Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry
- Indiana University School of Medicine, United States
- Indiana University, United States
- Indiana University-Purdue University, United States
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and tables.
Article and author information
Author details
Funding
National Institute on Alcohol Abuse and Alcoholism (R01AA027214)
- Brady K Atwood
National Institute on Alcohol Abuse and Alcoholism (F30AA028687)
- Gregory G Grecco
National Institute on Alcohol Abuse and Alcoholism (T32AA07462)
- David L Haggerty
- Kaitlin C Reeves
Indiana University
- Bryan K Yamamoto
- Hui-Chen Lu
- Brady K Atwood
Indiana University Health
- Brady K Atwood
IU Simon Cancer Center
- Andrea R Masters
Stark Neurosciences Research Institute
- Gregory G Grecco
- David L Haggerty
- Brady K Atwood
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The animal experimental procedures in this study were approved by the Institutional Animal Care and Use Committee at the Indiana University School of Medicine (Protocol Number 19017). Guidelines set forth by the National Institutes of Health (Maryland, USA) for ethical treatment and care for experimental animals were followed. Whenever possible, we sought to minimize pain and distress of animals. Euthanasia was only performed on mice that were under a deep plane of anesthesia (achieved using isoflurane) which was assessed via the pedal withdrawal reflex.
Reviewing Editor
- Alicia Izquierdo, University of California, Los Angeles, United States
Publication history
- Received: January 4, 2021
- Accepted: March 11, 2021
- Accepted Manuscript published: March 16, 2021 (version 1)
- Version of Record published: March 24, 2021 (version 2)
Copyright
© 2021, Grecco et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,309
- Page views
-
- 165
- Downloads
-
- 6
- Citations
Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry
eLife 10:e66230.
https://doi.org/10.7554/eLife.66230
Further reading
-
- Neuroscience
Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson's Disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of movement-related STN activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.
-
- Neuroscience
The hippocampus consists of a stereotyped neuronal circuit repeated along the septal-temporal axis. This transverse circuit contains distinct subfields with stereotyped connectivity that support crucial cognitive processes, including episodic and spatial memory. However, comprehensive measurements across the transverse hippocampal circuit in vivo are intractable with existing techniques. Here, we developed an approach for two-photon imaging of the transverse hippocampal plane in awake mice via implanted glass microperiscopes, allowing optical access to the major hippocampal subfields and to the dendritic arbor of pyramidal neurons. Using this approach, we tracked dendritic morphological dynamics on CA1 apical dendrites and characterized spine turnover. We then used calcium imaging to quantify the prevalence of place and speed cells across subfields. Finally, we measured the anatomical distribution of spatial information, finding a non-uniform distribution of spatial selectivity along the DG-to-CA1 axis. This approach extends the existing toolbox for structural and functional measurements of hippocampal circuitry.
