membrane><Microglia><Modern Man><Molecular><Morphia><Morphine><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Nucleus Accumbens><Opiates><Opioid><Oramorph><Oramorph SR><Phagocytosis><Pharmaceutical Preparations><Play><Rat><Rats Mammals><Rattus><Receptor Protein><Removal><Reporting><Rewards><Risk><Risk Taking><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Roxanol><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><Self Administered><Self Administration><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><Signal Transduction><Signal Transduction Systems><Signaling><Social Behavior><Social Environment><Social Interaction><Social isolation><Statex SR><Stress><Surgical Removal><Synapses><Synaptic><System><Testing><Tyrosine 3-Monooxygenase><Tyrosine Hydroxylase><Ventral Tegmental Area><Weaning><abuse of drugs><abuses drugs><addiction><addiction liability><addiction potential><addictive disorder><adolescence (12-20)><adult youth><adulthood><ages><alcohol ingestion><alcohol intake><alcohol product use><alcohol use><alcoholic beverage consumption><alcoholic drink intake><biological sex as a modifier><biological signal transduction><brain cell><complementation><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><critical period><developmental><developmental plasticity><drug use><drug/agent><early adolescence><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><experience><gitter cell><high school senior><illicit drug use><juvenile><juvenile human><late life><life span><lifespan><male><membrane structure><mesoglia><microglial cell><microgliocyte><mouse model><murine model><neural><neurobiological><neuronal><non-medical use of prescription opiates><non-medical use of prescription opioids><nonmedical use of prescription opiates><nonmedical use of prescription opioids><opiate abuse><opiate crisis><opiate drug abuse><opioid abuse><opioid analgesic misuse><opioid crisis><opioid drug abuse><opioid epidemic><opioid medication misuse><opioid prescription medication misuse><peer><perivascular glial cell><prescription opiate misuse><prescription opioid misuse><prevent><preventing><receptor><resection><resilience><resilient><response><reward circuitry><reward processing><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex as a biological factor><sex as a biological measure><sex as a biological risk factor><sex as a biological variable><sex as a biological variance><sex as a biologically significant variable><sex as a fundamental variable><social><social climate><social context><social role><sociobehavior><sociobehavioral><socioenvironment><socioenvironmental><synapse><twelfth grade><ventral tegmentum><young adult><young adulthood>