Sex Differences in the Activity of Basolateral Amygdalar Neurons That Project to the Bed Nucleus of the Stria Terminalis and Their Role in Anticipatory Anxiety

Abnormal fear and anxiety can manifest as psychiatric disorders. The bed nucleus of the stria terminalis (BNST) is implicated in sustained responding to, or anticipation of, an aversive event which can be expressed as anticipatory anxiety. The BLA is also active during anticipatory anxiety and sends projections to the BNST. However, little is known about the role for BLA neurons that project to BNST (BLA-BNST) in anticipatory anxiety in rodents. To address this, we tested whether chemogenetic inactivation of the BLA-BNST pathway attenuates sustained conditioned responses produced by anticipation of an aversive stimulus. For comparison, we also assessed BLA-BNST inactivation during social interaction, which is sensitive to unlearned anxiety. We found that BLA-BNST inactivation reduced conditioned sustained freezing and increased social behaviors, but surprisingly, only in males. To determine whether sex differences in BLA-BNST neuronal activity contribute to the differences in behavior, we used in vivo and ex vivo electrophysiological approaches. In males, BLA-BNST projection neurons were more active and excitable, which coincided with a smaller after-hyperpolarization current (I-AHP) compared with other BLA neurons; whereas in females, BLA-BNST neurons were less excitable and had larger I-AHP compared with other BLA neurons. These findings demonstrate that activity of BLA-BNST neurons mediates conditioned anticipatory anxiety-like behavior in males. The lack of a role of BLA-BNST in females in this behavior, possibly because of low excitability of these neurons, also highlights the need for caution when generalizing the role of specific neurocircuits in fear and anxiety.