Role of the Bed Nucleus of the Stria Terminalis in PTSD: Insights From Preclinical Models

Abstract

Post-traumatic stress disorder (PTSD) afflicts approximately 8% of the United States population and represents a significant public health burden, but the underlying neural mechanisms of this and other anxiety- and stressor-related disorders are largely unknown. Within the last few decades, several preclinical models of PSTD have been developed to help elucidate the mechanisms underlying dysregulated fear states. One brain area that has emerged as a critical mediator of stress-related behavioral processing in both clinical and laboratory settings is the bed nucleus of the stria terminalis (BNST). The BNST is interconnected with essential emotional processing regions, including prefrontal cortex, hippocampus and amygdala. It is activated by stressor exposure and undergoes neurochemical and morphological alterations as a result of stressor exposure. Stress-related neuro-peptides including corticotropin-releasing factor (CRF) and pituitary adenylate cyclase activating peptide (PACAP) are also abundant in the BNST, further implicating an involvement of BNST in stress responses. Behaviorally, the BNST is critical for acquisition and expression of fear and is well positioned to regulate fear relapse after periods of extinction. Here, we consider the role of the BNST in stress and memory processes in the context of preclinical models of PTSD.

A prefrontal-bed nucleus of the stria terminalis circuit limits fear to uncertain threat

“…Furthermore, lesioning this area reduces inappropriate fear to a non-reinforced CS in rats with high-trait anxiety ( Duvarci et al, 2009 ). Indeed, a growing number of lesion and functional neuroimaging studies in non-human primates and humans have implicated the BNST in the processing of uncertain threat (see Goode et al, 2019 ; Miles and Maren, 2019 ). Together, these findings suggest that inhibitory properties of the partially reinforced CS could be signaled by the IL downstream to the BNST, thereby limiting the expression of CS-induced fear to a level appropriate to its partial reinforcement history.…”

Rodent models of post-traumatic stress disorder: behavioral assessment

“…For example, both rodent and primate research has identified brain regions, such as the bed nucleus of the stria terminalis (BNST), amygdala, prefrontal cortex, cingulate cortex, and hippocampus, that regulate stress-related behavioral mechanisms and are dysfunctional in PTSD patients 146 . The BNST, in particular, has been investigated for its role in fear memory neural circuitry 221 . In mice, optogenetic photoinhibition of neurons projecting between the BNST and ventral tegmental area during electric shock stress decreased freezing in the exposure context and closed arm entries in the EPM 222 .…”

Cannabinoid receptor type 1 in the bed nucleus of the stria terminalis modulates cardiovascular responses to stress via local N-methyl-D-aspartate receptor/neuronal nitric oxide synthase/soluble guanylate cyclase/protein kinase G signaling

“…The bed nucleus of the stria terminalis (BNST) is a limbic forebrain structure activated during aversive situations that has been implicated in physiological and behavioral responses to stress (Crestani et al, 2013; Miles and Maren, 2019; Myers, 2017; Radley and Johnson, 2018). Regarding stress-evoked cardiovascular responses, previous studies have indicated that the control of stress-evoked cardiovascular adjustments by the BNST seem to depend on the type of stress (Crestani et al, 2013).…”