Cognitive neuroepigenetics

About

The extinction of conditioned fear (the reduction in response to a feared cue when the cue is repeatedly presented without any adverse consequence) is an important model for the treatment of anxiety disorders. Like other forms of learning, long-lasting memory for fear extinction depends on coordinated gene expression and the synthesis of new synaptic proteins. This process involves a tightly controlled interplay between transcriptional machinery and enzymes that regulate chromatin structure, a relatively recent field of research referred to as epigenetics.

Research in the Bredy laboratory is elucidating how the genome is connected to the environment through epigenetic modifications, and how this relationship shapes behaviour throughout life. The group is particularly interested in how epigenetic mechanisms, including DNA methylation, histone modifications and the activity of non-coding RNAs, regulate the formation and maintenance of memory.

It was a productive year for the laboratory, which published a ground-breaking new study on the role of long non-coding RNAs and neural plasticity in the journal Biological Psychiatry. In other work, which appeared in the journal Neuroepigenetics, the group demonstrated together with collaborators that neuron-specific changes in DNA methylation are associated with cocaine addiction. The work received significant exposure, with invited talks at several international meetings, including the Keystone conference on Neuroepigenetics and Behavioral Epigenetics at Janelia Research Campus.

Contact

  +61 7 334 66391

  t.bredy@uq.edu.au


Group Publications

Research Areas

  • Epigenetics 
  • Phobia, post-traumatic stress disorder (PTSD), and addiction 
  • Genomes and the environment 


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Transgenerational paternal transmission of acquired traits: stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes

Pang, Terence Y. C., Short, Annabel K., Bredy, Timothy W. and Hannan, Anthony J. (2017) Transgenerational paternal transmission of acquired traits: stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes. Current Opinion in Behavioral Sciences14 140-147. doi:10.1016/j.cobeha.2017.02.007

Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes

Yeshurun, Shlomo, Short, Annabel K., Bredy, Timothy W., Pang, Terence Y. and Hannan, Anthony J. (2017) Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes.Psychoneuroendocrinology77 225-235. doi:10.1016/j.psyneuen.2016.11.013

Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain

Ratnu, Vikram S., Emami, Michael R. and Bredy, Timothy W. (2017) Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain. Journal of Neuroscience Research95 1-2: 301-310. doi:10.1002/jnr.23886

MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-impaired mice

Murphy, Conor P., Li, Xiang, Maurer, Verena, Oberhauser, Michael, Gstir, Ronald, Wearick-Silva, Luis Eduardo, Viola, Thiago Wendt, Schafferer, Simon, Grassi-Oliverira, Rodrigo, Whittle, Nigel, Huttenhofer, Alexander, Bredy, Timothy W. and Singewald, Nicolas (2016) MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-impaired mice. Biological Psychiatry, . doi:10.1016/j.biopsych.2016.12.021

Evolving insights into RNA modifications and their functional diversity in the brain

Nainar, Sarah, Marshall, Paul R., Tyler, Christina R., Spitale, Robert C. and Bredy, Timothy W. (2016) Evolving insights into RNA modifications and their functional diversity in the brain. Nature Neuroscience19 10: 1292-1298. doi:10.1038/nn.4378

Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2

Viola, Thiago Wendt, Wearick-Silva, Luis Eduardo, De Azeredo, Lucas Araujo, Centeno-Silva, Anderson, Murphy, Conor, Marshall, Paul, Li, Xiang, Singewald, Nicolas, Garcia, Frederico, Bredy, Timothy W. and Grassi-Oliveira, Rodrigo (2016) Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2. Psychopharmacology233 17: 3279-3288. doi:10.1007/s00213-016-4373-z

Cognitive neuroepigenetics: the next evolution in our understanding of the molecular mechanisms underlying learning and memory?

Marshall, Paul and Bredy, Timothy W. (2016) Cognitive neuroepigenetics: the next evolution in our understanding of the molecular mechanisms underlying learning and memory?. n p j Science of Learning, 16014. doi:10.1038/npjscilearn.2016.14

Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice

Widagdo, Jocelyn, Zhao, Qiong-Yi, Kempen, Marie-Jeanne, Tan, Men Chee, Ratnu, Vikram S., Wei, Wei, Leighton, Laura, Spadaro, Paola A., Edson, Janette, Anggono, Victor and Bredy, Timothy W. (2016) Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice. Journal of Neuroscience36 25: 6771-6777. doi:10.1523/JNEUROSCI.4053-15.2016

Sex differences in learned fear expression and extinction involve altered gamma oscillations in medial prefrontal cortex

Fenton, Georgina E., Halliday, David M., Mason, Rob, Bredy, Timothy W. and Stevenson, Carl W. (2016) Sex differences in learned fear expression and extinction involve altered gamma oscillations in medial prefrontal cortex.Neurobiology of Learning and Memory135 66-72. doi:10.1016/j.nlm.2016.06.019

