A competitive inhibitory circuit for selection of active and passive fear responses

Abstract

When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses. Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents. However, rodents also exhibit active responses such as flight under natural conditions. The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established. Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF) mediate conditioned flight, and activation of somatostatin-positive (SOM) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF and SOM neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection.

Transcriptional Profiling of Primate Central Nucleus of the Amygdala Neurons to Understand the Molecular Underpinnings of Early Life Anxious Temperament

“…Because of the methods used to collect LCM neurons, we were unable to assess protein levels of PKCd in the animals used for RNA-Seq. Studies in the mouse demonstrate that CeL PRKCD expressing neurons are a component of a microcircuit that gates CeL output, modulating the expression of freezing and other threat-related behaviors Fadok et al, 2017;Haubensak et al, 2010;Li et al, 2013;Yu et al, 2016). Because little is known in primates about the proportion and distribution of CeL neurons that express PKCd protein, in three other animals, we systematically characterized CeL PKCd expressing neurons.…”

“…While PKCd has been extensively studied in the rodent CeL (Amano et al, 2012;Cui et al, 2017;Haubensak et al, 2010;Ye and Veinante, 2019;Yu et al, 2016), little is known about its expression in the nonhuman primate amygdala. Rodent studies demonstrate that other CeL neurons exist (Cassel and Gray, 1989;McCullough et al, 2018;Price et al, 1987;Roberts et al, 1982) and recent mouse studies reveal that SST expressing GABAergic neurons interact with and modulate the function of PRKCD expressing neurons (Fadok et al, 2017;Kim et al, 2017;Li et al, 2013). Because these cell types have not been well characterized in the nonhuman primate, we used stereological cell counting techniques to map the distribution of PKCd and SST expressing neurons in the rhesus CeL.…”

Response-specific sex difference in the retention of fear extinction

“…While these projections have been known for some time now, studies have begun to identify circuits within the central nucleus that govern whether active or passive fear responses are expressed (e.g., Gozzi et al 2010). Other recent work has identified specific cell types in the central nucleus which favor the expression of passive fear behavior (i.e., freezing), while other cell types drive the expression of active fear responses (Yu et al 2016;Fadok et al 2017). It is tempting to speculate that the balance of these mechanisms might be shifted in females such that they are more likely to engage in active fear responses.…”

A Network Model of the Emotional Brain

“…To illustrate this point, consider a recent study targeting local central amygdala circuits involved in selecting between active and passive fear responses (flight vs. freeze) [76]. A major finding of the study was that it revealed inhibitory connections between two subpopulations of central amygdala cells linked to the two behaviors.…”