ORCID Profile
0000-0002-7106-2298
Current Organisation
Australian National University
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Publisher: American Chemical Society (ACS)
Date: 05-04-2022
Publisher: Springer Science and Business Media LLC
Date: 27-09-2016
DOI: 10.1038/NN.4378
Publisher: Cold Spring Harbor Laboratory
Date: 15-07-2022
DOI: 10.1101/2022.07.14.500137
Abstract: Circular RNAs (circRNAs) comprise a novel class of regulatory RNAs that are abundant in the brain, particularly within synapses. They are highly stable, dynamically regulated, and display a range of functional roles, including as decoys for miRNAs and proteins and, in some cases, translation. Early work in animal models revealed an association between circRNAs and neurodegenerative and neuropsychiatric disorders however, relatively few studies have shown a causal link between circRNA function and memory. To address this knowledge gap, we sequenced circRNAs in the synaptosome compartment of the medial prefrontal cortex of fear extinction trained male C57BL/6J mice and found 12837 circRNAs enriched at the synapse, including Cdr1as . Targeted knockdown of Cdr1as in the neural processes of the infralimbic prefrontal cortex of male C57BL/6J mice led to impaired fear extinction memory. Altogether, our findings highlight the importance of localised circRNA activity at the synapse for memory formation and suggest that circRNAs may have a more widespread effect on brain function than previously thought.
Publisher: MDPI AG
Date: 22-05-2015
DOI: 10.3390/NU7053869
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.PSYNEUEN.2018.08.032
Abstract: While increasing evidence posits poor decision-making as a central feature of mental disorders, very few studies investigated the effects of early-life stress (ELS) on specific components of reward-related choice behaviors. Risk-taking (RT) involves the exposure to some danger, or negative consequences, in order to achieve a goal-directed behavior. Such behaviors are likely to be preceded by risk-assessment (RA), which is a dynamic cognitive process involving the acquisition of information in potentially dangerous situations. Here, we investigated the effects of being raised in impoverished housing conditions during early life (P2-P9) on RT, RA and dopaminergic and corticotrophinergic gene expression of adolescent male and female mice. Phenotypes were assessed by two protocols: the elevated plus-maze (EPM) and the predator-odor risk-taking (PORT). We found decreased RA in mice exposed to impoverished housing in the absence of a reward (EPM), with a more pronounced effect among females. Moreover, when exposed to a predatory olfactory cue, increased RT was observed in these females in a reward-related task (PORT), as well as decreased HPA axis responsivity. This sex-specific behavioral effect was associated with increased Crfr1 mRNA expression in the medial prefrontal cortex (mPFC) and higher levels of the histone mark H3R2
Publisher: Springer Science and Business Media LLC
Date: 18-02-2019
Publisher: Wiley
Date: 03-11-2016
DOI: 10.1002/DEV.21487
Abstract: Exposure to early life stress has been associated with memory impairments related to changes in brain-derived neurotrophic factor (BDNF) signaling. However, the potential impact of physical exercise to reverse these effects of maternal separation has been under investigated. Mice were subjected to maternal separation during the first 2 weeks of life and then exposed to a 3-week running protocol during adolescence. The spontaneous object recognition task was performed during adolescence followed by analysis of hippoc al expression of exons I, IV, and IX of the BDNF gene. As expected, maternal separation impaired recognition memory and this effect was reversed by exercise. In addition, running increased BDNF exon I expression, but decreased expression of BDNF exon IV in all groups, while exon IX expression increased only in MS animals exposed to exercise. Our data suggest that memory deficits can be attenuated by exercise and specific transcripts of the BDNF gene are dynamically regulated following both MS and exercise.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2015
DOI: 10.1007/S00213-015-4121-9
Abstract: It has been suggested that withdrawal from sugar produces a set of symptoms that resemble those observed following withdrawal from opiate drugs. This study explored naltrexone-induced withdrawal in animals pre-exposed to acute, chronic, and intermittent high fructose corn syrup (HFCS) or acute and chronic heroin administration. Experiment 1 examined conditioned place avoidance (CPA) induced by different doses of naltrexone (0.01-1 mg/kg) in naïve male Sprague-Dawley rats. In experiment 2, rats received continuous or intermittent home cage HFCS access (0 or 50 %) prior to conditioning with 1 mg/kg naltrexone. In experiment 3, HFCS ingestion was increased by food restriction and rats were conditioned with 3 mg/kg naltrexone. In experiment 4, the timing and quantity of HFCS ingestion (0, 0.5, 1, 2 g/kg) was controlled by intragastric administration, and rats were conditioned with 1 mg/kg naltrexone. In experiment 5, rats received acute (2 mg/kg) or chronic heroin (3.5 mg/kg/day) prior to conditioning with 1 mg/kg naltrexone. Administration of naltrexone produced moderate conditioned place avoidance in naïve rats. Importantly, acute, continuous, and intermittent HFCS pre-exposure did not significantly lify this effect, but acute and chronic heroin pre-exposure did. As assessed by CPA, these results in rats fail to support the hypothesis that an opioid antagonist can precipitate similar affective withdrawal states following pre-exposure to sugars and opiates.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2018
Publisher: Springer Science and Business Media LLC
