Peripheral nerve injury-induced alterations in VTA neuron firing properties

doi:10.1186/s13041-019-0511-y

. 2019 Nov 4;12(1):89.

doi: 10.1186/s13041-019-0511-y.

Peripheral nerve injury-induced alterations in VTA neuron firing properties

Shuo Huang^{1

2}, Stephanie L Borgland¹, Gerald W Zamponi^{3

4}

Affiliations

¹ Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Calgary, AB, Canada.
² Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Calgary, AB, Canada. zamponi@ucalgary.ca.
⁴ Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. zamponi@ucalgary.ca.

PMID: 31685030
PMCID: PMC6827252
DOI: 10.1186/s13041-019-0511-y

Peripheral nerve injury-induced alterations in VTA neuron firing properties

Shuo Huang et al. Mol Brain. 2019.

. 2019 Nov 4;12(1):89.

doi: 10.1186/s13041-019-0511-y.

Authors

Shuo Huang^{1

2}, Stephanie L Borgland¹, Gerald W Zamponi^{3

4}

Affiliations

¹ Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Calgary, AB, Canada.
² Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Calgary, AB, Canada. zamponi@ucalgary.ca.
⁴ Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. zamponi@ucalgary.ca.

PMID: 31685030
PMCID: PMC6827252
DOI: 10.1186/s13041-019-0511-y

Abstract

The ventral tegmental area (VTA) is one of the main brain regions harboring dopaminergic (DA) neurons, and plays important roles in reinforcement and motivation. Recent studies have indicated that DA neurons not only respond to rewarding stimuli, but also to noxious stimuli. Furthermore, VTA DA neurons undergo plasticity during chronic pain. Lateral and medial VTA neurons project to different brain areas, and have been characterized via their distinct electrophysiological properties. In this study, we characterized electrophysiological properties of lateral and medial VTA DA neurons using DAT-cre reporter mice, and examined their plasticity during neuropathic pain states. We observed various DA subpopulations in both the lateral and medial VTA, as defined by action potential firing patterns, independently of synaptic inputs. Our results demonstrated that lateral and medial VTA DA neurons undergo differential plasticity after peripheral nerve injury that leads to neuropathic pain. However, these changes only reside in specific DA subpopulations. This study suggests that lateral and medial VTA DA neurons are differentially affected during neuropathic pain conditions, and emphasizes the importance of subpopulation specificity when _targeting VTA DA neurons for treatment of neuropathic pain.

Keywords: Brain circuits; Dopamine; Pain; Prefrontal cortex; Ventral tegmental area.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Electrophysiological characterization of lateral and medial VTA DA neurons. a Spontaneous firing frequencies in the lateral and medial VTA. **b-f** Biophysical properties including membrane potential (b), leak current (c), capacitance (d), input resistance (e), and action potential threshold (f) of medial and lateral VTA DA neurons. h Current clamp stimulation protocols for measuring the F-I relation (upper) and Ih (lower). *Scale bar, 50 mV, 100 ms*. i Representative current clamp traces showing AP firing patterns at 100 pA from lateral (upper) and medial (lower) VTA DA neurons. *Scale bar, 20 mV, 100 ms*. j Representative current clamp traces showing activation of Ih in lateral (upper) and medial (lower) VTA DA neurons. The red dashed lines indicate where peak response and steady-state were measured for calculation of the voltage sag. *Scale bar, 10 mV, 100 ms*. k Average F-I relation curves for medial and lateral VTA DA neurons. l F-I slope for medial and lateral VTA DA neurons. m Ih amplitude recorded from medial and lateral VTA DA neurons. Statistics, Mann-Whitney test. **, p < 0.01; ****, p < 0.0001. Numbers in parentheses reflect numbers of cells and animals, and are presented as (N = cells/N = animals)

**Fig. 2**
Electrophysiological properties of lateral and medial VTA DA neurons isolated from in SHAM versus SNI groups. **a-f** Compariaon of spontaneous firing frequency (a), F-I slope (b), input resistance (c), first spike latency at 100 pA (d), AP threshold (e), and Ih amplitude (f) between SHAM and SNI groups in lateral VTA DA neurons. **g-l** Comparison of spontaneous firing frequency (g), F-I slope (h), input resistance (i), first spike latency at 100 pA (j), AP threshold (k), and Ih amplitufe (l) between SHAM and SNI groups in medial VTA DA neurons. Statistics, Mann-Whitney test. *, p < 0.05. Numbers in parentheses reflect numbers of cells and animals, and are presented as (N = cells/N = animals)

