Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity
- Baylor College of Medicine, United States
- Texas Children's Hospital, United States
Abstract
Clinical trials are currently underway to assess the efficacy of forniceal deep brain stimulation (DBS) for improvement of memory in Alzheimer's patients, and forniceal DBS has been shown to improve learning and memory in a mouse model of Rett syndrome (RTT), an intellectual disability disorder caused by loss-of-function mutations in MECP2. The mechanism of DBS benefits has been elusive, however, so we assessed changes in gene expression, splice isoforms, DNA methylation, and proteome following acute forniceal DBS in wild-type mice and mice lacking Mecp2. We found that DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis and normalized expression of ~25% of the genes altered in Mecp2-null mice. Moreover, DBS induced expression of 17-24% of the genes downregulated in other intellectual disability mouse models and in post-mortem human brain tissue from patients with Major Depressive Disorder, suggesting forniceal DBS could benefit individuals with a variety of neuropsychiatric disorders.
Data availability
-
RNA-Sequencing data - acute DBSPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE107357).
-
Whole-Genome bisulfite sequencingPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE107383).
-
RNA-Sequencing data - chronic DBSPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE111703).
-
Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE24095).
-
Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primatesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE39697).
-
Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selectionPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE13539).
-
Neuronal activity modifies the DNA methylation landscape in the adult brain.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE30493).
-
DNA methylation changes in plasticity genes accompany the formation and maintenance of memoryPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE74971).
-
Widespread transcription at neuronal activity-regulated enhancersPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE21161).
-
Nuclear RNA-seq of single neurons reveals molecular signatures of activation.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE77067).
-
Activity-dependent regulation of inhibitory synapse development by Npas4.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE11261).
-
Identification of activity-dependent gene expression profiles reveals specific subsets of genes induced by different routes of Ca(2+) entry in cultured rat cortical neurons.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE6254).
-
Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE61887).
-
Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE43261).
-
Transcriptome profile reveals AMPA receptor dysfunction in the hippocampus of the Rsk2-knockout mice, an animal model of Coffin-Lowry syndrome.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE22137).
-
Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mousePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE80312).
Article and author information
Author details
Funding
National Institutes of Health (5R01NS057819)
- Huda Y Zoghbi
Howard Hughes Medical Institute (HHMI Investigator)
- Huda Y Zoghbi
Robert and Janice McNair Foundation (Student Scholar)
- Amy E Pohodich
Baylor Research Advocates for Student Scientists (Student Scholar)
- Amy E Pohodich
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All research and animal care procedures were approved by the Baylor College of Medicine Institutional Animal Care and Use Committee (approved protocols: AN-1013 and AN-5585). All surgery was performed under isofluorane anesthesia, and every effort was made to minimize pain and suffering.
Copyright
© 2018, Pohodich 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
-
- 3,440
- views
-
- 606
- downloads
-
- 47
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity
eLife 7:e34031.
https://doi.org/10.7554/eLife.34031
Further reading
-
- Neuroscience
Studying infant minds with movies is a promising way to increase engagement relative to traditional tasks. However, the spatial specificity and functional significance of movie-evoked activity in infants remains unclear. Here, we investigated what movies can reveal about the organization of the infant visual system. We collected fMRI data from 15 awake infants and toddlers aged 5–23 months who attentively watched a movie. The activity evoked by the movie reflected the functional profile of visual areas. Namely, homotopic areas from the two hemispheres responded similarly to the movie, whereas distinct areas responded dissimilarly, especially across dorsal and ventral visual cortex. Moreover, visual maps that typically require time-intensive and complicated retinotopic mapping could be predicted, albeit imprecisely, from movie-evoked activity in both data-driven analyses (i.e. independent component analysis) at the individual level and by using functional alignment into a common low-dimensional embedding to generalize across participants. These results suggest that the infant visual system is already structured to process dynamic, naturalistic information and that fine-grained cortical organization can be discovered from movie data.
-
- Neuroscience
Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.
