Journal
NEUROPSYCHOPHARMACOLOGY
Volume 46, Issue 9, Pages 1658-1668Publisher
SPRINGERNATURE
DOI: 10.1038/s41386-021-01006-5
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Funding
- US National Institute of Health [R01MH120133]
- Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine
- Yerkes National Primate Research Center (YNPRC)
- Department of Pediatrics at USC Keck School of Medicine
- Division of Research on Children, Youth & Families at Children's Hospital Los Angeles
- Developmental Neuroscience and Neurogenetics Program at The Saban Research Institute
- Emory University Women's Club Memorial Fellowship Award
- Office of Research Infrastructure Programs [ODP51OD11132]
- [P50MH100023]
- [R01MH072908]
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Fear generalization and deficits in extinction learning are major aspects of PTSD. Studies suggest that the zona incerta and thalamic reuniens may play a role in modulating fear processes. Optogenetic stimulation of GABAergic ZI -> RE cell terminals can reduce fear generalization and enhance extinction recall.
Fear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI -> RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI -> RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI -> RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI -> RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI -> RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.
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