Compensation in the neural circuitry of fear conditioning awakens learning circuits in the bed nuclei of the stria terminalis

Abstract

The basolateral amygdala (BLA) is thought to be essential for fear learning. However, extensive training can overcome the loss of conditional fear evident following lesions and inactivation of the BLA. Such results suggest the existence of a primary BLA-dependent and a compensatory BLA-independent neural circuit. We tested the hypothesis that the bed nuclei of the stria terminalis (BST) provides this compensatory plasticity. Using extensive context-fear conditioning, we demonstrate that combined BLA and BST lesions prevented fear acquisition and expression. Additionally, protein synthesis in the BST was critical only for consolidation of BLA-independent but not BLA-dependent fear. Moreover, fear acquired after BLA lesions resulted in greater activation of BST regions that receive hippocampal efferents. These results suggest that the BST is capable of functioning as a compensatory site in the acquisition and consolidation of context-fear memories. Unlocking such neural compensation holds promise for understanding situations when brain damage impairs normal function or failure to regulate compensatory sites leads to anxiety disorders. amygdala | basolateral amygdala | context | plasticity | bed nucleus of the stria terminalis A largely supported view in the neuroscience of associative memory is the existence of essential neural circuits that have the capacity to learn, retain, and retrieve specific classes of experience 1-7). For example, in reflexive motor learning or Pavlovian eyeblink-conditioning, the integration of sensory stimuli within the cerebellar interpositus nuclei are required for the acquisition, retention, and retrieval conditional responses (8). Similarly, the striatum is considered critical for habit learning (9, 10) and the hippocampus essential for spatial learning (11). In fearconditioning, a circuit centered around the basolateral amygdala complex (BLA; consisting of the lateral amygdala, basomedial, basolateral, and posterior nuclei) is viewed essential for the acquisition and expression of fear memories (12-16). The importance of the BLA for fear memory has been supported by numerous studies showing that disruption of protein synthesis, NMDA receptor function, neuronal activity, synaptic transmission, and plasticity all prevent the establishment of fear memories (14-18).Context fear learning normally occurs when hippocampal context information, which exits the subiculum, converges with aversive information in the BLA (15). In turn, when the contextual information activates the BLA, this information is relayed to the central nucleus of the amygdala (CEA), whose efferents to the ventral periaqueductal gray (vPAG) trigger the expression of fear as indexed by conditional freezing (conditional response) (19). Lesions or inactivations of the CEA can disrupt contextual fear (20, 21; but see 22). Of particular relevance in this study is that pretraining lesions or inactivations of the BLA have been shown to strongly impair the acquisition of fear (23-25). However, with extensive overtraining (∼75 tr...

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

“…Cued and contextual testing conditions have been reported to be largely mediated by two distinct brain regions, the amygdala and the hippocampus, respectively (42,43), and also by a compensatory fear neurocircuitry involving the stria terminalis (44). NMDAR-dependent LTP has been demonstrated in the amygdala and has been reported to be necessary for cued fear conditioning (38).…”

Resolving the neural circuits of anxiety

“…For example, in the absence of a functional BLA, the BNST acts as a compensatory site in the acquisition of fear memories, although this BLAindependent fear learning requires additional training 84 . Moreover, individual subregions of the BNST have been shown to differentially regulate separable features of the anxiety phenotype 31,85 ( Figure 3).…”

Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress

“…The long-term anxiogenic effects of glucocorticoid signaling in the CeA are thought to be mediated by transcriptional interactions with CRF, perhaps driving synaptic plasticity (Kolber et al, 2010; Laryea et al, 2013; Myers and Greenwood-Van Meerveld, 2010b; Shekhar et al, 2005). In addition, downstream activation of the BST may play a role in behavioral responses to stress (Poulos et al, 2010; Singewald et al, 2003; Sullivan et al, 2004). Chronic glucocorticoid signaling in the BST appears to induce a shift toward anxiogenic behavior and enhance unconditioned fear and stress-induced learning (Bangasser et al, 2005; Shepard et al, 2009; Ventura-Silva et al, 2012).…”