Date: 09-07-2016
DOI: 10.1007/S00213-016-4373-Z
Abstract: Early life stress is a major risk factor for cocaine addiction however, the underlying molecular mechanisms remain relatively unexplored. MicroRNA-212 (miR-212) and methyl CpG binding protein 2 (MeCP2) have recently emerged as key regulators of brain-derived neurotrophic factor (BDNF) signaling during the acquisition and maintenance of cocaine-seeking behaviors. We therefore investigated the effect of maternal separation (MS) on cocaine-induced conditioned place preference (CPP) during periadolescence and how this influences miR-212, Mecp2, and Bdnf expressions in the prefrontal cortex. Male BALB/c mice subjected to MS (3 h/day) from postnatal day 2 to 15 or normal animal facility rearing (AFR) were tested for CPP at postnatal day 45, or not exposed to experimental manipulations (drug-naïve animals). Cultured primary cortical neurons were used to determine miR-212 expression changes following depolarization by KCL treatment. MS increased cocaine-induced CPP and decreased Bdnf exon IV expression, which correlated with higher CPP scores in such animals. An experience-dependent decrease in miR-212 expression was observed following CPP test. This effect was mimicked in primary cortical neurons in vitro, under activity-dependent conditions. In contrast, increased Mecp2 expression was found after CPP test, suggesting an opposing relationship between miR-212 and Mecp2 expression following cocaine place preference acquisition. However, these effects were not present in mice exposed to MS. Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.
Publisher: Wiley
Date: 23-02-2023
DOI: 10.1111/AJPH.12872
Abstract: The Queensland Aboriginals Protection and Restriction of the Sale of Opium Act 1897 , which introduced the system of exemption certificates, also initiated another form of “exemption” — one based on employment. The Act permitted “lawfully employed” Aboriginal people to be “excepted” from forcible removal to reserves. Those placed on an Aboriginal reserve faced a restrictive life of disconnection from Country, kin networks, and traditional practices and way of life. Many Aboriginal people found employment in the pastoral industry and thus avoided the Act 's provision of removal to a reserve. This paper interrogates government records and reports to provide an understanding of the development and implementation of this legislation and the racial ideologies underpinning it. The 1898 diary of a Queensland pastoralist who employed Aboriginal men on his station is also examined to obtain an understanding of the roles, experiences, and position of Aboriginal people in the pastoral industry during this period. These findings reveal that despite hardships faced in the pastoral industry, Aboriginal people found advantages in this form of employment. Through their highly sought‐after pastoral skills and expertise, and strategic engagement with Europeans, Aboriginal people excelled in the pastoral industry, and many achieved significant levels of freedom and success.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2OB01864K
Abstract: Our study describes how regio- and stereochemistry influences the antifouling activity of naturally inspired 2,5-diketopiperazines.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2016
DOI: 10.1038/NPJSCILEARN.2016.14
Abstract: A complete understanding of the fundamental mechanisms of learning and memory continues to elude neuroscientists. Although many important discoveries have been made, the question of how memories are encoded and maintained at the molecular level remains. So far, this issue has been framed within the context of one of the most dominant concepts in molecular biology, the central dogma, and the result has been a protein-centric view of memory. Here, we discuss the evidence supporting a role for neuroepigenetic mechanisms, which constitute dynamic and reversible, state-dependent modifications at all levels of control over cellular function, and their role in learning and memory. This neuroepigenetic view suggests that DNA, RNA and protein each influence one another to produce a holistic cellular state that contributes to the formation and maintenance of memory, and predicts a parallel and distributed system for the consolidation, storage and retrieval of the engram.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2020
Publisher: American Chemical Society (ACS)
Date: 05-06-2023
Publisher: Cold Spring Harbor Laboratory
Date: 09-06-2022
DOI: 10.1101/2022.06.07.495230
Abstract: The RNA modification N 6 -methyladenosine (m 6 A) is critically involved in the regulation of gene activity underlying experience-dependent plasticity, and is necessary for the functional interplay between RNA and RNA binding proteins (RBPs) in the nucleus. However, the complete repertoire of m 6 A-modified RNA interacting RBPs in the synaptic compartment, and whether they are involved in fear extinction, have yet to be revealed. Using RNA immunoprecipitation followed by mass spectrometry, we discovered 12 novel, synapsespecific, learning-induced m 6 A readers in the medial prefrontal cortex of male C57/B6 mice. m 6 A RNA-sequencing also revealed a unique population of learning-related m 6 A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 ( Malat1 ). m 6 A-modified Malat1 binds to a subset of novel m 6 A readers, including cytoplasmic FMR1 interacting protein 2 (CYFIP2) and dihydropyrimidase-related protein 2 (DPYSL2) and a cell-type-specific, state-dependent, and synapse-specific reduction in m 6 A-modified Malat1 disrupts the interaction between Malat1 and DPYSL2 and impairs fear extinction. The consolidation of fear-extinction memory therefore relies on an interaction between m 6 A-modified Malat1 and select RBPs in the synaptic compartment.
