Spinal Cord Injury: Is the vagus nerve our neural connectome?
What are the implications of the vagus nerve being able to mediate the time-dependent plasticity of an array of sensorimotor networks?.
- University of California, Los Angeles, United States
The vagus nerve reports on the state of many of the organs in our body, including the heart, the lungs and the gut, and it relays this information to various neural control networks that unconsciously regulate internal organs. It has also been shown that artificial electric stimulation of the vagus nerve helps with recovery in animal models of stroke, tinnitus and spinal cord injury (De Ridder et al., 2014; Hays, 2016). In particular, stimulation of the vagus nerve promotes the recuperation of motor skills and, maybe, autonomic functions (such as breathing), even when the injuries took place years before the intervention. However, we do not fully understand how stimulating this single nerve can lead to such results.
Now, in eLife, Patrick Ganzer, Robert Rennaker at the University of Texas at Dallas and the Texas Biomedical Device Center, and colleagues, report that stimulating the vagus nerve of a rat with spinal injuries helps it to recover mobility of an affected limb – in this case, its front paw (Ganzer et al., 2018). The stimulation has to be applied during a short time window after the rat manages to perform a specific movement with this paw, such as grasping a lever with a specific level of strength.
In this scenario, grasping the lever activates a network of neurons. The connections between these neurons will then be reinforced if the vagus nerve is stimulated within seconds of this task being completed (Figure 1). Classical long-term potentiation experiments show that simultaneous activation leaves ‘tags’ in neurons, which help to strengthen any connections between these neurons (He et al., 2015). Yet, during vagus nerve stimulation, there is no direct synaptic link between the circuits that perform the motor task and the synapses that are excited by the vagus nerve (Alvarez-Dieppa et al., 2016; Hulsey et al., 2017).
Figure 1
The effects of vagus nerve and spinal cord stimulations on neural networks.
The schematic shows the effect of two types of artificial stimulations on a network of neurons (circles), which is activated when a rat with spinal cord injury pulls a lever with its affected limb. Column A shows the effect of vagus nerve stimulation on neural networks that are activated when the rat pulls that lever. In A1, when the rat performs the task, it activates neurons. Some of these are specific to this task (encircled by solid black lines), some of which are not (dashed black line). In A2, the vagus nerve (not represented) is stimulated (pink cloud and lightning bolts). The neurons previously activated are also modulated by this stimulation, and certain new neurons are activated (dashed red line). This combination of activation and modulation strengthens the connections between the neurons that previously fired together, which leads to a transformation of the network. Ultimately, this more robust network supports better physical performance by the rats. Column B shows the effect of spinal cord stimulation on the same neural networks. In B1, spinal cord stimulation is applied (blue cloud and lighting bolt) before the task takes place. When the task is performed (B2), the synapses between the groups of neurons that are involved are further reinforced, a result that is comparable to what is obtained with vagus nerve stimulation. Similar results may also be obtained by performing the stimulation during the task itself. Both vagus nerve and spinal cord stimulations depend on the subject performing a certain task that activates the networks which need reinforcing. However, how these two types of stimulations differ, and how they modulate neural connections, remains unclear.
IMAGE CREDITS: Figure courtesy of V Reggie Edgerton.
Instead, the effects of vagus nerve stimulation could be mediated by a wide range of neuromodulatory mechanisms, which are non-specific to a given synapse. Because the vagus nerve is connected to so many different organs, both in sensorimotor and autonomic ways, it provides the entry point to various neuroendocrine and neurotransmitter systems. Essentially, it seems that the vagus nerve can form a 'connectome' for many functions, which means that interventions via the vagus nerve have the potential to help with the recovery of multiple functions.
Remarkably, similar effects can be obtained by stimulating the spinal cord before the action is performed (Figure 1; Gad et al., 2013). In both cases, there are activity-dependent mechanisms that identify the synapses that have been activated, and the stimulation triggers a series of time-dependent events that reinforce the connections between the relevant neurons.
