Sparse genetically defined neurons refine the canonical role of periaqueductal gray columnar organization
Mimi Q La-Vu,
Ekayana Sethi,
Sandra Maesta-Pereira,
Peter J Schuette,
Brooke C Tobias,
Fernando MCV Reis,
Weisheng Wang,
Anita Torossian,
Amy Bishop,
Saskia J Leonard,
Lilly Lin,
Catherine M Cahill,
Avishek Adhikari
Affiliations
Mimi Q La-Vu
Neuroscience Interdepartmental Program, University of California, Los Angeles, Los Angeles, United States; Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Ekayana Sethi
Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Sandra Maesta-Pereira
Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Peter J Schuette
Neuroscience Interdepartmental Program, University of California, Los Angeles, Los Angeles, United States; Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Fernando MCV Reis
Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Weisheng Wang
Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Anita Torossian
Neuroscience Interdepartmental Program, University of California, Los Angeles, Los Angeles, United States; Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Amy Bishop
Hatos Center for Neuropharmacology, University of California, Los Angeles, Los Angeles, United States
Saskia J Leonard
Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Lilly Lin
Department of Psychology, University of California, Los Angeles, Los Angeles, United States
Catherine M Cahill
Hatos Center for Neuropharmacology, University of California, Los Angeles, Los Angeles, United States; Department of Psychiatry and Biobehavioral Sciences, Los Angeles, United States; Semel Institute for Neuroscience and Human Behavior, Los Angeles, United States
During threat exposure, survival depends on defensive reactions. Prior works linked large glutamatergic populations in the midbrain periaqueductal gray (PAG) to defensive freezing and flight, and established that the overarching functional organization axis of the PAG is along anatomically-defined columns. 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 diverse cell types that vary in neurochemistry. How these cell types contribute to defense remains unknown, indicating that targeting sparse, genetically-defined populations may reveal how the PAG generates diverse behaviors. Though 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 predator avoidance without altering other defensive behaviors like freezing. Lastly, l/vlPAG-CCK activity decreased when approaching threat and increased during movement to safer locations. These results suggest CCK cells drive threat avoidance states, which are epochs during which mice increase distance from threat and perform evasive escape. Conversely, l/vlPAG pan-neuronal activation promoted freezing, and these cells were activated near threat. Thus, CCK l/vlPAG cells have opposing function and neural activation motifs compared to the broader local ensemble defined solely by columnar boundaries. 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.