The role of active DNA demethylation and Tet enzyme function in memory formation and cocaine action

Alaghband, Yasaman, Bredy, Timothy W. and Wood, Marcelo A. (2016) The role of active DNA demethylation and Tet enzyme function in memory formation and cocaine action. Neuroscience Letters625 40-46. doi:10.1016/j.neulet.2016.01.023

Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring

Short, A. K., Fennell, K. A., Perreau, V. M., Fox, A., O'Bryan, M. K., Kim, J. H., Bredy, T. W., Pang, T. Y. and Hannan, A. J. (2016) Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring. Translational Psychiatry6 . doi:10.1038/tp.2016.109

Synergistic Actions of Ogg1 and Mutyh DNA Glycosylases Modulate Anxiety-like Behavior in Mice

Bjorge, Monica D., Hildrestrand, Gunn A., Scheffler, Katja, Suganthan, Rajikala, Rolseth, Veslemoy, Kusnierczyk, Anna, Rowe, Alexander D., Vagbo, Cathrine B., Vetlesen, Susanne, Eide, Lars, Slupphaug, Geir, Nakabeppu, Yusaku, Bredy, Timothy W., Klungland, Arne and Bjoras, Magnar (2015) Synergistic Actions of Ogg1 and Mutyh DNA Glycosylases Modulate Anxiety-like Behavior in Mice. Cell Reports13 12: 2671-2678. doi:10.1016/j.celrep.2015.12.001

Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice

Baker-Andresen, Danay, Zhao, Qiongyi, Li, Xiang, Jupp, Bianca, Chesworth, Rose, Lawrence, Andrew J. and Bredy, Timothy (2015) Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice. Neuroepigenetics4 1-11. doi:10.1016/j.nepig.2015.10.001

Long noncoding RNA-directed epigenetic regulation of gene expression is associated with anxiety-like behavior in mice

Spadaro, Paola A., Flavell, Charlotte R., Widagdo, Jocelyn, Ratnu, Vikram S., Troup, Michael, Ragan, Chikako, Mattick, John S. and Bredy, Timothy W. (2015) Long noncoding RNA-directed epigenetic regulation of gene expression is associated with anxiety-like behavior in mice. Biological Psychiatry78 12: 848-859. doi:10.1016/j.biopsych.2015.02.004

Activation-induced cytidine deaminase regulates activity-dependent BDNF expression in post-mitotic cortical neurons

Ratnu, Vikram S., Wei, Wei and Bredy, Timothy W. (2014) Activation-induced cytidine deaminase regulates activity-dependent BDNF expression in post-mitotic cortical neurons. European Journal of Neuroscience40 7: 3032-3039. doi:10.1111/ejn.12678

Methyl CpG Binding Domain Ultra-Sequencing: a novel method for identifying inter-individual and cell-type-specific variation in DNA methylation

Li, X., Baker-Andresen, D., Zhao, Q., Marshall, V. and Bredy, T. W. (2014) Methyl CpG Binding Domain Ultra-Sequencing: a novel method for identifying inter-individual and cell-type-specific variation in DNA methylation.Genes, Brain and Behavior13 7: 721-731. doi:10.1111/gbb.12150

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Li, Xiang, Wei, Wei, Zhao, Qiong-Yi, Widagdo, Jocelyn, Baker-Andresen, Danay, Flavell, Charlotte R., D'Alessio, Ana, Zhang, Yi and Bredy, Timothy W. (2014) Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proceedings of the National Academy of Sciences111 19: 7120-7125. doi:10.1073/pnas.1318906111

Persistent prelimbic cortex activity contributes to enhanced learned fear expression in females

Fenton, Georgina E., Pollard, Amelia K, Halliday, David M., Mason, Rob, Bredy, Timothy W. and Stevenson, Carl W. (2014) Persistent prelimbic cortex activity contributes to enhanced learned fear expression in females. Learning and Memory21 2: 55-60. doi:10.1101/lm.033514.113

Mechanisms governing the reactivation-dependent destabilization of memories and their role in extinction

Flavell, Charlotte R., Lambert, Elliot A., Winters, Boyer D. and Bredy, Timothy W. (2013) Mechanisms governing the reactivation-dependent destabilization of memories and their role in extinction. Frontiers in Behavioral Neuroscience,7 DEC: 214.1-214.11. doi:10.3389/fnbeh.2013.00214

Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior

Ploense, Kyle L., Kerstetter, Kerry A., Wade, Matthew A., Woodward, Nicholas C., Maliniak, Dan, Reyes, Michael, Uchizono, Russell S., Bredy, Timothy W. and Kippin, Tod E. (2013) Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior. Behavioural Pharmacology24 3: 164-171. doi:10.1097/FBP.0b013e32836104ea

