The Basolateral Amygdala Is Essential for Rapid Escape: A Human and Rodent Study

Abstract

SummaryRodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans.

Role of oxytocin in the control of stress and food intake

“…Pharmacological studies in rats have shown that administration of oxytocin into the central amygdala before recall of conditioned fear (context re-exposure) enhances freezing behaviour, whereas administration of an oxytocin receptor antagonist suppresses freezing behaviour in rats, suggesting that the oxytocin receptor in the central amygdala facilitates the expression of conditioned freezing behaviour. 106 100 Consistent with the facilitative role of oxytocin in fear conditioning, administration of an oxytocin agonist into the amygdala has been reported to enhance fear acquisition in juvenile rats.…”

“…On the other hand, oxytocin has been suggested to facilitate active coping behaviour in certain conditions and to switch from passive stress-coping behaviour to active stress-coping behaviour. 24 Recently, oxytocin has been shown to reduce passive coping behaviour such as freezing behaviour by acting on neurones in the lateral part of the central amygdala, which inhibits the activity of periaqueductal gray-projecting central amygdala neurones, and, as a result, induces active escape behaviour 106 or active defensive behaviour. 269 Consistent with this idea, oxytocin has been shown to suppress social loss-induced passive coping behaviour in male prairie voles 84 and to induce social defeat-induced risk assessment behaviour (head orientation) in female mice by acting on the bed nucleus of the stria terminalis.…”

“…105 The activation of the oxytocin receptor has been shown to increase active escape performance and reduce freezing behaviour in rats. 106…”

Subcortical Shape Alterations in Major Depressive Disorder: Findings from the ENIGMA Major Depressive Disorder Working Group

“…The CMA, with its reciprocal connections with the basal ganglia, midbrain, and brain stem, appears to be involved in allocating attention and generating the appropriate autonomic responses to environmental stimuli. In contrast, the BLA, with its connections to the CMA and with extensive cortical regions, is primarily involved in evaluating the emotional content of sensory inputs and plays a major role in threat responses (Mosher et al 2010;Terburg et al 2018). Although some post mortem evidence suggests that MDD selectively affects the receptors and number of nuclei in the BLA (Karolewicz et al 2009;Rubinow et al 2016), it is not clear if MDD is associated with larger or smaller BLA volume.…”

Reducing shock imminence eliminates poor avoidance in rats

“…Though there are some reports of improved SigAA learning with slightly longer or more complex WSs (Archer et al, 1984;Coll-Andreu et al, 1993;Levis and Stampfl, 1972;Satorra-Marin et al, 2001;Solomon and Brush, 1954;Terburg et al, 2018), this has not been systematically studied. There are far more studies of US imminence using Pavlovian paradigms.…”