HDAC3 Inhibitor RGFP966 Modulates Neuronal Memory for Vocal Communication Signals in a Songbird Model

Abstract

Epigenetic mechanisms that modify chromatin conformation have recently been under investigation for their contributions to learning and the formation of memory. For example, the role of enzymes involved in histone acetylation are studied in the formation of long-lasting memories because memory consolidation requires gene expression events that are facilitated by an open state of chromatin. We recently proposed that epigenetic events may control the entry of specific sensory features into long-term memory by enabling transcription-mediated neuronal plasticity in sensory brain areas. Histone deacetylases, like HDAC3, may thereby regulate the specific sensory information that is captured for entry into long-term memory stores (Phan and Bieszczad, 2016). To test this hypothesis, we used an HDAC3-selective inhibitor (RGFP966) to determine whether its application after an experience with a sound stimulus with unique acoustic features could contribute to the formation of a memory that would assist in mediating its later recognition. We gave adult male zebra finches limited exposure to unique conspecific songs (20 repetitions each, well below the normal threshold to form long-term memory), followed by treatment with RGFP966 or vehicle. In different groups, we either made multi-electrode recordings in the higher auditory area NCM (caudal medial nidopallidum), or determined expression of an immediate early gene, zenk (also identified as zif268, egr-1, ngfi-a and krox24), known to participate in neuronal memory in this system. We found that birds treated with RGFP966 showed neuronal memory after only limited exposure, while birds treated with vehicle did not. Strikingly, evidence of neuronal memory in NCM induced by HDAC3-inhibition was lateralized to the left-hemisphere, consistent with our finding that RGFP966-treatment also elevated zenk expression only in the left hemisphere. The present findings show feasibility for epigenetic mechanisms to control neural plasticity underlying the formation of specific memories for conspecific communication sounds. This is the first evidence in zebra finches that epigenetic mechanisms may contribute to gene expression events for memory of acoustically-rich sensory cues.

Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats

“…However, a limitation of our approach is that we used only one dose of RGFP966. Several previous studies have found that systemic administration of 10 mg/kg of RGFP966 promotes memory and plasticity (Bieszczad, et al 2015; Malvaez et al 2013; Phan et al 2017). Malvaez et al (2013) found that a lower dose (3 mg/kg) enhanced object memory relative to vehicle but this effect was smaller compared to 10 mg/kg and 30 mg/kg of RGFP966.…”

Avian ecological epigenetics: pitfalls and promises

“…The role of histone modifications has also been studied in this context. Pharmacological inhibition of histone deacetylases (HDAC) in Zebra Finches contributed to the memorization of conspecific vocalizations (Phan et al 2017). The fact that HDAC can be recruited by DNA methylation, which leads to the removal of acetyl groups resulting in constricted access to chromatin and transcriptional silencing (Day and Sweatt 2011), might indicate that DNA methylation regulates song memory formation in birds through the modulation of the structure of chromatin.…”

Does Functional Lateralization in Birds Have any Implications for Their Welfare?

“…This discovery was followed by similar evidence in other songbird species, including two species of sparrow, Zonotrichia spp., and the canary, Serinus canarius [9]. Not surprisingly, these discoveries began an active field of research on lateralization of bird song at the behavioural, anatomical and cellular levels (see [10] for a recent study) and parallels have been drawn between acquisition of bird song and of human speech [11]. However, we mention this only in passing since, in this paper, we focus on lateralization of visual perception and response to visual stimuli.…”