260. Insulin-like Growth Factor 1 in the Brain and Addiction --- the Vulnerable Prefrontal Cortex in Opioid Use Disorder
Year: 2025
Type: conference-abstract
Abstract: Background Opioid use disorder (OUD) is a debilitating psychiatric disease that affects millions of people in the United States. OUD exhibits a high relapse rate despite current treatment efforts. Opioid induces chronic structural and functional adaptations within the brain reward circuitry including prefrontal cortex (PFC), which lead to the life-long propensity for relapse. However, the molecular and neuronal mechanisms underlying opioid abstinence-induced neural plasticity is still unclear, especially in PFC. Aims & Objectives Both clinical and preclinical studies have shown that neurotrophic factor insulin-like growth factor (Igf1) and its receptors (Igf1r) are altered after opioid exposure. Yet, the role of Igf1/Igf1r in opioid relapse is completely unknown. Our preliminary data show that Igf1 level was decreased in the prelimbic cortex (PrL) from mice that underwent heroin abstinence, suggesting Igf1 may play a key role in opioid addiction. In addition, Igf1 influences synaptic function beyond its role in brain development and aging. Although Igf1 and Igf1r levels peak during development and decline with age, the adult brain has abundant Igf1 or Igf1r expression. Studies reveal that Igf1 regulates the synaptic transmission in neurons from young animals. However, the action of Igf1 on neurons in the adult brain is still unclear. Therefore, we aim to test how Igf1 regulates synaptic transmission in adult PFC neurons, and then examine how Igf1/Igf1r system in PFC modulates opioid-induced behavioral, neuronal and transcriptional plasticity. Method To achieve our goals, we first used whole-cell patch-clamp recording method to identify how Igf1 regulates excitatory synaptic transmission in the adult PFC neurons. Then we used a mouse self-administration model combined with Cre-inducible genetic tools, patch clamping and translating ribosome affinity purification (TRAP)-based sequencing (TRAP-seq) methods to elucidate how Igf1 infusions in the PFC affect the heroin-induced changes in relapse behavior and neuronal and transcriptional plasticity in PFC neurons. Results First, we found that Igf1 bath application onto brain slices containing PFC attenuated the amplitude of evoked excitatory postsynaptic current (EPSC) without affecting the frequency and amplitude of miniature EPSC in adult excitatory neurons. Furthermore, this decrease in excitatory neurotransmission was blocked by pharmacological inhibition of Igf1r or conditionally knockdown of Igf1r in PFC pyramidal neurons. These data suggest that Igf1 regulates excitatory synaptic transmission in adult PFC via the interaction between Igf1r-depedent signaling pathway. Then we started to examine the role of Igf1/Igf1r in opioid addiction. By combining pharmacological and Cre-inducible genetic tools, we found that Igf1 infusions into PFC attenuated heroin-seeking behavior. Using ex vivo electrophysiology and TRAP-seq, we found that Igf1 rescued the heroin-induced reduction in excitatory synaptic transmission and partially reversed the changes in gene transcription in PFC neurons. Discussion & Conclusions Together, these studies confirm the crucial role of Igf1 in regulating synaptic transmission in adult PFC and reveal a novel involvement of the Igf1/Igf1r system in opioid addiction. By elucidating the role of Igf1/Igf1r in modulating PFC function under both normal and diseased conditions, our findings pave the way for future research into the potential involvement of Igf1/Igf1r in the neurobiology of brain disorders characterized by PFC dysfunction, extending beyond opioid addiction.
Authors: Z-J Wang, S Yue, Y Wang
Institution: University of Kansas
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,693
OpenAlex ID: W4413313896