Rachel Hill

Dr

Accepting PhD Students

PhD projects

Title: Understanding the role of ARX in psychiatric disorders Supervisors: Rachel Hill and Anna Schroeder This project stems from a recent breakthrough finding in our laboratory whereby we identified a new mutation in a gene called ARX in a patient with schizophrenia. We now wish to understand the functional consequence of this mutation. We are generating, using CRIPR-CAS9 technology a mutant mouse with our identified mutation inserted into its genome. This project will involve behavioural and cellular experiments to characterise the effects of this new mutation on CNS function in mice. This exciting new project is the first in the world to characterise variants in the ARX gene with relevance to schizophrenia. Title: Using single-nuclei RNA-Sequencing to uncover novel candidate genes and/or signalling pathways that are altered in people with schizophrenia. Supervisors: Prof. Suresh Sundram and Dr Rachel Hill The cause of schizophrenia is not yet known but there is undoubtedly a strong genetic component. However, there remains a frequent lack of reproducibility, across different research groups and patient cohorts, of significant associations between specific genes and schizophrenia risk. This is particularly true in studies assessing mRNA expression in post-mortem human brain tissue. This variability may be due to a number of factors associated with post-mortem tissue, e.g. cause of death, agonal state, age, gender, etc. Another major contributing factor to this variability is that studies tend to use extracts of whole tissue, including a mixture of different populations of cells. How each individual cell functions is dependent upon its transcriptional program. Therefore, to analyse homogenates of multiple cell types, with different functions and thus different transcriptional programming is non-specific – and thus individual cell specific signals are lost. Here, very recent advances in single-nucleus RNA sequencing [1] will allow us to probe the cell specific transcriptome of patients with schizophrenia, adding an exceptional layer of specificity to the understanding of schizophrenia pathology. Single Nucleus RNA-Sequencing (DroNc-Seq): In conjunction with Monash Genomics core facility, this project will test the above mentioned novel methodology recently published in Nature Methods [1]; Massively parallel single-nucleus RNA-seq with DroNc-seq (droplet nuclei sequencing) in human postmortem tissue from schizophrenia patients. This technique isolates nuclei from human post-mortem tissue then co-encapsulates individual nuclei with a barcoded bead within a nanolitre-scale oil droplet. This bar-coded bead retains a molecular memory of the identity of the cell from which the mRNA transcript was isolated. This is referred to as a STAMP (Single-cell Transcriptomics Attached to Microparticles). Thousands of STAMPs are collected for reverse transcription, amplification and sequencing with the individual barcodes within each STAMP allowing identification of each transcript’s cellular origin. In preliminary studies we have shown successful co-encapsulation of nuclei isolated from frozen human brain (prefrontal cortex) with the barcoded beads. This project will expand this in a large cohort of tissue samples, then process RNA for RNA-Seq analysis using the Illumina HiSeq3000 instrument at the Monash Health Translation Precinct genomics facility. This study using highly innovative techniques at the forefront of cellular genetics will uncover cell-type specific detail on the genetic pathology of schizophrenia with great potential for novel targets to be identified and assessed in preclinical animal model testing. Title: Using advanced genetic tools to guide the future of precision medicine in psychiatry Supervisors: Prof. Suresh Sundram and Dr Rachel Hill Schizophrenia is a psychiatric disorder that is characterized by frightening hallucination, and delusions as well as severe cognitive and mood disturbances. It is a developmental disorder that emerges during late adolescence / early adulthood and there is currently no cure. There is strong support for a genetic component to schizophrenia, and current findings from genome-wide association studies (GWAS) have unearthed many low-penetrance mutations that marginally increase risk as well as a very small number of high-penetrance mutations that are incredibly rare. Importantly, more recently it has been shown that genetic mutations associated with schizophrenia are shared across other major psychiatric disorders, such as bipolar disorder, suggesting that perhaps psychiatry needs to move away from traditional diagnosis and look toward a biological diagnostic tool which may then aid in targeted biological treatments. Before such a tool can be created we need to better understand the familial patterns of specific genetic anomalies and determine how they are expressed across multiple family members, and what their biological function is. This project will be part of a large scale human clinical genomics study to identify families with multiple members affected by a psychiatric disorder. Biological samples from affected and non-affected family members will be collected for whole exome genetic sequencing to identify genetic mutations that increase risk for psychiatric disorders. By analysing multiple family members we may then ascertain which genetic anomalies are associated with psychiatric disorders and which are associated with specific disorders. The project will involve recruitment of participants and biological sample prep and analysis. The biological relevance of identified genetic mutations will then be studied in our neuroscience laboratories using preclinical cellular and animal models.

