BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior

Maynard, Kristen R.; Hobbs, John W.; Phan, BaDoi N.; Gupta, Amolika; Rajpurohit, Sumita; Williams, Courtney; Rajpurohit, Nina; Shin, Joo Heon; Jaffe, Andrew E.

doi:10.1101/250332

Cited by 10 publications

(14 citation statements)

References 84 publications

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“…BDNF gene expression is regulated in a sophisticated manner, with the transcription of every 5Ј exon being controlled by a separate promoter (Timmusk et al, 1993;Aid et al, 2007;Pruunsild et al, 2007) and by numerous transcription factors (e.g., NPAS4, USF family, MeCP2, NFAT family, and CREB) in response to various stimuli (for review, see West et al, 2014). Interestingly, disruption of specific BDNF transcripts has proven important roles for different BDNF promoters in the formation of neural circuits underlying social behavior (Maynard et al, 2016(Maynard et al, , 2018.…”

Section: Introductionmentioning

confidence: 99%

CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons

et al. 2020

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BDNF signaling via its transmembrane receptor TrkB has an important role in neuronal survival, differentiation, and synaptic plasticity. Remarkably, BDNF is capable of modulating its own expression levels in neurons, forming a transcriptional positive feedback loop. In the current study, we have investigated this phenomenon in primary cultures of rat cortical neurons using overexpression of dominantnegative forms of several transcription factors, including CREB, ATF2, C/EBP, USF, and NFAT. We show that CREB family transcription factors, together with the coactivator CBP/p300, but not the CRTC family, are the main regulators of rat BDNF gene expression after TrkB signaling. CREB family transcription factors are required for the early induction of all the major BDNF transcripts, whereas CREB itself directly binds only to BDNF promoter IV, is phosphorylated in response to BDNF-TrkB signaling, and activates transcription from BDNF promoter IV by recruiting CBP. Our complementary reporter assays with BDNF promoter constructs indicate that the regulation of BDNF by CREB family after BDNF-TrkB signaling is generally conserved between rat and human. However, we demonstrate that a nonconserved functional cAMP-responsive element in BDNF promoter IXa in humans renders the human promoter responsive to BDNF-TrkB-CREB signaling, whereas the rat ortholog is unresponsive. Finally, we show that extensive BDNF transcriptional autoregulation, encompassing all major BDNF transcripts, occurs also in vivo in the adult rat hippocampus during BDNF-induced LTP. Collectively, these results improve the understanding of the intricate mechanism of BDNF transcriptional autoregulation.

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Section: Introductionmentioning

confidence: 99%

CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons

et al. 2020

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“…Although the signaling pathway linking OT to BDNF regulation is not entirely known, robust OT-induced regulation of BDNF expression and associated neuronal plasticity has been shown in various contexts. OT is able to enhance BDNF protein expression (79-81), increase neurogenesis and brain volume (80), and modulate behavior via BDNF-TrkB signaling in OT neurons (82). Functionally, OT acts via the cAMP/PKA-CREB signaling pathway to gate BDNF actions (83,84).…”

Section: Discussionmentioning

confidence: 99%

“…Functionally, OT acts via the cAMP/PKA-CREB signaling pathway to gate BDNF actions (83,84). Moreover, OT-enriched mRNAs encode proteins critical for structural and functional plasticity, including cytoskeletal and postsynaptic organization and pathways involved in rapid activity-induced, experience-dependent plasticity (82).…”

Section: Discussionmentioning

confidence: 99%

Regional Differences in Brain Plasticity and Behaviour as a Function of Sex and Enrichment Type: Oxytocin Matters

Faraji

Lotfi

Moharrerie

et al. 2021

Preprint

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The early environment is critical to brain development, but the relative contribution of physical vs. social stimulation is unclear. Here, we investigated in male and female rats the response to early physical and social environmental enrichment in relation to oxytocin (OT) and brain-derived neurotrophic factor (BDNF) expression. The findings show that males and females respond differently to prolonged sensorimotor stimulation from postnatal day 21-110 in terms of functional, structural and molecular changes in the hippocampus vs. medial prefrontal cortex (mPFC). Physical enrichment promoted motor and cognitive functions and hippocampal BDNF mRNA and protein expression in both sexes. Combined physical and social enrichment, however, promoted functional and structural gain predominantly in females. These changes were accompanied by elevated plasma oxytocin (OT) levels and BDNF mRNA expression in the mPFC while the hippocampus was not affected. Administration of an OT antagonist in females blocked the beneficial effects of enrichment and led to reduced cortical BDNF signaling. These findings suggest that an OT-based mechanism selectively stimulates a region-specific BDNF response which is dependent on the type of experience.

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“…One example of this complexity occurs at the brain-derived neurotrophic factor gene Bdnf, which uses divergent non-coding exons (1-Xa) combined with a single coding exon (IX) in multiple alternatively spliced forms produced from distinct gene promoters (Figure 3a) 59 . The most highly expressed transcripts employ either the noncoding exon I or IV, and the specific functionality of this transcript heterogeneity remains an area of active investigation 44,[60][61][62] . We designed short hairpin RNAs (shRNAs) and CRISPRi sgRNAs to compare these targeted transcript suppression methods at the Bdnf I and Bdnf IV individual transcripts.…”

Section: Dcas9-krab-mecp2 Induces Targeted Transcriptspecific Bdnf Gementioning

confidence: 99%

An improved CRISPR/dCas9 interference tool for neuronal gene suppression

Duke

Revanna

Sultan

et al. 2020

Preprint

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The expression of genetic material governs brain development, differentiation, and function, and targeted manipulation of gene expression is required to understand contributions of gene function to health and disease states. Although recent improvements in CRISPR/dCas9 interference (CRISPRi) technology have enabled targeted transcriptional repression at selected genomic sites, integrating these techniques for use in non-dividing neuronal systems remains challenging. Previously, we optimized a dual lentivirus expression system to express CRISPR-based activation machinery in post-mitotic neurons. Here we used a similar strategy to adapt an improved dCas9-KRAB-MeCP2 repression system for robust transcriptional inhibition in neurons. We find that lentiviral delivery of a dCas9-KRAB-MeCP2 construct driven by the neuron-selective promoter human synapsin 1 enabled transgene expression in primary rat neurons. Next, we demonstrate transcriptional repression using CRISPR sgRNAs targeting diverse gene promoters, and show superiority of this system in neurons compared to existing RNA interference methods for robust transcript specific manipulation at the complex Brain-derived neurotrophic factor (Bdnf) gene. Our findings advance this improved CRISPRi technology for use in neuronal systems for the first time, potentially enabling improved ability to manipulate gene expression states in the nervous system.Correspondence to Jeremy Day (jjday@uab.edu | day-lab.org | @DayLabUAB)

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BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior

Cited by 10 publications

References 84 publications

CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons

CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons

Regional Differences in Brain Plasticity and Behaviour as a Function of Sex and Enrichment Type: Oxytocin Matters

An improved CRISPR/dCas9 interference tool for neuronal gene suppression

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