Regulation of HDAC1 and HDAC2 during consolidation and extinction of fear memory.

Histone deacetylases (HDACs) regulate gene expression epigenetically through synchronized removal of acetyl groups from histones required towards memory consolidation. Moreover, dysregulated epigenetic machinery during fear or extinction learning may result in altered expression of some of these genes and result in Post Traumatic Stress Disorder (PTSD). In the present study, region-specific expression of Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC2) was correlated to the acetylation of histones H3 and H4 and the resultant conditioned response, in rats undergone fear and extinction learning. The neuronal activation, histone acetylation at H3/H4 and expression of HDAC1/HDAC2 in centrolateral amygdala (CeL) and centromedial amygdala (CeM) of central Amygdala (CeA) and prelimbic (PL) and infralimbic (IL) of Prefrontal cortex (PFC) were found to be associated in a differential manner following fear and extinction learning. Moreover in CeM, the main output of the fear circuitry, the level of HDAC1 was down-regulated following conditioning and up-regulated following extinction as opposed to which HDAC2 was down-regulated in CeM following conditioning but not following extinction. Furthermore, in CeL the HDAC1 was upregulated and HDAC2 was downregulated following conditioning and extinction. This has important implications in speculating of the role of HDACs in fear memory consolidation and its extinction.

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

OBJECTIVE: The 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. METHODS: The 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. RESULTS: We 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. CONCLUSION: The 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.

Enhanced Histone Acetylation in the Infralimbic Prefrontal Cortex is Associated with Fear Extinction.

The molecular processes that establish fear memory are complex and involve a combination of genetic and epigenetic influences. Dysregulation of these processes can manifest in humans as a range of fear-related anxiety disorders like post-traumatic stress disorders (PTSD). In the present study, immunohistochemistry for acetyl H3, H4, c-fos, CBP (CREB-binding protein) in the infralimbic prefrontal cortex (IL-PFC) and prelimbic prefrontal cortex (PL-PFC) of mPFC (medial prefrontal cortex) and basal amygdala (BA), lateral amygdala (LA), centrolateral amygdala (CeL), centromedial amygdala (CeM) of the amygdala was performed to link region-specific histone acetylation to fear and extinction learning. It was found that the PL-PFC and IL-PFC along with the sub-regions of the amygdala responded differentially to the fear learning and extinction. Following fear learning, c-fos and CBP expression and acetylation of H3 and H4 increased in the BA, LA, CeM, and CeL and the PL-PFC but not in the IL-PFC as compared to the naive control. Similarly, following extinction learning, c-fos and CBP expression increased in BA, LA, CeL, and IL-PFC but not in PL-PFC and CeM as compared to the naive control and conditioned group. However, the acetylation of H3 increased in both IL and PL as opposed to H4 which increased only in the IL-PFC following extinction learning. Overall, region-specific activation in amygdala and PFC following fear and extinction learning as evident by the c-fos activation paralleled the H3/H4 acetylation in these regions. These results suggest that the differential histone acetylation in the PFC and amygdala subnuclei following fear learning and extinction may be associated with the region-specific changes in the neuronal activation pattern resulting in more fear/less fear.