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

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe amygdala is an almond-shaped group of nuclei in the temporal lobe that is crucial for defensive behaviors in all mammals, including humans (, ). The nuclei of the amygdala are partly of striatal origin (central amygdala [CeA]) and partly of cortical origin (basolateral amygdala [BLA]), with the BLA in particular having undergone a large evolutionary expansion in humans compared to rodents (). Cross-species translational research on the behavioral functions of this circuitry is thus essential. A seminal body of rodent research has delineated how amygdala circuitry controls defensive behaviors (, , , , , , , ), but cross-species translation is a challenge (), because in human studies, evidence of causal mechanisms and sub-region specificity are lacking.Recently, we identified a group of humans with focal, bilateral calcifications in the BLA; these patients can potentially provide such causal evidence. BLA damage in these individuals is caused by an extremely rare autosomal recessive disorder—Urbach-Wiethe disease (UWD) ()—which was introduced to South Africa with the arrival of Dutch-German settlers in 1652 and continued to spread locally because of the founder effect (). Using structural and functional neuroimaging methods in affected individuals, we recently demonstrated that, in this group, there is a focal bilateral neurodegeneration that is restricted to within the BLA without affecting CeA (). This group of individuals could therefore contribute significantly to cross-species translation of functions of the different nuclei in the amygdala.In rodents, the BLA is crucial for threat conditioning (href="#bib8" rid="bib8" class=" bibr popnode">Davis and Whalen, 2001). Although initial behavioral results in the South-African UWD population found that BLA pathology reduced acquisition of threat-potentiated startle (href="#bib29" rid="bib29" class=" bibr popnode">Klumpers et al., 2015), such pathology also increased vigilance for facial and bodily threat stimuli across multiple behavioral paradigms (href="#bib10" rid="bib10" class=" bibr popnode">de Gelder et al., 2014, href="#bib24" rid="bib24" class=" bibr popnode">Hortensius et al., 2016, href="#bib47" rid="bib47" class=" bibr popnode">Terburg et al., 2012). This hyper-vigilance for threat was also observed in response to non-consciously processed threat stimuli in a paradigm precluding cortical control (href="#bib47" rid="bib47" class=" bibr popnode">Terburg et al., 2012). This suggested that threat reactivity downstream of the BLA is potentiated by BLA damage (href="#bib33" rid="bib33" class=" bibr popnode">Liddell et al., 2005, href="#bib51" rid="bib51" class=" bibr popnode">van Honk et al., 2002, href="#bib52" rid="bib52" class=" bibr popnode">van Honk et al., 2005). In rodent models, there is also evidence that threat reactivity is increased after BLA inhibition (href="#bib35" rid="bib35" class=" bibr popnode">Macedo et al., 2006) and that anxious behaviors are increased by inhibition of BLA projections to the lateral CeA (CeL) (href="#bib49" rid="bib49" class=" bibr popnode">Tye et al., 2011). Recent evidence furthermore indicates that the CeL can act as a switch between passive—freezing—and active—escape—defensive behaviors, specifically due to inhibitory projections to the medial subdivision (CeM) and the brainstem (href="#bib5" rid="bib5" class=" bibr popnode">Ciocchi et al., 2010, href="#bib13" rid="bib13" class=" bibr popnode">Fadok et al., 2017, href="#bib19" rid="bib19" class=" bibr popnode">Gozzi et al., 2010, href="#bib21" rid="bib21" class=" bibr popnode">Haubensak et al., 2010, href="#bib48" rid="bib48" class=" bibr popnode">Tovote et al., 2016, href="#bib55" rid="bib55" class=" bibr popnode">Viviani et al., 2011). Given that the BLA-CeL pathway can activate these inhibitory projections to the CeM (href="#bib49" rid="bib49" class=" bibr popnode">Tye et al., 2011), we hypothesized that BLA input is necessary to induce the passive to active switch, that is the switch from freezing to active escape, in the CeA. Neuroimaging in humans indeed suggests that the BLA is involved in goal-directed active escape behavior (href="#bib38" rid="bib38" class=" bibr popnode">Mobbs et al., 2007), but direct and causal evidence for this model and its cross-species translation is currently unavailable.We therefore set out to investigate BLA-damaged human subjects in parallel with rodents with the aim of translating across species and elucidating the role of the BLA and CeA in active compared to passive defensive behaviors. Under threat, mammals, including humans, can either respond passively with defensive reactions, such as freezing, or actively by goal-directed actions, such as escape (href="#bib36" rid="bib36" class=" bibr popnode">McNaughton and Corr, 2004, href="#bib38" rid="bib38" class=" bibr popnode">Mobbs et al., 2007, href="#bib39" rid="bib39" class=" bibr popnode">Montoya et al., 2015). The neural mechanism that selects when to freeze and when to escape is, however, not well understood (href="#bib31" rid="bib31" class=" bibr popnode">LeDoux et al., 2017). Accordingly, we developed cross-species paradigms that extend recent research on responses to inescapable threat (href="#bib13" rid="bib13" class=" bibr popnode">Fadok et al., 2017, href="#bib29" rid="bib29" class=" bibr popnode">Klumpers et al., 2015) to situations where behavior can lead to successful escape. Outcome measures included behavioral escape performance and freezing, acoustic startle reflexes, fMRI, and ex vivo cell recordings.By comparing in both species individuals with and without a functional BLA, we identified a vital inhibitory control function of the BLA over passive defensive behaviors. This inhibitory control by the BLA was adaptively tuned, that is, selectively present in situations of imminent threat that requested rapid escape and not present in distant or inescapable threat conditions. Neuroimaging evidence in humans suggested that, to execute this inhibitory control function, the BLA acts on the CeA in order to influence the downstream brainstem and its initiation of passive defensive behavior. In rodents, we found that training by exposure to imminent escapable threat selectively upregulated BLA projections to a group of neurons in the CeL identifiable by their sensitivity to oxytocin. By increasing the oxytocin signaling in the CeA (href="#bib26" rid="bib26" class=" bibr popnode">Huber et al., 2005, href="#bib30" rid="bib30" class=" bibr popnode">Knobloch et al., 2012, href="#bib55" rid="bib55" class=" bibr popnode">Viviani et al., 2011), we rescued the responses to imminent escapable threat during downregulated function of the BLA. Together, these cross-species findings not only uncover a dynamically tuned regulation by the BLA of the CeA under conditions of imminent escapable threat but also show how this is mechanistically established by the BLA via activation of inhibitory projections from the CeL to CeM. Finally, this key role of the BLA in escape behavior is evolutionary conserved across humans and rodents.