Publisher: Society for Neuroscience
Date: 13-12-2018
DOI: 10.1523/JNEUROSCI.2024-18.2018
Abstract: We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45γ, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57BL/6 mice. Gadd45γ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises (1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and (2) a second wave of IEG expression associated with the recruitment of Gadd45γ and active DNA demethylation at the same site, which is necessary for memory consolidation. SIGNIFICANCE STATEMENT How does the pattern of immediate early gene transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how Gadd45γ, a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, Gadd45γ serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.
Publisher: American Chemical Society (ACS)
Date: 04-03-2019
DOI: 10.1021/ACS.ACCOUNTS.8B00624
Abstract: The alarming rate at which micro-organisms are developing resistance to conventional antibiotics represents one of the global challenges of our time. There is currently le space in the antibacterial drug pipeline, and scientists are trying to find innovative and novel strategies to target the microbial enemies. Nature has remained a source of inspiration for most of the antibiotics developed and used, and the immune molecules produced by the innate defense systems, as a first line of defense, have been heralded as the next source of antibiotics. Most living organisms produce an arsenal of antimicrobial peptides (AMPs) to rapidly fend off intruding pathogens, and several different attempts have been made to transform this versatile group of compounds into the next generation of antibiotics. However, faced with the many hurdles of using peptides as drugs, the success of these defense molecules as therapeutics remains to be realized. AMPs derived from the proteolytic degradation of the innate defense protein lactoferrin have been shown to display several favorable antimicrobial properties. In an attempt to investigate the biological and pharmacological properties of these much shorter AMPs, the sequence dependence was investigated, and it was shown, through a series of truncation experiments, that these AMPs in fact can be prepared as tripeptides, with improved antimicrobial activity, via the incorporation of unnatural hydrophobic residues and terminal cappings. In this Account, we describe how this class of promising cationic tripeptides has been developed to specifically address the main challenges limiting the general use of AMPs. This has been made possible through the identification of the antibacterial pharmacophore and via the incorporation of a range of unnatural hydrophobic and cationic amino acids. Incorporation of these residues at selected positions has allowed us to extensively establish how these compounds interact with the major proteolytic enzymes trypsin and chymotrypsin and also the two major drug-binding plasma proteins serum albumin and α-1 glycoprotein. Several of the challenges associated with using AMPs relate to their size, susceptibility to rapid proteolytic degradation, and poor oral bioavailability. Our studies have addressed these issues in detail, and the results have allowed us to effectively design and prepare active and metabolically stable AMPs that have been evaluated in a range of functional settings. The optimized short AMPs display inhibitory activities against a plethora of micro-organisms at low micromolar concentrations, and they have been shown to target resistant strains of both bacteria and fungi alike with a very rapid mode of action. Our Account further describes how these compounds behave in in vivo experiments and highlights both the challenges and possibilities of the intriguing compounds. In several areas, they have been shown to exhibit comparable or superior activity to established antibacterial, antifungal, and antifouling commercial products. This illustrates their ability to effectively target and eradicate various microbes in a variety of settings ranging from the ocean to the clinic.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.NLM.2019.04.002
Abstract: The Piwi pathway is a conserved gene regulatory mechanism comprised of Piwi-like proteins and Piwi-interacting RNAs, which modulates gene expression via RNA interference and through interaction with epigenetic mechanisms. The mammalian Piwi pathway has been defined by its role in transposon control during spermatogenesis however, despite an increasing number of studies demonstrating its expression in the nervous system, relatively little is known about its function in neurons or potential contribution to behavioural regulation. We have discovered that all three Piwi-like genes are expressed in the adult mouse brain, and that viral-mediated knockdown of the Piwi-like genes Piwil1 and Piwil2 in the dorsal hippoc us leads to enhanced contextual fear memory without affecting generalised anxiety. These results implicate the Piwi pathway in behavioural regulation in the adult mammalian brain, likely through modulation of plasticity-related gene expression.
Publisher: Cold Spring Harbor Laboratory
Date: 10-01-2023
DOI: 10.1101/2023.01.09.523337
Abstract: The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here we report that DNA G-quadruplex (G4-DNA) accumulates in neurons in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation. G4-DNA is a molecular switch that enables the temporal regulation of the gene expression underlying the formation of fear extinction memory.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier
Date: 2017
Publisher: American Chemical Society (ACS)
Date: 06-06-2018
No related grants have been discovered for Paul Marshall.