Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis

Abstract

Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST). To further explore the nature of this effect, we infused ALLO into the BNST of male rats prior to both conditioning and testing. We found that suppression of contextual fear occurred when the hormone was present during either conditioning or testing but not during both procedures, suggesting that ALLO acts in a state-dependent manner within the BNST. A shift in interoceptive context during testing for animals conditioned under ALLO provided further support for this mechanism of hormonal action on contextual fear. Interestingly, infusions of ALLO into the basolateral amygdala produced a state-independent suppression of both conditioned contextual and auditory freezing. Altogether, these results suggest that ALLO can influence the acquisition and expression of fear memories by both state-dependent and state-independent mechanisms.

Role of the bed nucleus of the stria terminalis in aversive learning and memory

“…At the behavioral level, posttraining lesions or inactivation of the BNST rapidly attenuate freezing responses to an aversive context (e.g., as early as within the first minute; Zimmerman and Maren 2011; Goode et al 2015b)-these effects coincide with rapid prevention of reinstatement to the onset of discrete extinguished CSs. Other studies examining the effects of various neuromodulators or neurosteroids within the BNST have also shown rapid alterations in behavioral responding upon return to a conditioned context (Nagaya et al 2015;Acca et al 2017). At the physiological level, Resstel et al (2008) demonstrated that blockade of neurotransmitter release within the BNST (via the infusion of cobalt chloride) prevented the immediate increase in mean arterial pressure and heart rate that coincided with being placed in a previously conditioned context.…”

“…Finally, it is worth noting that in humans (Allen and Gorski 1990;Chung et al 2002) and rodents (Hines et al 1985;Hines et al 1992), the male BNST is generally larger than in females (also, see Avery et al 2014). It is not yet clear if this sexual dimorphism impacts BNST function in aversive learning, but (perhaps re-latedly) male rodents generally express greater levels of contextual (but not discretely cued) freezing when compared with females (Maren et al 1994;Markus and Zecevic 1997;Pryce et al 1999;Gupta et al 2001;Barker and Galea 2010;Nagaya et al 2015;Acca et al 2017;Bangasser and Wicks 2017; also, see Gruene et al 2015;Pellman et al 2017). With these connections in mind, we will now explore the various factors that may account for the roles of the BNST in conditioned fear.…”

“…BNST function in fear conditioning: state-dependence Recently, it has been observed that intra-BNST infusions of the neurosteroid allopregnanolone (ALLO, a progesterone metabolite that potentiates GABA A receptors) produce state-dependent retention deficits of contextual fear (Nagaya et al 2015;Acca et al 2017). In other words, animals trained or tested after ALLO infusions exhibit impaired contextual freezing, however animals trained and tested after ALLO infusions exhibit robust freezing.…”

“…This suggests that the BNST not only processes environmental (i.e., exteroceptive) conditioned contexts, but might also be involved in representing interoceptive contexts (such as hormonal states). Moreover, state-dependence is not observed when ALLO is infused into the BLA, suggesting that the effects of ALLO on state-dependence relates to its actions within the BNST (Acca et al 2017). However, it is not yet clear if other drugs that are commonly used to assess BNST function also induce state-dependence via the BNST, or if other brain areas might mediate these state-dependent effects.…”

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

“…505 506 Surgeries. For animals receiving intracranial microinfusions into the BNST, rats were transported 507 to the surgical suite and deeply anesthetized using isoflurane (5% for induction, 1-2% for 508 maintenance) (Acca et al, 2017;Goode et al, 2015;Nagaya et al, 2015;Zimmerman and Maren, 509 2011). Rats were then secured in a stereotaxic frame (Kopf Instruments).…”