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Abstract

This doctoral thesis is devoted to studying the neural basis of innate defensive behaviors. Defensive behaviors are a group of evolved responses to threats and comprise risk assessment, defensive attack, freezing, and escape. Importantly, these behaviors are often dysregulated in neuropsychiatric disorders, and most prominently in anxiety disorders, the most prevalent mental disorder of our times. How does the brain encode and regulate defensive behaviors? The neural circuits responsible for these behaviors are evolutionarily conserved and comprise a collection of structures in the forebrain, including the amygdala, hypothalamus, and cerebral cortex. Remarkably, these circuits ultimately converge in the midbrain, in an area that surrounds the aqueduct, the periaqueductal gray (PAG). How exactly specific PAG cell types and circuits initiate, regulate, and execute defensive behaviors is largely unknown. This is exactly the question I address here.

In this thesis, I used a multilevel analysis approach to uncover a critical PAG node for regulation of defensive behaviors. I found that a specific subset of neurons within the dorsal PAG (dPAG), which express the calcium-binding protein Calbindin (Calb1), is essential for promoting and regulating escape responses. These neurons localize to a well-defined column within the dPAG, release glutamate as a main fast neurotransmitter, are highly excitable in nature, and can sustain high rates of spiking with little adaptation, resembling fast-spiking interneurons in the hippocampus and cerebral cortex. In vivo calcium imaging experiments using miniaturized micro-endoscopes revealed that the activity of dPAG Calb1 neurons correlates well with escape. Remarkably, I found that that high- but not low-frequency spiking of dPAG Calb1 is necessary and sufficient to promote escape. Chemogenetic manipulations that specifically and robustly decreased dPAG Calb1 spiking dramatically reduced escape probability in response to presentation of threatening visual stimuli, whereas direct high-frequency optogenetic activation of these cells triggered escape in the absence of visual stimuli. At the circuit level, dPAG Calb1 cells promote and regulate escape by recruiting a local excitatory network within the dPAG, which in turn directly promotes escape by activating the midbrain locomotor regions. At the synaptic level, the recruitment of the local excitatory network relies on supra-linear summation of synaptic currents, which is triggered by high- not by low-frequency bursts of spikes in dPAG Calb1 neurons.

Thus, at the most fundamental level, my PhD project has uncovered the crucial dPAG cell types, circuits, and synaptic mechanisms, controlling the initiation regulation, and execution of escape defensive behaviors. Future studies will likely aim to uncover how this dPAG node is dysregulated in models of anxiety disorder and will be expected to shed light to the etiology of these devastating mental disorders, which we currently know very little about. Last, I anticipate the findings of my PhD thesis might also be instrumental to develop future strategies to treat anxiety disorders using targeted, circuit- and computation-specific therapeutics.