More broadly, there are at least four fundamental biological concepts relevant to the findings by Ganzer et al. First, the vagus nerve mediates physiological systems (including sensorimotor and autonomic systems) which are extensively and comprehensively integrated together. Second, these systems are dynamic and can reorganize and interact in ways that can dramatically change our behavior. Third, time-dependence has a central role in defining activity-dependent plasticity. Fourth, the networks under the influence of the vagus nerve may be constantly reshaped by neural and biochemical signals via activity-dependent mechanisms.
These four points are consistent with the theory of neural group selection put forward by Gerald Edelman, the American biologist who shared the Nobel Prize in Physiology or Medicine in 1972 (Edelman, 1987). According to this theory, during early and neonatal development neurons form somewhat malleable connections based on genetic (i.e., internal) signals. Thereafter, throughout life, these networks dynamically and continuously create different combinations of functional neuronal connections – called neural networks, or somatically formed groups – by functionally pruning or reinforcing the strength of their connections. This remodeling is determined by the level of activity of the neural connections as they are constantly responding to internal and external stimuli. Finally, which neural groups fire together determines the overall shape of these networks. In terms of behavior, the basic functional unit of the brain is therefore not a neuron, but instead a group of connections among neurons that tend to fire together. Thus, fully understanding the mechanisms at play during vagus nerve stimulation requires thinking at the level of systems, as well as of subcellular components.
References
-
Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case seriesNeuromodulation: Technology at the Neural Interface 17:170–179.https://doi.org/10.1111/ner.12127
-
Sub-threshold spinal cord stimulation facilitates spontaneous motor activity in spinal ratsJournal of NeuroEngineering and Rehabilitation 10:108.https://doi.org/10.1186/1743-0003-10-108
-
Enhancing rehabilitative therapies with vagus nerve stimulationNeurotherapeutics 13:382–394.https://doi.org/10.1007/s13311-015-0417-z
Article and author information
Author details
Publication history
Copyright
© 2018, Edgerton et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,470
- views
-
- 220
- downloads
-
- 8
- 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)
Spinal Cord Injury: Is the vagus nerve our neural connectome?
eLife 7:e35592.
https://doi.org/10.7554/eLife.35592
Further reading
-
- Developmental Biology
- Neuroscience
Williams syndrome (WS; OMIM#194050) is a rare disorder, which is caused by the microdeletion of one copy of 25–27 genes, and WS patients display diverse neuronal deficits. Although remarkable progresses have been achieved, the mechanisms for these distinct deficits are still largely unknown. Here, we have shown that neural progenitor cells (NPCs) in WS forebrain organoids display abnormal proliferation and differentiation capabilities, and synapse formation. Genes with altered expression are related to neuronal development and neurogenesis. Single cell RNA-seq (scRNA-seq) data analysis revealed 13 clusters in healthy control and WS organoids. WS organoids show an aberrant generation of excitatory neurons. Mechanistically, the expression of transthyretin (TTR) are remarkably decreased in WS forebrain organoids. We have found that GTF2IRD1 encoded by one WS associated gene GTF2IRD1 binds to TTR promoter regions and regulates the expression of TTR. In addition, exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids. Gtf2ird1-deficient mice display similar neurodevelopmental deficits as observed in WS organoids. Collectively, our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway.
-
- Computational and Systems Biology
- Neuroscience
Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of gonadotropin-releasing hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, neurokinin B (NKB), and dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases Slc17a6 (Vglut2) mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current that contributes to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of canonical transient receptor potential (TPRC) 5 and G protein-coupled K+ (GIRK) channels. When Trpc5 channels in Kiss1ARH neurons were deleted using CRISPR/SaCas9, the slow excitatory postsynaptic potential was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of Kiss1ARH neurons, suggesting that E2 modifies ionic conductances in these neurons, enabling the transition from high-frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARH neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.