**Fig. 3**
Electrophysiological characterization of three subpopulations of lateral VTA DA neurons. a Examples of AP firing patterns evoked by a 100 pA current step in Type 1–3 DA neurons. b Ih activation evoked by a − 150 pA current step in Type 1–3 DA neurons. c Quantification of F-I slope in Type 1–3 DA neurons. d Quantification of Ih amplitude in Type 1–3 DA neurons. e) Proportion of Type 1–3 neuronal subtypes in the lateral VTA DA neurons. *Scale bar, 20 mV, 100 ms*. Statistics, One-way ANOVA and Bonferroni post-hoc test. *, p < 0.05; **, p < 0.01; ***, p < 0.001. Numbers in parentheses reflect numbers of cells and animals, and are presented as (N = cells/N = animals). Characterization was done with SHAM operated mice

**Fig. 4**
Electrophysiological properties of Type 1 and 3 lateral VTA DA neuron subpopulations in SHAM and SNI groups. **a-f** (a) Representative traces of spontaneous firing of Type 1 neurons in SHAM (left) and SNI (right) operated mice. *Scale bar, 20 mV, 1 s*. Comparison of spontaneous firing frequency (b), F-I slope (c), input resistance (d), first spike latency at 100 pA (e), AP threshold (f), and Ih amplitude (g) between SHAM and SNI groups in Type 1 lateral VTA DA neurons. **h-m** Comparison of spontaneous firing frequency (h), F-I slope (i), input resistance (j), first spike latency at 100 pA (k), AP threshold (l), and Ih amplitude (m) between SHAM and SNI groups in Type 3 lateral VTA DA neurons. Statistics, Mann-Whitney test. *, p < 0.05. Numbers in parentheses reflect numbers of cells and animals, and are presented as (N = cells/N = animals)

**Fig. 5**
Electrophysiological properties of DA neuronal subpopulations in the medial VTA in SHAM and SNI groups. a Examples of AP firing patterns evoked by a 200 pA current step of different DA neuronal subpopulations in the medial VTA. b Electrophysiological properties of *Delayed-nonaccommodating firing type* DA neurons in SHAM versus SNI groups. c Electrophysiological properties of *Irregular firing type* DA neurons in SHAM versus SNI groups. d Representative current clamp traces showing the number of APs during a 150 pA current step in SHAM (upper) and SNI (lower) groups. *Scale bar, 20 mV, 100 ms*. Statistics, Mann-Whitney test. *, p < 0.05. Numbers in parentheses reflect numbers of cells and animals, and are presented as (N = cells/N = animals)

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References

1. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68(5):815–834. doi: 10.1016/j.neuron.2010.11.022. - DOI - PMC - PubMed
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1. Lammel S, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491(7423):212–217. doi: 10.1038/nature11527. - DOI - PMC - PubMed
1. Gunaydin LA, et al. Natural neural projection dynamics underlying social behavior. Cell. 2014;157(7):1535–1551. doi: 10.1016/j.cell.2014.05.017. - DOI - PMC - PubMed
1. Zweifel LS, et al. Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci. 2011;14(5):620. doi: 10.1038/nn.2808. - DOI - PMC - PubMed

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[1] Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68(5):815–834. doi: 10.1016/j.neuron.2010.11.022. - DOI - PMC - PubMed

[2] Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68(5):815–834. doi: 10.1016/j.neuron.2010.11.022. - DOI - PMC - PubMed

[3] Budygin EA, et al. Aversive stimulus differentially triggers subsecond dopamine release in reward regions. Neuroscience. 2012;201:331–337. doi: 10.1016/j.neuroscience.2011.10.056. - DOI - PMC - PubMed

[4] Budygin EA, et al. Aversive stimulus differentially triggers subsecond dopamine release in reward regions. Neuroscience. 2012;201:331–337. doi: 10.1016/j.neuroscience.2011.10.056. - DOI - PMC - PubMed

[5] Lammel S, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491(7423):212–217. doi: 10.1038/nature11527. - DOI - PMC - PubMed

[6] Lammel S, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491(7423):212–217. doi: 10.1038/nature11527. - DOI - PMC - PubMed

[7] Gunaydin LA, et al. Natural neural projection dynamics underlying social behavior. Cell. 2014;157(7):1535–1551. doi: 10.1016/j.cell.2014.05.017. - DOI - PMC - PubMed

[8] Gunaydin LA, et al. Natural neural projection dynamics underlying social behavior. Cell. 2014;157(7):1535–1551. doi: 10.1016/j.cell.2014.05.017. - DOI - PMC - PubMed

[9] Zweifel LS, et al. Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci. 2011;14(5):620. doi: 10.1038/nn.2808. - DOI - PMC - PubMed

[10] Zweifel LS, et al. Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci. 2011;14(5):620. doi: 10.1038/nn.2808. - DOI - PMC - PubMed

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Peripheral nerve injury-induced alterations in VTA neuron firing properties

Affiliations

Peripheral nerve injury-induced alterations in VTA neuron firing properties

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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