Chronice stress and its affect on PAC1- CRF neurons in the BNST

Mahafuza Aktar

Abstract

Repeated or severe stress has an impact on physiological and psychological systems, as a part of homeostasis, and can promote maladaptive changes (Hammack et al., 2009). These maladaptive changes mediated by chronic stress can produce anxiety-like behavior, which has been argued to be an underlying cause of many psychological diseases, especially anxiety disorder (Hammack et al., 2010). Anxiety disorders have become most the common mental health problem in the U.S, affecting 19.6% of adults (National Comorbidity Survey. 2017). Though there are different pharmacological drugs available to manage anxiety disorders, most have limited efficacy and/or unwanted side effects (Griebel et al., 2013). In order to develop a more effective treatment of anxiety disorders, we need to have a better understanding of how exposure to chronic stress leads to maladaptive behavior. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide encoded by ADCYAP1 gene that is known to regulate stress responding and may play an important role in maladaptive anxiety-like behavior (Ressler et al., 2011).

PACAP and its cognate receptor, PAC1, have been found in many of the stress- and anxiety-associated brain regions (Hammack et al., 2009), such as - bed nucleus of stria terminalis (BNST), central nucleus of amygdala (CeA), parabrachial nucleus (PBn), and hypothalamus. Our lab has demonstrated that PACAP is critical for stress-related anxiety-like behavior in rodents, and our group has argued that PACAP is critical for stress-induced long-term changes in the functions of anxiety-related brain regions. The stress induced neuroplasticity can produce maladaptive stress response of those brain regions and can cause anxiety disorders (Hammack et al., 2015).

Among these brain regions, the BNST has been argued to be a particularly important area for anxiety-like behavior where PACAP and corticotropin-releasing factor (CRF) working together can cause anxiogenic effects following chronic variant stress (Roman et al., 2014, Walker et al., 2009). As cells in the BNST are diverse in terms of their physiology and chemistry, the roles of different cell populations in stress-related behaviors such as anxiety are not clear. Neurons in the BNST mostly express GABA as a neurotransmitter, with some glutamatergic neurons present (Gungor et al., 2016). These BNST cells also often co-express different neuropeptides, such as PACAP and CRF (Hammack et al., 2009). We have argued that PACAP is targeting BNST CRF neurons (Dore et al., 2013), via the PAC1 receptor, which utilizes different signaling pathways depending on its isoform (Hammack et al., 2015). The PAC1 downstream signaling pathway that contributes to anxiety-like behavior is important to understand because it will help us to find a better target for treatment. PACAP modulates the CRF PAC1 expressing cells in BNST and its downstream signaling pathway during chronic stress and produce anxiety-like behavior.

 

Chronice stress and its affect on PAC1- CRF neurons in the BNST

Repeated or severe stress has an impact on physiological and psychological systems, as a part of homeostasis, and can promote maladaptive changes (Hammack et al., 2009). These maladaptive changes mediated by chronic stress can produce anxiety-like behavior, which has been argued to be an underlying cause of many psychological diseases, especially anxiety disorder (Hammack et al., 2010). Anxiety disorders have become most the common mental health problem in the U.S, affecting 19.6% of adults (National Comorbidity Survey. 2017). Though there are different pharmacological drugs available to manage anxiety disorders, most have limited efficacy and/or unwanted side effects (Griebel et al., 2013). In order to develop a more effective treatment of anxiety disorders, we need to have a better understanding of how exposure to chronic stress leads to maladaptive behavior. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide encoded by ADCYAP1 gene that is known to regulate stress responding and may play an important role in maladaptive anxiety-like behavior (Ressler et al., 2011).

PACAP and its cognate receptor, PAC1, have been found in many of the stress- and anxiety-associated brain regions (Hammack et al., 2009), such as - bed nucleus of stria terminalis (BNST), central nucleus of amygdala (CeA), parabrachial nucleus (PBn), and hypothalamus. Our lab has demonstrated that PACAP is critical for stress-related anxiety-like behavior in rodents, and our group has argued that PACAP is critical for stress-induced long-term changes in the functions of anxiety-related brain regions. The stress induced neuroplasticity can produce maladaptive stress response of those brain regions and can cause anxiety disorders (Hammack et al., 2015).

Among these brain regions, the BNST has been argued to be a particularly important area for anxiety-like behavior where PACAP and corticotropin-releasing factor (CRF) working together can cause anxiogenic effects following chronic variant stress (Roman et al., 2014, Walker et al., 2009). As cells in the BNST are diverse in terms of their physiology and chemistry, the roles of different cell populations in stress-related behaviors such as anxiety are not clear. Neurons in the BNST mostly express GABA as a neurotransmitter, with some glutamatergic neurons present (Gungor et al., 2016). These BNST cells also often co-express different neuropeptides, such as PACAP and CRF (Hammack et al., 2009). We have argued that PACAP is targeting BNST CRF neurons (Dore et al., 2013), via the PAC1 receptor, which utilizes different signaling pathways depending on its isoform (Hammack et al., 2015). The PAC1 downstream signaling pathway that contributes to anxiety-like behavior is important to understand because it will help us to find a better target for treatment. PACAP modulates the CRF PAC1 expressing cells in BNST and its downstream signaling pathway during chronic stress and produce anxiety-like behavior.