Activation of BDNF signaling prevents the return of fear in female mice

Baker-Andresen, Danay, Flavell, Charlotte R., Li, Xiang and Bredy, Timothy W. (2013) Activation of BDNF signaling prevents the return of fear in female mice. Learning & Memory20 5: 237-240. doi:10.1101/lm.029520.112

The amygdala and medial prefrontal cortex: partners in the fear circuit

Marek, Roger, Strobel, Cornelia, Bredy, Timothy W. and Sah, Pankaj (2013) The amygdala and medial prefrontal cortex: partners in the fear circuit. Journal of Physiology591 10: 2381-2391. doi:10.1113/jphysiol.2012.248575

Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaptation

Baker-Andresen, Danay, Ratnu, Vikram and Bredy, Timothy (2013) Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaptation. Trends In Neurosciences36 1: 3-13. doi:10.1016/j.tins.2012.09.003

On the potential role of active DNA demethylation in establishing epigenetic states associated with neural plasticity and memory

Li, Xiang, Wei, Wei, Ratnu, Vikram and Bredy, Timothy (2013) On the potential role of active DNA demethylation in establishing epigenetic states associated with neural plasticity and memory. Neurobiology of Learning and Memory,105 125-132. doi:10.1016/j.nlm.2013.06.009

The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing

Barry, Guy, Briggs, J. A., Vanichkina, D. P., Poth, E. M., Beveridge, N. J., Vikram Ratnu, Nayler, S. P., Nones, K., Hu, J., Timothy Bredy, Nakagawa, S., Rigo, F., Taft, R. J., Cairns, M. J., Blackshaw, S., Wolvetang, E. J. and Mattick, J. S. (2013) The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Molecular Psychiatry19 4: 486-494. doi:10.1038/mp.2013.45

p300/CBP-associated factor selectively regulates the extinction of conditioned fear

Wei, Wei, Coelho, Carlos M., Li, Xiang, Marek, Roger, Yan, Shanzhi, Anderson, Shawn, Meyers, David, Mukherjee, Chandrani, Sbardella, Gianluca, Castellano, Sabrina, Milite, Ciro, Rotili, Dante, Mai, Antonello, Cole, Philip A., Sah, Pankaj, Kobor, Michael S. and Bredy, Timothy W. (2012) p300/CBP-associated factor selectively regulates the extinction of conditioned fear. Journal of Neuroscience32 35: 11930-11941. doi:10.1523/JNEUROSCI.0178-12.2012

Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders

Spadaro, Paola A. and Bredy, Timothy W. (2012) Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders. Frontiers in Genetics3 JUL: 132.1-132.16. doi:10.3389/fgene.2012.00132

The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

Lin, Quan, Wei, Wei, Coelho, Carlos M., Li, Xiang, Baker-Andresen, Dannay, Dudley, Kevin, Ratnu, Vikram S., Boskovic, Zoran, Kobor, Michael S., Sun, Yi E. and Bredy, Timothy W. (2011) The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory. Nature Neuroscience14 9: 1115-1117. doi:10.1038/nn.2891

MicroRNA regulation of neural plasticity and memory

Bredy, Timothy W., Lin, Quan, Wei, Wei, Baker-Andresen, Danay and Mattick, John S. (2011) MicroRNA regulation of neural plasticity and memory. Neurobiology of Learning and Memory96 1: 89-94. doi:10.1016/j.nlm.2011.04.004

Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders

Dudley, Kevin J., Li, Xiang, Kobor, Michael S., Kippin, Tod E. and Bredy, Timothy W. (2011) Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders. Neuroscience and Biobehavioral Reviews35 7: 1544-1551. doi:10.1016/j.neubiorev.2010.12.016

Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300

Marek, Roger, Coelho, Carlos M., Sullivan, Robert K. P., Baker-Andresen, Danay, Li, Xiang, Ratnu, Vikram, Dudley, Kevin J., Meyers, David, Mukherjee, Chandrani, Cole, Philip A., Sah, Pankaj and Bredy, Timothy W. (2011) Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300. Journal of Neuroscience31 20: 7486-7491. doi:10.1523/JNEUROSCI.0133-11.2011

How the epigenome contributes to the development of psychiatric disorders

Bredy, Timothy W., Sun, Yi E. and Kobor, Michael S. (2010) How the epigenome contributes to the development of psychiatric disorders. Developmental Psychobiology52 4: 331-342. doi:10.1002/dev.20424

Paternal deprivation during infancy results in dendrite- and time-specific changes of dendritic development and spine formation in the orbitofrontal cortex of the biparental rodent Octodon degus

Helmekea, C., Seidel, K., Poeggel, G., Bredy, Timothy, Abraham, A. and Braun, K. (2009) Paternal deprivation during infancy results in dendrite- and time-specific changes of dendritic development and spine formation in the orbitofrontal cortex of the biparental rodent Octodon degus. Neuroscience163 3: 790-798. doi:10.1016/j.neuroscience.2009.07.008

