Florey Department of Neuroscience and Mental Health - Research Publications
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ItemEarly life stress alters pituitary growth during adolescence-A longitudinal study(PERGAMON-ELSEVIER SCIENCE LTD, 2015-03)The pituitary gland is integral in mediating the stress-response via its role in hypothalamic-pituitary-adrenal (HPA) axis function. Pituitary gland volume (PGV) is altered in stress-related psychopathology, and one study to date has shown stress to be associated with age-related PGV change during adolescence. The current study investigated the effects of a number of different types of early life (i.e., childhood and adolescent) stress (including childhood maltreatment, stressful life events, and maternal affective behavior) on PGV development from mid- to late adolescence using a longitudinal design. The influence of PGV development on depressive and anxiety symptoms was also investigated. Ninety one (49 male) adolescents took part in mother-child dyadic interaction tasks when they were approximately 12 years old, reported on childhood maltreatment and stressful life events when they were approximately 15 years old, and underwent two waves of structural magnetic resonance imaging (MRI) scans, when they were approximately 16 and 19 years old. Results revealed that childhood maltreatment predicted accelerated PGV development in females, and maternal dysphoric behavior predicted accelerated PGV development in the whole sample. PGV development was not associated with depressive or anxiety symptoms. These results suggest an effect of early life stress on altered HPA axis function across mid- to late adolescence. Further research is required to assess functional implications and whether these changes might be associated with risk for subsequent psychopathology.
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ItemExtinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor(WILEY, 2015-05)We investigated the effects of extinguishing action-reward versus context-reward associations on drug-primed reinstatement, and the potential role of the metabotropic glutamate 5 receptor (mGlu5) in these different types of extinction in rats that self-administer cocaine. We observed that daily context extinction (non-reinforced exposures to the cocaine-taking context with retracted levers) was just as effective as daily lever extinction in reducing cocaine-primed reinstatement compared with passive abstinence. Additionally, systemic injections of the mGlu5 negative allosteric modulator MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) following each extinction session significantly impaired the ability of context extinction to reduce cocaine-primed reinstatement, without affecting reinstatement after lever extinction or passive abstinence.
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ItemPostnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2017-02)Remembering and forgetting are fundamental features of an organism. Extinction is a type of forgetting where there is a decrease in the significance and/or the meaning of an associative memory when elements of that memory no longer predict one another. The neural mechanisms underlying extinction of fear memories have been extensively studied in the laboratory because extinction processes are clinically relevant to exposure therapies that treat anxiety disorders. However, only in the last decade have we begun to unveil the similarities and differences in plasticity underlying extinction across development. So far it is clear that extinction is a developmentally dissociated process in behavior and in pharmacology, however there are many large gaps in the literature in understanding how the developmental trajectory of different neurotransmitters contribute to changes in the nature of extinction across development. We attempt to address these gaps in the present review. Major neurotransmitter systems including the glutamatergic and GABAergic systems, the monoamines, the endogenous opioid and cannabinoid systems, acetylcholines, and neuropeptides such as oxytocin have all been identified to play some role in extinction of fear memories and have been covered in this review. We hope to facilitate more research into mechanisms of extinction at different stages of life, especially noting that mental disorders are increasingly classified as neurodevelopmental disorders.
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ItemDevelopmental perspectives on methamphetamine abuse: Exploring adolescent vulnerabilities on brain and behavior(PERGAMON-ELSEVIER SCIENCE LTD, 2018-12-20)Most people that experience illicit drugs do so for the first time during adolescence, and methamphetamine (meth) is no exception. Therefore, research into the effects of meth should highlight the adolescent period. Despite this, the vast majority of current literature has mainly focused on meth exposure during adulthood. In this review, we first describe existing literature that compares the behavioral effects of meth where exposure occurs in adolescence compared to adulthood. Given that there are actually very few such studies, we also look at what is known about neural effects of meth in the adult brain, and relate these to normal neural development occurring during the adolescent period to establish how meth may target maturing regions and related neurochemistry. What emerges overall is that adolescents appear to be more vulnerable to the rewarding and reinforcing effects of meth, and that meth indeed has effects on areas that are in flux during adolescence. However, there is some evidence for a paradoxical resistance to the neurotoxic effects during this period. We highlight the need for further age-related research to better understand, treat, and prevent meth use disorders and addiction in general.
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ItemP2X7 Receptor-mediated Scavenger Activity of Mononuclear Phagocytes toward Non-opsonized Particles and Apoptotic Cells Is Inhibited by Serum Glycoproteins but Remains Active in Cerebrospinal Fluid(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2012-05-18)Rapid phagocytosis of non-opsonized particles including apoptotic cells is an important process that involves direct recognition of the target by multiple scavenger receptors including P2X7 on the phagocyte surface. Using a real-time phagocytosis assay, we studied the effect of serum proteins on this phagocytic process. Inclusion of 1-5% serum completely abolished phagocytosis of non-opsonized YG beads by human monocytes. Inhibition was reversed by pretreatment of serum with 1-10 mM tetraethylenepentamine, a copper/zinc chelator. Inhibitory proteins from the serum were determined as negatively charged glycoproteins (pI < 6) with molecular masses between 100 and 300 kDa. A glycoprotein-rich inhibitory fraction of serum not only abolished YG bead uptake but also inhibited phagocytosis of apoptotic lymphocytes or neuronal cells by human monocyte-derived macrophages. Three copper- and/or zinc-containing serum glycoproteins, ceruloplasmin, serum amyloid P-component, and amyloid precursor protein, were identified, and the purified proteins were shown to inhibit the phagocytosis of beads by monocytes as well as phagocytosis of apoptotic neuronal cells by macrophages. Human adult cerebrospinal fluid, which contains very little glycoprotein, had no inhibitory effect on phagocytosis of either beads or apoptotic cells. These data suggest for the first time that metal-interacting glycoproteins present within serum are able to inhibit the scavenger activity of mononuclear phagocytes toward insoluble debris and apoptotic cells.
