The Consequences of Early Life Stress on Midbrain Reward Circuitry
Abstract
Adverse early life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in relevant brain systems including the mesolimbic dopamine (DA) pathway and extrahypothalamic corticotropin releasing factor (CRF) system. We first investigated whether a severe early life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through anepigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. We next demonstrate for the first time that extrahypothalamic CRF neurotransmission exists in the lateral habenula (LHb), an epithalamic brain region involved in stress evasion. CRF-CRF receptor 1(CRFR1) signaling increases the intrinsic excitability of LHb neurons through modulation of small- and large-conductance SK- and BK-type K+ channels. In addition, CRF reduces GABAergic synaptic transmission onto LHb neuron promoting LHb hyperactivity. MD increases LHb neuronal excitability and blunts the excitatory actions of CRF on LHb neurons due to down-regulation of SK2 channel expression. Increasing the function of SK channels by positive allosteric modulation prevents CRF excitatory action on LHb intrinsic excitability and reverses the effects of MD on LHb intrinsic excitability. Additionally, we investigated the function of histone acetylation and HDAC2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 31, 2017
- Accession Number
- AD1128227
Entities
People
- Michael E Authement
Organizations
- Uniformed Services University of the Health Sciences