20032020

Research output per year

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Research Output

2020

Bazedoxifene – a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory

Hill, R. A., Kouremenos, K., Tull, D., Maggi, A., Schroeder, A., Gibbons, A., Kulkarni, J., Sundram, S. & Du, X., Nov 2020, In : Psychoneuroendocrinology. 121, 9 p., 104830.

Research output: Contribution to journalArticleResearchpeer-review

Involvement of brain-derived neurotrophic factor (BDNF) in the long-term memory effects of glucocorticoid stimulation during adolescence/young adulthood

van den Buuse, M., Buret, L. & Hill, R., 13 Jan 2020, In : Behavioural Brain Research. 377, 5 p., 112223.

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)
2019

Effect of adolescent androgen manipulation on psychosis-like behaviour in adulthood in BDNF heterozygous and control mice

Du, X., McCarthny, C. R., Notaras, M., van den Buuse, M. & Hill, R. A., 1 Jun 2019, In : Hormones and Behavior. 112, p. 32-41 10 p.

Research output: Contribution to journalArticleResearchpeer-review

Hypothalamic-pituitary-gonadal axis dysfunction: An innate pathophysiology of schizophrenia?

Du, X. & Hill, R. A., 1 May 2019, In : General and Comparative Endocrinology. 275, p. 38-43 6 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

2 Citations (Scopus)

Raloxifene recovers effects of prenatal immune activation on cognitive task-induced gamma power

Schroeder, A., Nakamura, J. P., Hudson, M., Jones, N. C., Du, X., Sundram, S. & Hill, R. A., 1 Dec 2019, In : Psychoneuroendocrinology. 110, 12 p., 104448.

Research output: Contribution to journalArticleResearchpeer-review

Sex-specific spatial memory deficits in mice with a conditional TrkB deletion on parvalbumin interneurons

Grech, A. M., Du, X., Murray, S. S., Xiao, J. & Hill, R. A., 17 Oct 2019, In : Behavioural Brain Research. 372, 10 p., 111984.

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

The maternal immune activation model uncovers a role for the Arx gene in GABAergic dysfunction in schizophrenia

Nakamura, J. P., Schroeder, A., Hudson, M., Jones, N., Gillespie, B., Du, X., Notaras, M., Swaminathan, V., Reay, W. R., Atkins, J. R., Green, M. J., Carr, V. J., Cairns, M. J., Sundram, S. & Hill, R. A., Oct 2019, In : Brain, Behavior, and Immunity. 81, p. 161-171 11 p.

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)
2018

Brain-derived neurotrophic factor haploinsufficiency impairs high-frequency cortical oscillations in mice

Jones, N. C., Hudson, M., Foreman, J., Rind, G., Hill, R., Manning, E. E. & van den Buuse, M., Oct 2018, In : European Journal of Neuroscience. 48, 8, p. 2816-2825 10 p.

