Dataset Information

Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

ABSTRACT: Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. Methadone accumulated in the placenta and fetal brain, but methadone levels in offspring dropped rapidly at birth which was associated with symptoms and behaviors consistent with neonatal opioid withdrawal. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition. Furthermore, these behavioral alterations were associated with reduced neuronal density in the motor cortex and a disruption in motor neuron intrinsic properties and local circuit connectivity. The present study adds to the limited body of work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring physical and neurobehavioral development.

SUBMITTER: Grecco GG

PROVIDER: S-EPMC7993998 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

Grecco Gregory G GG Mork Briana E BE Huang Jui-Yen JY Metzger Corinne E CE Haggerty David L DL Reeves Kaitlin C KC Gao Yong Y Hoffman Hunter H Katner Simon N SN Masters Andrea R AR Morris Cameron W CW Newell Erin A EA Engleman Eric A EA Baucum Anthony J AJ Kim Jiuen J Yamamoto Bryan K BK Allen Matthew R MR Wu Yu-Chien YC Lu Hui-Chen HC Sheets Patrick L PL Atwood Brady K BK

eLife 20210316

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physic ...[more]

PMID: 33724184

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Project description:As problematic opioid use has reached epidemic levels over the past 2 decades, the annual prevalence of opioid use disorder (OUD) in pregnant women has also increased 333%. Yet, how opioids affect the developing brain of offspring from mothers experiencing OUD remains understudied and not fully understood. Animal models of prenatal opioid exposure have discovered many deficits in the offspring of prenatal opioid exposed mothers, such as delays in the development of sensorimotor function and long-term locomotive hyperactivity. In attempt to further understand these deficits and link them with protein changes driven by prenatal opioid exposure, we used a mouse model of prenatal methadone exposure (PME) and preformed an unbiased multi-omic analysis across many sensoriomotor brain regions known to interact with opioid exposure. The effects of PME exposure on the primary motor cortex (M1), primary somatosensory cortex (S1), the dorsomedial striatum (DMS), and dorsolateral striatum (DLS) were assessed using quantitative proteomics and phosphoproteomics. PME drove many changes in protein and phosphopeptide abundance across all brain regions sampled. Gene and gene ontology enrichments were used to assess how protein and phosphopeptide changes in each brain region were altered. Our findings showed that M1 was uniquely affected by PME in comparison to other brain regions. PME uniquely drove changes in M1 glutamatergic synapses and synaptic function. Immunohistochemical analysis also identified anatomical differences in M1 for upregulating the density of glutamatergic and downregulating the density of GABAergic synapses due to PME. Lastly, comparisons between M1 and non-M1 multi-omics revealed conserved brain wide changes in phosphopeptides associated with synaptic activity and assembly, but only specific protein changes in synapse activity and assembly were represented in M1. Together, our studies show that lasting changes in synaptic function driven by PME are largely represented by protein and anatomical changes in M1, which may serve as a starting point for future experimental and translational interventions that aim to reverse the adverse effects of PME on offspring.

Project description:Upper cervical spinal cord injuries (SCI) disrupt descending inputs to phrenic motor neurons (PhMNs), impairing respiratory function. Unilateral spinal hemisection at C2 (C2SH) results in loss of ipsilateral rhythmic diaphragm muscle (DIAm) EMG activity associated with lower force behaviors accomplished by recruitment of smaller PhMNs in rats. Activity during higher force, non-ventilatory behaviors that recruit larger PhMNs is minimally impaired following C2SH. We previously showed neuroplasticity in glutamatergic receptor expression in PhMN post-C2SH with changes in NMDA receptor expression reflecting functional recovery over time. We hypothesize that C2SH-induced changes in glutamatergic receptor (AMPA and NMDA) mRNA expression in PhMNs vary with motor neuron size, with more pronounced changes in smaller PhMNs. Retrogradely-labelled PhMNs were classified in tertiles according to somal surface area and mRNA expression was measured using single-cell, multiplex fluorescence in situ hybridization. Ipsilateral to C2SH, a pronounced reduction in NMDA mRNA expression in PhMNs was evident at 3 days post-injury with similar impact on PhMNs in the lower size tertile (~68% reduction) and upper tertile (~60%); by 21 days, there was near complete restoration of NMDA receptor mRNA expression across all PhMNs. There were no changes in NMDA mRNA expression contralateral to C2SH. There were no changes in AMPA mRNA expression at PhMNs on either side of the spinal cord or at any time-point post-C2SH. In summary, following C2SH there is ipsilateral reduction in PhMN NMDA mRNA expression at 3 days that is not limited to smaller PhMN recruited in the generation of lower force ventilatory behaviors. The recovery of NMDA mRNA expression by 21 days post-C2SH is consistent with evidence of spontaneous recovery of ipsilateral DIAm activity at this timepoint. These findings suggest a possible role for NMDA receptor mediated glutamatergic signaling in mechanisms supporting postsynaptic neuroplasticity at the PhMN pool and recovery of DIAm activity after cervical SCI.

Dataset Information

Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

Publications

Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

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