Sparse genetically-defined neurons refine the canonical role of periaqueductal gray columnar organization
- University of California, Los Angeles, United States
Abstract
During encounters with external threats, survival depends on the engagement of appropriate defensive reactions to minimize harm. There are major clinical implications for identifying the neural circuitry and activation patterns that produce such defensive reactions, as maladaptive overactivation of these circuits underlies pathological human anxiety and fear responses. A compelling body of work has linked activation of large glutamatergic neuronal populations in the midbrain periaqueductal gray (PAG) to defensive reactions such as freezing, flight and threat-induced analgesia. These pioneering data have firmly established that the overarching functional organization axis of the PAG is along anatomically-defined columnar boundaries. Accordingly, broad activation of the dorsolateral column induces flight, while activation of the lateral or ventrolateral (l and vl) columns induces freezing. However, the PAG contains a diverse arrangement of cell types that vary in neurochemical profile and location. How these cell types contribute to defensive responses remains largely unknown, indicating that targeting sparse, genetically-defined populations can lead to a deeper understanding of how the PAG generates a wide array of behaviors. Though several prior works showed that broad excitation of the lPAG or vlPAG causes freezing, we found in mice that activation of lateral and ventrolateral PAG (l/vlPAG) cholecystokinin-expressing (CCK) cells selectively caused flight to safer regions within an environment. Furthermore, inhibition of l/vlPAG-CCK cells reduced avoidance of a predatory threat without altering other defensive behaviors like freezing. Lastly, l/vlPAG-CCK activity decreased when approaching threat and increased during movement to safer locations. Taken together, these data suggest CCK cells are driving threat avoidance states, which are epochs during which mice increase distance from threat and perform evasive escape. In contrast, activating l/vlPAG cells pan-neuronally promoted freezing and these cells were activated near threat. These data underscore the importance of investigating genetically-identified PAG cells. Using this approach, we found a sparse population of CCK-expressing l/vlPAG cells that have distinct and opposing function and neural activation motifs compared to the broader local ensemble defined solely by columnar anatomical boundaries. Thus, in addition to the anatomical columnar architecture of the PAG, the molecular identity of PAG cells may confer an additional axis of functional organization, revealing unexplored functional heterogeneity.
Data availability
Data is available on Dryad: https://doi.org/10.5068/D12Q32
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Sparse genetically-defined neurons refine the canonical role of periaqueductal gray columnar organizationDryad Digital Repository, doi:10.5068/D12Q32.
Article and author information
Author details
Funding
National Institute of Mental Health (R00 MH106649)
- Avishek Adhikari
Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/23092-3)
- Fernando MCV Reis
Fundação de Amparo à Pesquisa do Estado de São Paulo (2017/08668-1)
- Fernando MCV Reis
National Science Foundation (NSF-GRFP DGE-1650604)
- Peter J Schuette
National Institute of Mental Health (R01 MH119089)
- Avishek Adhikari
National Institute of Mental Health (F31 MH121050-01A1)
- Mimi Q La-Vu
Achievement Rewards for College Scientists Foundation
- Mimi Q La-Vu
Brain and Behavior Research Foundation (22663)
- Avishek Adhikari
Brain and Behavior Research Foundation (27654)
- Fernando MCV Reis
Brain and Behavior Research Foundation (27780)
- Weisheng Wang
UCLA Health System (UCLA Affiliates fellowship)
- Peter J Schuette
Hellman Foundation
- Avishek Adhikari
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures conformed to guidelines established by the National Institutes of Health and have been approved by the University of California, Los Angeles Institutional Animal Care and Use Committee (protocol #2017-011) .
Copyright
© 2022, La-Vu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Sparse genetically-defined neurons refine the canonical role of periaqueductal gray columnar organization
eLife 11:e77115.
https://doi.org/10.7554/eLife.77115
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