The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. Here we show that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruit parvalbumin (PV)-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala projecting pyramidal neurons in the IL is dominated by feed-forward inhibition. Selectively silencing PV- but not somatostatin (SOM)-expressing interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impairs extinction recall, whereas silencing IL projectors diminishes fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, these experiments reveal a novel circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.

The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.

Early psychological interventions, such as exposure therapy, rely on extinction learning to reduce the development of stress- and trauma-related disorders. However, recent research suggests that extinction often fails to reduce fear when administered soon after trauma. This immediate extinction deficit (IED) may be due to stress-induced dysregulation of neural circuits involved in extinction learning. We have shown that systemic β-adrenoceptor blockade with propranolol rescues the IED, but impairs delayed extinction. Here we sought to determine the neural locus of these effects. Rats underwent auditory fear conditioning and then received either immediate (30 min) or delayed (24 h) extinction training. We used bilateral intracranial infusions of propranolol into either the infralimbic division of the medial prefrontal cortex (mPFC) or the basolateral amygdala (BLA) to examine the effects of β-adrenoceptor blockade on immediate and delayed extinction learning. Interestingly, intra-BLA, but not intra-mPFC, propranolol rescued the IED; animals receiving intra-BLA propranolol prior to immediate extinction showed less spontaneous recovery of fear during extinction retrieval. Importantly, this was not due to impaired consolidation of the conditioning memory. In contrast, neither intra-BLA nor intra-mPFC propranolol affected delayed extinction learning. Overall, these data contribute to a growing literature suggesting dissociable roles for key nodes in the fear extinction circuit depending on the timing of extinction relative to conditioning. These data also suggest that heightened noradrenergic activity in the BLA underlies stress-induced extinction deficits. Propranolol may be a useful adjunct to behavioral therapeutic interventions in recently traumatized individuals who are at risk for developing trauma-related disorders.

The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.IMPACT STATEMENTThe bed nucleus of the stria terminalis (BNST) is required for the expression of defensive behavior to unpredictable threats, a function that may be central to pathological anxiety.

Recent work indicates that the bed nucleus of the stria terminalis (BNST) is critically involved in the regulation of conditioned fear responses to unpredictable threats. Here we examined whether the involvement of the BNST in contextual fear conditioning in male rats depends on the imminence of shock after placement in the conditioning chamber. Specifically, we hypothesized that the BNST supports contextual freezing after conditioning with delayed, but not imminent, footshock (relative to placement in the context). Rats were implanted with cannulae targeting the BNST and underwent a contextual fear conditioning procedure in which a single footshock unconditioned stimulus (US) was delivered either 1 minute or 9 minutes after the rat was placed in the context; the rats received a total of four identical conditioning sessions over two days, all with equivalent exposure to the context. Contexts associated with either imminent or delayed US onsets produced distinct patterns of freezing and shock-induced activity but freezing in each case was context-dependent. Reversible inactivation of the BNST reduced the expression of contextual freezing in the context paired with delayed (9 min), but not imminent (1 min), footshock onset. Implications of these data are discussed in the light of recent conceptualizations of BNST function, as well as for anxiety behaviors.