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Investigating the Interactive Effects of Sex Steroid Hormones and Brain-Derived Neurotrophic Factor during Adolescence on Hippocampal NMDA Receptor Expression

McCarthny, C. R., Du, X., Wu, Y. C. & Hill, R. A., 1 Jan 2018, In : International Journal of Endocrinology. 2018, 13 p., 7231915.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
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4 Citations (Scopus)

On the developmental timing of stress: Delineating sex-specific effects of stress across development on adult behavior

Schroeder, A., Notaras, M., Du, X. & Hill, R. A., 1 Jul 2018, In : Brain Sciences. 8, 7, 29 p., 121.

Research output: Contribution to journalReview ArticleResearchpeer-review

Open Access
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9 Citations (Scopus)

Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex

Du, X., Serena, K., Hwang, W., Grech, A. M., Wu, Y. W. C., Schroeder, A. & Hill, R. A., 1 Apr 2018, In : Molecular and Cellular Neuroscience. 88, p. 177-188 12 p.

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Reelin haploinsufficiency and late-adolescent corticosterone treatment induce long-lasting and female-specific molecular changes in the dorsal hippocampus

Schroeder, A., Van den Buuse, M. & Hill, R. A., 1 Jul 2018, In : Brain Sciences. 8, 7, 15 p., 118.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
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2 Citations (Scopus)
Open Access
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2 Citations (Scopus)
2017

BDNF Val66Met genotype interacts with a history of simulated stress exposure to regulate sensorimotor gating and startle reactivity

Notaras, M. J., Hill, R. A., Gogos, J. A. & van den Buuse, M., 2017, In : Schizophrenia Bulletin. 43, 3, p. 665-672 8 p.

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Estradiol and raloxifene modulate hippocampal gamma oscillations during a spatial memory task

Schroeder, A., Hudson, M., Du, X., Wu, Y. W. C., Nakamura, J., van den Buuse, M., Jones, N. C. & Hill, R., 1 Apr 2017, In : Psychoneuroendocrinology. 78, p. 85-92 8 p.

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

Notaras, M., Du, X., Gogos, J., van den Buuse, M. & Hill, R. A., 19 Sep 2017, In : Translational Psychiatry. 7, 9, 16 p., e1233.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
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18 Citations (Scopus)
2016

BDNF Val66Met genotype determines hippocampus-dependent behavior via sensitivity to glucocorticoid signaling.

Notaras, M., Hill, R., Gogos, JA. & van den Buuse, M., 1 Jun 2016, In : Molecular Psychiatry. 21, 6, p. 730-732 3 p.

Research output: Contribution to journalLetterResearchpeer-review

Open Access
22 Citations (Scopus)

Dissecting a Genomic Role of BDNF in Schizophrenia and Psychosis.

Notaras, M., Hill, R. A. & van den Buuse, M., Aug 2016, In : Journal of Clinical Psychiatry. 77, 8, p. 1029-31 3 p.

Research output: Contribution to journalComment / DebateOtherpeer-review

Open Access
3 Citations (Scopus)

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

Hill, R. A., Aug 2016, In : Neuroscience and Biobehavioral Reviews. 67, p. 41-56 16 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

25 Citations (Scopus)

Sex-Steroid Hormones and Neuropsychiatric Disorders: Pathophysiology, Symptomology and Treatment

Schroeder, A., Notaras, M. & Hill, R. A., Jan 2016, Horizons in Neuroscience Research: Neuropsychiatric Disorders: Symptoms, Diagnosis and Treatment. Villalba, E. & Costa, A. (eds.). New York NY USA: Nova Publishers, Vol. 24. p. 157-202 51 p.

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Otherpeer-review

Studies on the effects prenatal immune activation on postnatal behavior: Models of developmental origins of schizophrenia

Ratnayake, U. & Hill, R. A., 1 Nov 2016, Prenatal and Postnatal Determinants of Development . Walker, D. W. (ed.). New York NY USA: Humana Press, Vol. 109. p. 263-278 16 p. (Neuromethods; vol. 109).

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Otherpeer-review

2 Citations (Scopus)

The Potential of Gonadal Hormone Signalling Pathways as Therapeutics for Dementia

Du, X. & Hill, R. A., 1 Nov 2016, In : Journal of Molecular Neuroscience. 60, 3, p. 336-348 13 p.

