Differential Histone Acetylation in Sub-Regions of Bed Nucleus of the Stria Terminalis Underlies Fear Consolidation and Extinction

Abstract

ObjectiveThe hallmark of anxiety disorders is excessive fear. Previous studies have suggested that selective neural projections from Basal nucleus of stria terminalis (BNST) to amygdala and vice-versa precisely control the fear learning process. However the exact mechanism how the BNST controls fear consolidation and its extinction is largely unknown. In the present study we observed the changes in the BNST sub-regions following fear conditioning and its extinction.MethodsThe change in the number of positive neurons was determined by immunohistochemistry for Acetyl H3 (Histone 3), Acetyl H4 (Histone 4), cAMP response element binding Protein (CBP) and c-fos in three sub-regions of the BNST namely the anterio-lateral BNST (STLP) and anterio-medial BNST (STMA), and lateral-ventral BNST (STLV) of rats subjected to auditory fear conditioning and extinction.ResultsWe found significant increase in the number of CBP, acetyl H3 and acetyl H4 positive neurons in the STMA and STLV but not in the STLP after fear conditioning. However, following fear extinction the number of CBP, acetyl H3 and acetyl H4 positive neurons increased significantly in the STLP but not in the STMA and STLV. Similar changes were observed in the number of c-fos positive neurons after fear consolidation and extinction.ConclusionThe results from this study suggest that the differential histone acetylation in the different sub-regions of the BNST following fear learning and its extinction may be responsible for changes in the neuronal activation patterns resulting in either fear or less fear.

Epigenetic Mechanisms Within the Cingulate Cortex Regulate Innate Anxiety-Like Behavior

“…Furthermore, challenge-induced alterations in neural activity coincide with epigenetic changes, particularly modulation of acetylation levels. For instance, we and others have shown enhanced lysine or histone acetylation in neurons activated during fear extinction (c-Fos positive or Zif268 positive) in brain regions such as the infralimbic cortex, basal amygdala, and the dorsal and ventral CA1 hippocampus (Whittle et al, 2016; Ranjan et al, 2017). Therefore, we wanted to investigate whether aberrant neuronal activity within the Cg1 is associated with altered epigenetic mechanisms, in particular lysine/histone acetylation.…”

Role of the bed nucleus of the stria terminalis in aversive learning and memory

“…However, there are a handful of studies using temporary or post-training lesions (or inhibitors of protein synthesis) that implicate BNST function in the acquisition (Davis and Walker 2014; also, see Asok et al 2017), consolidation (Poulos et al 2010), and expression of context fear (Sullivan et al 2004;Zimmerman and Maren 2011;Goode et al 2015b; but, see Davis and Walker 2014). Consistent with these ideas, cued or contextual conditioning increases immediate early gene expression (e.g., c-fos) in the BNST (Passerin et al 2000;Ranjan et al 2017), as does the expression of contextual fear (Beck and Fibiger 1995;also, see Luyten et al 2012). Furthermore, the BNST has been shown to be important for consolidation of contextual fear in overtrained animals if the BLA is lesioned (this consolidation effect is eliminated if the BLA remains intact; Poulos et al 2010;Zimmerman and Maren 2011).…”

“…are processed upstream of the BNST in the hippocampus. It has not yet been demonstrated whether unconditional fearand stress-attenuating circuits of the BNST (Jennings et al 2013;Kim et al 2013;Crowley et al 2016;Marcinkiewcz et al 2016;Mazzone et al 2016) (or BNST neurons in general) play any fundamental role in the extinction of conditioned fear to cues or contexts (also, see Ranjan et al 2017).…”

Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders

“…; Ranjan et al . ; Siddiqui et al . ), to the best of our knowledge no study has been published so far on histone modifications in human anxiety phenotypes.…”