Gap Junctions in the Ventral Hippocampal-Medial Prefrontal Pathway Are Involved in Anxiety Regulation
Open accessAbstract
Anxiety disorders are highly prevalent but little is known about their underlying mechanisms. Gap junctions exist in brain regions important for anxiety regulation, such as the ventral hippocampus (vHIP) and mPFC, but their functions in these areas have not been investigated. Using pharmacological blockade of neuronal gap junctions combined with electrophysiological recordings, we found that gap junctions play a role in theta rhythm in the vHIP and mPFC of adult mice. Bilateral infusion of neuronal gap junction blockers into the vHIP decreased anxiety-like behavior on the elevated plus maze and open field. Similar anxiolytic effects were observed with unilateral infusion of these drugs into the vHIP combined with contralateral infusion into the mPFC. No change in anxious behavior was observed with gap junction blockade in the unilateral vHIP alone or in the bilateral dorsal HIP. Since physical exercise is known to reduce anxiety, we examined the effects of long-term running on the expression of the neuronal gap junction protein connexin-36 among inhibitory interneurons and found a reduction in the vHIP. Despite this change, we observed no alteration in theta frequency or power in long-term runners. Collectively, these findings suggest that neuronal gap junctions in the vHIP–mPFC pathway are important for theta rhythm and anxiety regulation under sedentary conditions but that additional mechanisms are likely involved in running-induced reduction in anxiety.
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Disconnection of LFP coherence by unilateral administration of gap junction blockers in contralateral vHPC and mPFC reduces theta activity in both regions, as well as innate anxiety-like behaviors in ethological tasks.
“disconnection of LFP coherence by unilateral administration of gap junction blockers in contralateral vHPC and mPFC reduces theta activity in both regions, as well as innate anxiety-like behaviors in ethological tasks135.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [135]
Disruption of the vHPC theta rhythm using pharmacological blockade of gap junctions reduces anxiety-like behaviors in the elevated plus maze and open field test.
“Disruption of the vHPC theta rhythm using pharmacological blockade of gap junctions reduces anxiety-like behaviors in the EPM and OFT”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [135]
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Resolving the neural circuits of anxiety
Calhoon, G. G., & Tye, K. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4101 · Cited by 766 · see citing works
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“For example, the HPC and mPFC exhibit increased synchrony in anxiogenic environments (Adhikari et al., 2010; Schoenfeld et al., 2014; Abdallah et al., 2015).”
BackgroundDistributed circuits underlying anxiety
Adhikari, A. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00112 · Cited by 204 · see citing works
Opendak, M., Offit, L., Monari, P., Schoenfeld, T. J., Sonti, A. N., Cameron, H. A., & Gould, E. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4435-15.2016 · Cited by 61 · see citing works
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- Authors
- Schoenfeld, T. J., Kloth, A. D., Hsueh, B., Runkle, M. B., Kane, G. A., Wang, S. S.-H., & Gould, E.
- Affiliations
- Princeton University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-11-19
- Volume
- 34
- Issue
- 47
- Pages
- 15679-15688
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4236399
- OpenAlex
- W2083218589
- Cited by
- 49
- References
- 55
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 1
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R21MH091567, MH098651, MH091567, F31MH098651)
- National Institute of General Medical Sciences (T32GM007388)
- National Institute of Neurological Disorders and Stroke (NS045193, R01NS045193)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- gap junctions, ventral hippocampus, medial prefrontal cortex, anxiety regulation, anxiety-like behavior, theta oscillations, connexin 36, gap junction blockers, physical activity, running, inhibitory interneurons, elevated plus maze
- MeSH terms
- Gap Junction delta-2 Protein, Animals, Anxiety, Behavior, Animal, Electroencephalography, Hippocampus, Male, Mice, Inbred C57BL, Neural Pathways, Running, Theta Rhythm, Prefrontal Cortex, Gap Junctions, Connexins, Mice
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