A Novel Corticothalamic Circuit Through Thalamic Reticular Nucleus Mediates Flight

Fear is a natural feeling that arises when facing threats,the survival of the animal depends on rapid response to the dangerous stimuli.Flight,as an active defensive response,is evoked when the stimulus is controllable or escapable while freezing,as a passive coping strategy,is elicited when the dangerous stimulus is inescapable.Thalamic reticular nucleus(TRN),a GABAergic nucleus integrating information from cortex and thalamus,filters information between the cortex and the thalamus.It has been implicated in sensorimotor processing,sleep rhythms and attention.Rather than a homogeneous GABAergic nucleus,the TRN presents heterogeneous neuronal activity and connectivity pattern.The cytoarchitecture and organization of the limbic TRN(putatively the anterior-dorsal part)and the sensory TRN(putatively the posterior part)differ.Recent studies show that the TRN has also been implicated in fear acquisition in rodents.Furthermore,the TRN receives several inputs from key brain regions(such as medial prefrontal cortex and amygdala)involved in regulation of defensive behavior,but little is known about their specific TRN cellular targets.In addition,the functional roles of long-range inputs to TRN,as well as outputs from TRN,in the expression of active or passive defensive behaviors are poorly understood.To answer the scientific questions above,by using fiber photometry system we found that increased activity of parvalbumin-expressing(PV+)neurons in the limbic TRN is tightly coupled with flight onset and optogenetic activation/inactivation of PV+neurons in the limbic TRN bi-directionally regulates flight.Next,combining cell type-specific input-output viral tracing with electrophysiology,we demonstrated that the limbic TRN PV+neurons projecting to the mediodorsal thalamic nucleus(MD)are selectively targeted by glutamatergic inputs from cingulate cortex(Cg).Furthermore,optogenetic activation of the Cg→limbic TRN→MD tri-circuit mediated flight.Our study elucidates an important role of the limbic TRN in flight via corticothalamic pathway.This study makes a significant stride towards elucidating how the corticothalamic pathway mediate flight behavior and reveals a subregion-specific role of the TRN in fear response.Further investigation of this corticothalamic circuit will provide new insights into the underlying mechanisms of human psychiatric conditions associated with maladaptive coping behaviors under stressful conditions,such as anxiety disorders.