Social modulation of associative fear learning by pheromone communication

Bredy, Timothy W. and Barad, Mark (2009) Social modulation of associative fear learning by pheromone communication. Learning and Memory16 1: 12-18. doi:10.1101/lm.1226009

The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear

Timothy, Bredy and Barad, Mark (2008) The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Learning & Memory15 1: 39-45. doi:10.1101/lm.801108

Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear

Bredy, Timothy, Wu, Hao, Crego, Cortney, Zellhoefer, Jessica, Sun, Yi E. and Barad, Mark (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learning & Memory14 4: 268-276. doi:10.1101/lm.500907

Effect of resource availability on biparental care, and offspring neural and behavioral development in the California mouse (Peromyscus californicus)

Bredy, Timothy W., Brown, Richard E. and Meaney, Michael J. (2007) Effect of resource availability on biparental care, and offspring neural and behavioral development in the California mouse (Peromyscus californicus). European Journal of Neuroscience25 2: 567-575. doi:10.1111/j.1460-9568.2006.05266.x

Behavioural epigenetics and psychiatric disorders

Bredy, Timothy (2006) Behavioural epigenetics and psychiatric disorders. Medical Hypotheses68 2: 453-453. doi:10.1016/j.mehy.2006.07.009

Maternal programming of defensive responses through sustained effects on gene expression

Zhang, Tie-Yuan, Bagot, Rose, Parenta, Carine, Nesbitt, Cathy, Bredy, Timothy W., Caldji, Christian, Fish, Eric, Anisman, Hymie, Szyf, Moshe and Meaney, Michael J. (2006) Maternal programming of defensive responses through sustained effects on gene expression. Biological Psychology73 1: 72-89. doi:10.1016/j.biopsycho.2006.01.009

Conference Publication

Activity-dependent RNA methylation in learning and memory

Widagdo, J., Zhao, Q. -Y., Anggono, V. and Bredy, T. (2015). Activity-dependent RNA methylation in learning and memory. In: Special Issue: 25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society. 25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society, Cairns, QLD Australia, (118-118). 23-27 August 2015. doi:10.1111/jnc.13188

Dissociable roles of GADD45A/B in the rat perirhinal cortex and hippocampus for object memory: different forms of dna methylation?

Mitchnick, K., Wei, W., Creighton, S., Kalisch, B., Bredy, T. and Winters, B. (2015). Dissociable roles of GADD45A/B in the rat perirhinal cortex and hippocampus for object memory: different forms of dna methylation?. In: Special Issue: 25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society. 25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society, Cairns, QLD Australia, (115-115). 23-27 August 2015. doi:10.1111/jnc.13188

Epitranscriptomic mechanisms of memory stability

Bredy, T., Widagdo, J. and Zhao, Q.-Y. (2015). Epitranscriptomic mechanisms of memory stability. In: Special Issue: 25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society.25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society, Cairns, QLD Australia, (29-29). 23-27 August 2015. doi:10.1111/jnc.13185

Exploring the role of histone demethylase, UTX, in mediating sex differences in fear-related learning and memory

Ratnu, V., Li, X., Emami, M., Zhao, Q. -Y. and Bredy, T. (2015). Exploring the role of histone demethylase, UTX, in mediating sex differences in fear-related learning and memory. In: Special Issue: 25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society. 25th Biennial Meeting of the International Society for Neurochemistry Jointly with the 13th Meeting of the Asian Pacific Society for Neurochemistry in Conjunction with the 35th Meeting of the Australasian Neuroscience Society, Cairns, QLD Australia, (116-116). 23-27 August 2015. doi:10.1111/jnc.13188

Epigenetic programming of stress responses through variations in maternal care

Fish, Eric W., Shahrokh, Dara, Bagot, Rose, Caldji, Christian, Bredy, Timothy W., Szyf, Moshe and Meaney, Michael J. (2004). Epigenetic programming of stress responses through variations in maternal care. In: John Devine, James Gilligan, Klaus A. Miczek, Rashid Shaikh and Donald Pfaff, Youth Violence: Scientific Approaches to Prevention.Conference on Scientific Approaches to Youth Violence Prevention, New York, United States, (167-180). 24-26 April 2004. doi:10.1196/annals.1330.011


  • Professor John Mattick, Institute for Molecular Bioscience, The University of Queensland
  • Professor Andrew Lawrence, Howard Florey Institute
  • Associate Professor Tod Kippin, University of California (Santa Barbara)

 

Transgenerational impacts of paternal stress on offspring mental health: Epigenetic mechanisms and therapeutic interventions
(2015–2017) NHMRC Project Grant (administered by the University of Melbourne)