The brain-specific Neural Zinc Finger transcription factor 2b (NZF-2b/7ZFMyt1) causes suppression of cocaine-induced locomotor activity

Abstract

Chronic cocaine induces high expression of the brain-specific Neural-Zinc-Finger transcription factor-2b (NZF-2b/7ZFMyt1), particularly in the mesolimbic dopaminergic pathway, resulting in a 11-fold increase in NZF-2b/7ZFMyt1 expression in the Nucleus Accumbens (NAc). Overexpression of this gene in the NAc with a NZF-2b/7ZFMyt1-expressing lentivirus resulted in N55% decrease in locomotor activity upon chronic cocaine administration, compared to control animals. In contrast knocking-down the gene in the NAc with lentiviruses expressing shRNAs against NZF-2b/7ZFMyt1 induced strong hyperlocomotor activity upon cocaine. Strong inhibition of BDNF is observed upon NZF-2b/7ZFMyt1 expression, concomitant with strong induction of transcription factors REST1 (RE silencing transcription factor-1) and NAC1, probably leading to regulation of gene expression by interaction with histone deacetylases. These changes lead to decreased responsiveness of the animal to the locomotor-activating effects of cocaine, indicating that NZF-2b/7ZFMyt1 expression plays an important role in phenotypic changes induced by the drug.

The Role of Histone Acetylation in Cocaine-Induced Neural Plasticity and Behavior

“…NZF2b/7ZFMyt1 is upregulated in the NAc after chronic cocaine administration and represses as well as facilitates the expression of genes necessary for cocaine's locomotor effects (Chandrasekar and Dreyer, 2010b), and self-administration (Chandrasekar and Dreyer, 2010). A precise role for HDAC2 in cocaineinduced, NZF2b/7ZFMyt1-mediated transcriptional responses, however, remains unstudied.…”

Viral-mediated overexpression of the Myelin Transcription Factor 1 (MyT1) in the dentate gyrus attenuates anxiety- and ethanol-related behaviors in rats

“…Our results confirm that using viral vectors aimed at increasing MyT1 expression in discrete and specific brain region (such as the DG) reduces both the expression of anxiety-like behavior and ethanol intake in well-validated rodent models. The observed effectiveness of MyT1-expressing lentiviral vectors in reducing ethanol drinking while apparently inducing anxiolysis is very encouraging, as these findings correspond with their efficacy in attenuating both cocaineinduced locomotor stimulation (Chandrasekar and Dreyer 2010a) and cocaine self-administration (Chandrasekar and Dreyer 2010b) in rats.…”

The brain-specific neural zinc finger transcription factor 2b (NZF-2b/7ZFMyt1) suppresses cocaine self-administration in rats

“…Stereotaxical injections were performed into the NAc shell; one group was injected LV-7ZFMyt1 (a doxycycline-regulatable lentiviral vector), the second group LV-7ZFMyt-shRNAs (a mixture of three non-regulatable lentiviral vectors expressing shRNAs targeted against NZF-2b/7ZFMyt1) and the third group the regulatable LV-GFP (control group). LV-7ZFMyt1 expression and specific silencing efficiency with LV-7ZFMyt1-siRNAs have been confirmed in vitro (Chandrasekar and Dreyer, 2010). After intravenous catheterization, training and acquisition of cocaine SA under FR5, the effects of LV-mediated gene expression were assessed over a period of 4–5 weeks.…”

“…In the previous studies we have shown that the brain-specific transcription factor NZF2b/7ZFMyt1 (Neural Zinc Finger Transcription Factor-2b/7-Zinc Finger Myelin Transcription Factor-1) is induced significantly in the brain reward pathway after chronic cocaine administration and may play a key role in regulating the locomotor effects of cocaine (Chandrasekar and Dreyer, 2010). Expressed predominantly in the developing CNS, neural precursors and some subpopulations of mature neurons (Kim and Hudson, 1992; Bellefroid et al, 1996; Kim et al, 1997; Matsushita et al, 2002) NZF-2b/7ZFMyt1 is also expressed in developing oligodendrocytes and tightly regulates expression of several myelin-specific gene products, such as PLP1, MAL2, etc.…”

“…Brain-specific neural-zinc-finger transcription factor-2b (NZF2b/7ZFMyt1) is induced in the mesolimbic dopaminergic region after chronic cocaine exposure and lentiviral-mediated expression of NZF2b/7ZFMyt1 in the nucleus accumbens results in decreased locomotor activity (Chandrasekar and Dreyer, 2010). In this study the role of NZF2b/7ZFMyt1 in active cocaine seeking and of its interaction with histone deacetylase on the altered behavior has been observed.…”