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Research Articles, Systems/Circuits

Estrous Cycle Mediates Midbrain Neuron Excitability Altering Social Behavior upon Stress

Mary R. Shanley, Yuka Miura, Christopher A. Guevara, Amanda Onoichenco, Rufina Kore, Emine Ustundag, Rania Darwish, Lauren Renzoni, Ashley Urbaez, Ella Blicker, Alec Seidenberg, Teresa A. Milner and Allyson K. Friedman
Journal of Neuroscience 1 February 2023, 43 (5) 736-748; DOI: https://doi.org/10.1523/JNEUROSCI.1504-22.2022
Mary R. Shanley
1Department of Biological Sciences, Hunter College, New York, New York 10065
2Graduate Center, City University of New York, New York, New York 10016
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Yuka Miura
1Department of Biological Sciences, Hunter College, New York, New York 10065
2Graduate Center, City University of New York, New York, New York 10016
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Christopher A. Guevara
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Amanda Onoichenco
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Rufina Kore
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Emine Ustundag
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Rania Darwish
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Lauren Renzoni
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Ashley Urbaez
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Ella Blicker
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Alec Seidenberg
1Department of Biological Sciences, Hunter College, New York, New York 10065
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Teresa A. Milner
3Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
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Allyson K. Friedman
1Department of Biological Sciences, Hunter College, New York, New York 10065
2Graduate Center, City University of New York, New York, New York 10016
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Abstract

The estrous cycle is a potent modulator of neuron physiology. In rodents, in vivo ventral tegmental area (VTA) dopamine (DA) activity has been shown to fluctuate across the estrous cycle. Although the behavioral effect of fluctuating sex steroids on the reward circuit is well studied in response to drugs of abuse, few studies have focused on the molecular adaptations in the context of stress and motivated social behaviors. We hypothesized that estradiol fluctuations across the estrous cycle acts on the dopaminergic activity of the VTA to alter excitability and stress response. We used whole-cell slice electrophysiology of VTA DA neurons in naturally cycling, adult female C57BL/6J mice to characterize the effects of the estrous cycle and the role of 17β-estradiol on neuronal activity. We show that the estrous phase alters the effect of 17β-estradiol on excitability in the VTA. Behaviorally, the estrous phase during a series of acute variable social stressors modulates subsequent reward-related behaviors. Pharmacological inhibition of estrogen receptors in the VTA before stress during diestrus mimics the stress susceptibility found during estrus, whereas increased potassium channel activity in the VTA before stress reverses stress susceptibility found during estrus as assessed by social interaction behavior. This study identifies one possible potassium channel mechanism underlying the increased DA activity during estrus and reveals estrogen-dependent changes in neuronal function. Our findings demonstrate that the estrous cycle and estrogen signaling changes the physiology of DA neurons resulting in behavioral differences when the reward circuit is challenged with stress.

SIGNIFICANCE STATEMENT The activity of the ventral tegmental area encodes signals of stress and reward. Dopaminergic activity has been found to be regulated by both local synaptic inputs as well as inputs from other brain regions. Here, we provide evidence that cycling sex steroids also play a role in modulating stress sensitivity of dopaminergic reward behavior. Specifically, we reveal a correlation of ionic activity with estrous phase, which influences the behavioral response to stress. These findings shed new light on how estrous cycle may influence dopaminergic activity primarily during times of stress perturbation.

  • dopamine
  • estrogen
  • estrous cycle
  • potassium channel
  • stress
  • ventral tegmental area

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The Journal of Neuroscience: 43 (5)
Journal of Neuroscience
Vol. 43, Issue 5
1 Feb 2023
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Estrous Cycle Mediates Midbrain Neuron Excitability Altering Social Behavior upon Stress
Mary R. Shanley, Yuka Miura, Christopher A. Guevara, Amanda Onoichenco, Rufina Kore, Emine Ustundag, Rania Darwish, Lauren Renzoni, Ashley Urbaez, Ella Blicker, Alec Seidenberg, Teresa A. Milner, Allyson K. Friedman
Journal of Neuroscience 1 February 2023, 43 (5) 736-748; DOI: 10.1523/JNEUROSCI.1504-22.2022

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Estrous Cycle Mediates Midbrain Neuron Excitability Altering Social Behavior upon Stress
Mary R. Shanley, Yuka Miura, Christopher A. Guevara, Amanda Onoichenco, Rufina Kore, Emine Ustundag, Rania Darwish, Lauren Renzoni, Ashley Urbaez, Ella Blicker, Alec Seidenberg, Teresa A. Milner, Allyson K. Friedman
Journal of Neuroscience 1 February 2023, 43 (5) 736-748; DOI: 10.1523/JNEUROSCI.1504-22.2022
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Keywords

  • dopamine
  • estrogen
  • estrous cycle
  • potassium channel
  • stress
  • ventral tegmental area

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