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ItemDiacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-12-23)Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
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ItemEarly Development of Electrical Excitability in the Mouse Enteric Nervous System(SOC NEUROSCIENCE, 2012-08-08)Neural activity is integral to the development of the enteric nervous system (ENS). A subpopulation of neural crest-derived cells expresses pan-neuronal markers at early stages of ENS development (at E10.5 in the mouse). However, the electrical activity of these cells has not been previously characterized, and it is not known whether all cells expressing neuronal markers are capable of firing action potentials (APs). In this study, we examined the activity of "neuron"-like cells (expressing pan-neuronal markers or with neuronal morphology) in the gut of E11.5 and E12.5 mice using whole-cell patch-clamp electrophysiology and compared them to the activity of neonatal and adult enteric neurons. Around 30-40% of neuron-like cells at E11.5 and E12.5 fired APs, some of which were very similar to those of adult enteric neurons. All APs were sensitive to tetrodotoxin (TTX), indicating that they were driven by voltage-gated Na+ currents. Expression of mRNA encoding several voltage-gated Na+ channels by the E11.5 gut was detected using RT-PCR. The density of voltage-gated Na+ currents increased from E11.5 to neonates. Immature active responses, mediated in part by TTX- and lidocaine-insensitive channels, were observed in most cells at E11.5 and E12.5, but not in P0/P1 or adult neurons. However, some cells expressing neuronal markers at E11.5 or E12.5 did not exhibit an active response to depolarization. Spontaneous depolarizations resembling excitatory postsynaptic potentials were observed at E12.5. The ENS is one of the earliest parts of the developing nervous system to exhibit mature forms of electrical activity.
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ItemThe Minimal Active Structure of Human Relaxin-2(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-10-28)H2 relaxin is a peptide hormone associated with a number of therapeutically relevant physiological effects, including regulation of collagen metabolism and multiple vascular control pathways. It is currently in phase III clinical trials for the treatment of acute heart failure due to its ability to induce vasodilation and influence renal function. It comprises 53 amino acids and is characterized by two separate polypeptide chains (A-B) that are cross-linked by three disulfide bonds. This size and complex structure represents a considerable challenge for the chemical synthesis of H2 relaxin, a major limiting factor for the exploration of modifications and derivatizations of this peptide, to optimize effect and drug-like characteristics. To address this issue, we describe the solid phase peptide synthesis and structural and functional evaluation of 24 analogues of H2 relaxin with truncations at the termini of its peptide chains. We show that it is possible to significantly truncate both the N and C termini of the B-chain while still retaining potent biological activity. This suggests that these regions are not critical for interactions with the H2 relaxin receptor, RXFP1. In contrast, truncations do reduce the activity of H2 relaxin for the related receptor RXFP2 by improving RXFP1 selectivity. In addition to new mechanistic insights into the function of H2 relaxin, this study identifies a critical active core with 38 amino acids. This minimized core shows similar antifibrotic activity as native H2 relaxin when tested in human BJ3 cells and thus represents an attractive receptor-selective lead for the development of novel relaxin therapeutics.
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ItemN-Glycosylation Determines Ionic Permeability and Desensitization of the TRPV1 Capsaicin Receptor(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2012-06-22)The balance of glycosylation and deglycosylation of ion channels can markedly influence their function and regulation. However, the functional importance of glycosylation of the TRPV1 receptor, a key sensor of pain-sensing nerves, is not well understood, and whether TRPV1 is glycosylated in neurons is unclear. We report that TRPV1 is N-glycosylated and that N-glycosylation is a major determinant of capsaicin-evoked desensitization and ionic permeability. Both N-glycosylated and unglycosylated TRPV1 was detected in extracts of peripheral sensory nerves by Western blotting. TRPV1 expressed in HEK-293 cells exhibited various degrees of glycosylation. A mutant of asparagine 604 (N604T) was not glycosylated but did not alter plasma membrane expression of TRPV1. Capsaicin-evoked increases in intracellular calcium ([Ca(2+)](i)) were sustained in wild-type TRPV1 HEK-293 cells but were rapidly desensitized in N604T TRPV1 cells. There was marked cell-to-cell variability in capsaicin responses and desensitization between individual cells expressing wild-type TRPV1 but highly uniform responses in cells expressing N604T TRPV1, consistent with variable levels of glycosylation of the wild-type channel. These differences were also apparent when wild-type or N604T TRPV1-GFP fusion proteins were expressed in neurons from trpv1(-/-) mice. Capsaicin evoked a marked, concentration-dependent increase in uptake of the large cationic dye YO-PRO-1 in cells expressing wild-type TRPV1, indicative of loss of ion selectivity, that was completely absent in cells expressing N604T TRPV1. Thus, TRPV1 is variably N-glycosylated and glycosylation is a key determinant of capsaicin regulation of TRPV1 desensitization and permeability. Our findings suggest that physiological or pathological alterations in TRPV1 glycosylation would affect TRPV1 function and pain transmission.
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ItemCellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-03-11)The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.