Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats

Abstract

Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.

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

“…Half of the animals were counterbalanced for order of context and cued tests. As previously shown (Nagaya et al, 2015), the suppressive effect of intra-BNST ALLO on freezing was limited to context exposure. Therefore, the remaining half of the animals only received context tests.…”

“…Fresh dummy cannulae were then inserted and rats remained in buckets until 10 min post-infusion after which they were transported to the testing rooms in plastic boxes for behavior. Previous work in our laboratory has found reliable effects of ALLO at this dosage without producing sedation (Nagaya et al, 2015). …”

“…Allopregnanolone (ALLO), a major metabolite of progesterone, has been associated with decreased levels of context-related fear (Pibiri et al, 2008; Toufexis et al, 2004) and its synthetic analogue, ganaxolone, has been shown to facilitate extinction in mice (Pinna and Rasmusson, 2014). We have recently shown that local ALLO activity in the bed nucleus of the stria terminalis (BNST) modulates the expression of conditioned contextual fear (Nagaya et al, 2015). In male rats, increased ALLO activity via local infusion suppressed context-dependent freezing whereas in female rats, decreased ALLO activity via pharmacological means resulted in enhanced freezing.…”

Estrogen and Transdiagnostics: A Systematic Review

“…Case-control studies show that the incapacity to suppress fear responses in safe conditions may be a biomarker for PTSD. The low level of estrogen in women with normal cycle is associated with deficits in the extinction of fear [41][42][43]. Studies show that women are protected against psychotic illnesses when their levels of estrogen are high, which is an emphatic result of our revision.…”

“…This was the first study to examine the role of estrogen receptor genes in predisposition to OCD [50,51]. The ESR1 gene may contribute to genetic susceptibility to certain OCD subphenotypes; specifically, these findings may influence the development of contamination/cleaning obsessions and compulsions [41]. Affective disorders, such as premenstrual syndrome, postnatal and post-menopausal depression and depression, are the most common mental disorders associated with low serum levels (i.e., in the blood) of estrogens [52][53][54][55][56][57].…”