Dissecting the function of the thalamocortical circuit involving the central lateral (and neighboring) thalamic nuclei and the anterior cingulate cortex in the noise-induced flight behavior of mice

Innate defensive behavior is a crucial survival response for animals. Previous research has established the importance of various lower-level brain regions and pathways in directly controlling innate defensive responses. Furthermore, our and other studies have recognized the modulation effect of higher-order cortical areas, especially the anterior cingulate cortex (ACC), on these behaviors, highlighting the ACC’s role in flight behavior through direct and indirect projections to lower-level pathways. However, the role of the thalamocortical circuit involving thalamic nuclei and the ACC in innate defensive behavior remains largely unknown. Therefore, we raise the question of how this circuit participates in generating proper defensive behavior. We hypothesize that thalamic input significantly drives ACC neurons to modulate this defensive behavior.In this proposed study, first, we will characterize the anatomical connection between the thalamus and ACC using retrograde and anterograde tracing, alongside c-fos staining, to visualize activation patterns in noise-induced flight behavior (Objective 1). Preliminary data have indicated an intensive projection from the central lateral (and neighboring)thalamic nuclei (CLN) to the ACC. Second, we plan to investigate neuronal activities within this circuit during noise-induced flight behavior, employing fiber photometry recording and electrophysiological tagging techniques (Objective 2). Early data show robust activation in the circuit correlating with flight behavior. Third, we will test the necessity and sufficiency of the CLN to ACC projection in mediating flight behavior using optogenetic and chemogenetic manipulation (Objective 3). Our hypothesis is supported by initial findings that manipulating this pathway alters the flight response,and intriguingly, preliminary data suggest that this pathway suppresses the noise-induced running in the head-fixing paradigm and leads to an optimal flight route in the free-moving paradigm. Lastly, we intend to explore the mechanisms underlying this suppression effect by the thalamocortical circuit (Objective 4). This will involve in vivo and in vitro electrophysiological recordings to examine neuronal responses in the ACC and its various downstream areas when activating the projection from the CLN to the ACC, and check connectivity patterns between these areas.This research will answer critical questions about the involvement of this circuit in generating appropriate defensive behavior, aiming to reveal how this pathway potentially works as a "brake" to optimize flight behavior and avoid an aimless charge. The findings will contribute to a deeper apprehension of the neural basis of fear and anxiety,potentially highlighting new targets for disorders such as PTSD and specific phobias.