Elsevier

Neurobiology of Aging

Volume 85, January 2020, Pages 140-144
Neurobiology of Aging

Regular article
Pharmacological activation of Nr4a rescues age-associated memory decline

https://doi.org/10.1016/j.neurobiolaging.2019.10.001Get rights and content

Highlights

  • Pharmacological activation of Nr4a using C-DIM drugs enhances long-term memory in young mice.

  • C-DIM drug reverses long-term memory deficits in aged mice.

  • Nr4a could be a potential therapeutic target to treat age-related cognitive impairment.

Abstract

Age-associated cognitive impairments affect an individual's quality of life and are a growing problem in society. Therefore, therapeutic strategies to treat age-related cognitive decline are needed to enhance the quality of life among the elderly. Activation of the Nr4a family of transcription factors has been closely linked to memory formation and dysregulation of these transcription factors is thought to be associated with age-related cognitive decline. Previously, we have shown that Nr4a transcription can be activated by synthetic bisindole-derived compounds (C-DIM). C-DIM compounds enhance synaptic plasticity and long-term contextual fear memory in young healthy mice. In this study, we show that activation of Nr4a2 by 1,1-bis(3′-Indolyl)-1-(p-chlorophenyl) methane (C-DIM12), enhances long-term spatial memory in young mice and rescues memory deficits in aged mice. These findings suggest that C-DIM activators of Nr4a transcription may be suitable to prevent memory deficits associated with aging.

Introduction

Aging is associated with a decline in cognitive ability. These deficits are particularly noticeable in hippocampus-dependent spatial and episodic memory (Gallagher et al., 2010, Wimmer et al., 2012). Studies using rodent models have demonstrated that age-associated cognitive decline may be due to deficits in transcriptional activity within the hippocampus that typically follow learning (Kwapis et al., 2019, Spiegel et al., 2014). Transcription is required for memory consolidation as well as the long-term stability and maintenance of hippocampal memories (Alberini and Kandel, 2014, Peixoto and Abel, 2013). Age-related impairments in transcription may prevent newly learned events from being stored properly as long-term memory and may explain some of the cognitive deficits that accompany aging. The Nr4a family of transcription factors is among the genes whose expression is downregulated in aged mice (Kwapis et al., 2018, Kwapis et al., 2019, Rowe et al., 2007). The Nr4a family of transcription factors consists of 3 members: Nr4a1/Nur77/HZF-3, Nr4a2/Nurr1/NGFI-B, and Nr4a3/NOR-1/TEC (Maxwell and Muscat, 2006); Nr4a1 and Nr4a2 are critical for hippocampus-dependent long-term memory (Hawk and Abel, 2011, Hawk et al., 2012, McNulty et al., 2012, Pena de Ortiz et al., 2000). Furthermore, restoring the expression level of Nr4a1 or Nr4a2 is sufficient to prevent memory deficits in aged mice (Kwapis et al., 2019).

The members of the Nr4a family are orphan receptors lacking endogenous ligands (Hawk and Abel, 2011), but paraphenyl substituted diindolylmethane analogs—or “C-DIM” compounds—have been designed to specifically and selectively activate members of the Nr4a family (Bridi et al., 2017, Hammond et al., 2018, Li et al., 2012). C-DIM5, an activator of Nr4a1, has been found to increase long-term fear memory in young adult mice and enhance hippocampal synaptic plasticity (Bridi et al., 2017). A recently developed Nr4a ligand, 1,1-bis(3′-indolyl)-1-(p-chlorophenyl)methane (C-DIM12/DIM-C-pPhCl), predominantly activates Nr4a2, but also shows some affinity toward Nr4a1 (Hammond et al., 2018). Although the cognitive enhancing effects of Nr4A activation have been demonstrated in young mice (Bridi et al., 2017), the question remains as to whether the select activation of endogenous Nr4a in aged mice would be sufficient to rescue memory deficits. In this study, we administered the Nr4a2 selective agonist, C-DIM12, via oral gavage to young and aged mice, resulting in enhanced long-term memory in a spatial object recognition task (SOR).

Section snippets

Animals

Mice were maintained under standard conditions consistent with National Institute of Health guidelines and approved by the Institutional Animal Care and Use Committee of the University of Iowa. Mice were individually housed and kept on a 12 hours light/12 hours dark cycle. Food and water were available ad libitum, and all experiments performed during the light cycle between zeitgeber time (ZT) 0 to 3. Young male C57BL/6J (2–4 months old) were from Jackson Laboratory and aged male C57BL/6NIA

Results

To test whether Nr4a activation by C-DIM12 enhances memory in young adult mice (2–4 month old) using a weak SOR protocol, we administered C-DIM12 or vehicle via oral gavage one hour before SOR training (Fig. 1A). We examined the efficacy of C-DIM12 using a dose response analysis (10 mg/kg, 35 mg/kg or 100 mg/kg) to assess the impact on long-term memory. Vehicle-treated animals failed to show any discrimination toward the DO during the test session compared with the training session (Fig. 1B, %

Discussion

Our main finding is that C-DIM12 enhances long-term memory, but not short-term memory, in young and aged mice. This result is consistent with our earlier work demonstrating that Nr4a transcription is a critical regulator of long-term memory (Bridi et al., 2017, Hawk et al., 2012). Even though we do not have direct evidence that the memory enhancement by C-DIM drugs are due directly to activation of Nr4a transcription factors in vivo, previous studies show that C-DIM compounds activate

Disclosure

The authors declare no competing financial interests.

Acknowledgements

This work was funded by National Institute of Health grants P50 AG 017628, RO1 MH 087463, and R01 MH 087463-08S1 to TA and Nellie Ball trust to SC. TA is supported by the Roy J. Carver Charitable Trust. We thank Tania Chatterjee and Joseph Lederman for technical assistance. We also thank the University of Iowa Neural Circuits and Behavior Core for use of the facility.

Mice were maintained under standard conditions consistent with National Institute of Health guidelines and approved by the

References (29)

  • S. Buervenich et al.

    NURR1 mutations in cases of schizophrenia and manic-depressive disorder

    Am. J. Med. Genet.

    (2000)
  • S. Chatterjee et al.

    Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator

    EMBO Mol. Med.

    (2018)
  • Y. Chu et al.

    Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra

    J. Comp. Neurol.

    (2002)
  • S.M. Corley et al.

    Transcriptomic analysis shows decreased cortical expression of NR4A1, NR4A2 and RXRB in schizophrenia and provides evidence for nuclear receptor dysregulation

    PLoS One

    (2016)
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