Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula
The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-11-01
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| Series: | Neurobiology of Stress |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352289520300576 |
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| author | Sarah C. Simmons Ryan D. Shepard Shawn Gouty Ludovic D. Langlois William J. Flerlage Brian M. Cox Fereshteh S. Nugent |
| author_facet | Sarah C. Simmons Ryan D. Shepard Shawn Gouty Ludovic D. Langlois William J. Flerlage Brian M. Cox Fereshteh S. Nugent |
| author_sort | Sarah C. Simmons |
| collection | DOAJ |
| description | The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn/KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABAAR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABAAR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD. |
| first_indexed | 2024-12-17T15:59:54Z |
| format | Article |
| id | doaj.art-88499a55428542f7ac83e5501b9e346f |
| institution | Directory Open Access Journal |
| issn | 2352-2895 |
| language | English |
| last_indexed | 2024-12-17T15:59:54Z |
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| series | Neurobiology of Stress |
| spelling | doaj.art-88499a55428542f7ac83e5501b9e346f2022-12-21T21:42:08ZengElsevierNeurobiology of Stress2352-28952020-11-0113100267Early life stress dysregulates kappa opioid receptor signaling within the lateral habenulaSarah C. Simmons0Ryan D. Shepard1Shawn Gouty2Ludovic D. Langlois3William J. Flerlage4Brian M. Cox5Fereshteh S. Nugent6Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology and Molecular Therapeutics, Bethesda, MD, 20814, USAUniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology and Molecular Therapeutics, Bethesda, MD, 20814, USAUniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology and Molecular Therapeutics, Bethesda, MD, 20814, USAUniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology and Molecular Therapeutics, Bethesda, MD, 20814, USAUniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology and Molecular Therapeutics, Bethesda, MD, 20814, USAUniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology and Molecular Therapeutics, Bethesda, MD, 20814, USACorresponding author.; Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology and Molecular Therapeutics, Bethesda, MD, 20814, USAThe lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn/KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABAAR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABAAR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.http://www.sciencedirect.com/science/article/pii/S2352289520300576Lateral habenulaLHbKappa opioid receptorKORDynorphinEarly life stress |
| spellingShingle | Sarah C. Simmons Ryan D. Shepard Shawn Gouty Ludovic D. Langlois William J. Flerlage Brian M. Cox Fereshteh S. Nugent Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula Neurobiology of Stress Lateral habenula LHb Kappa opioid receptor KOR Dynorphin Early life stress |
| title | Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula |
| title_full | Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula |
| title_fullStr | Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula |
| title_full_unstemmed | Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula |
| title_short | Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula |
| title_sort | early life stress dysregulates kappa opioid receptor signaling within the lateral habenula |
| topic | Lateral habenula LHb Kappa opioid receptor KOR Dynorphin Early life stress |
| url | http://www.sciencedirect.com/science/article/pii/S2352289520300576 |
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