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)
2015

7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders

Du, X. & Hill, R. A., 25 Apr 2015, In : Neurochemistry International. 89, p. 170-180 11 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

16 Citations (Scopus)

Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol

Wu, Y. W. C., Du, X., Van Den Buuse, M. & Hill, R. A., 1 Jan 2015, In : Translational Psychiatry. 5, 1, e498.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
File
18 Citations (Scopus)

A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review.

Notaras, M., Hill, R. A. & van den Buuse, M., Apr 2015, In : Neuroscience and Biobehavioral Reviews. 51, p. 15-30 16 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

80 Citations (Scopus)

Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment.

Gururajan, A., Hill, R. A. & van den Buuse, M., 17 Oct 2015, In : Neuroscience. 22, 284, p. 297-310 14 p.

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Gene-environment interaction of reelin and stress in cognitive behaviours in mice: Implications for schizophrenia

Schroeder, A., Buret, L., Hill, R. A. & van den Buuse, M., 1 Jul 2015, In : Behavioural Brain Research. 287, p. 304-314 11 p.

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy.

Notaras, M., Hill, R. A. & van den Buuse, M., Aug 2015, In : Molecular Psychiatry. 20, 8, p. 916-930 14 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

116 Citations (Scopus)

‘Two Hit’ Neurodevelopmental Mechanisms in Schizophrenia: Focus on Animal Models and the Role of BDNF

Klug, M., Hill, R. A. & van den Buuse, M., 2015, Psychiatry and Neuroscience Update: Bridging the Divide . Gargiulo, P. Á. & Mesones-Arroyo, H. L. (eds.). 1st ed. Switzerland: Springer, p. 335-352 17 p.

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Otherpeer-review

2014

BDNF–TrkB signaling as a therapeutic target in neuropsychiatric disorders

Du, X., Wu, Y. C. & Hill, R. A., 6 Oct 2014, In : Journal of Receptor, Ligand and Channel Research. 7, p. 61-79 19 p.

Research output: Contribution to journalReview ArticleOtherpeer-review

Open Access
2 Citations (Scopus)

High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

Mo, C., Pang, T. Y. C., Ransome, M. I., Hill, R. A., Renoir, T. & Hannan, A. J., Sep 2014, In : Neurobiology of Disease. 69, p. 248-262 15 p.

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

Long-term differential effects of chronic young-adult corticosterone exposure on anxiety and depression-like behaviour in BDNF heterozygous rats depend on the experimental paradigm used.

Gururajan, A., Hill, R. A. & van den Buuse, M., 25 Jul 2014, In : Neuroscience Letters. 576, p. 6-10 5 p.

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Long-term effects of combined neonatal and adolescent stress on brain-derived neurotrophic factor and dopamine receptor expression in the rat forebrain.

Hill, R. A., Kiss von Soly, S., Ratnayake, U., Klug, M., Binder, M., Hannan, A. J. & van den Buuse, M., 23 Aug 2014, In : Biochimica et Biophysica Acta - Molecular Cell Research. 1842, 11, p. 2126-2135 10 p.

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: A role for estradiol

Wu, Y. C., Du, X., Van den Buuse, M. & Hill, R. A., 2014, In : Psychoneuroendocrinology. 45, p. 167-178 12 p.

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Sex-specific disruptions in spatial memory and anhedonia in a "two hit" rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signaling.

Hill, R. A., Klug, M. & Kiss von Soly, S., 16 May 2014, In : Hippocampus. 24, 10, p. 1197-1211 15 p.

Research output: Contribution to journalArticleResearchpeer-review

53 Citations (Scopus)
2013

Sex-dependent alterations in BDNF-TrkB signaling in the hippocampus of reelin heterozygous mice: a role for sex steroid hormones.

Hill, R. A., Wu, C., Gogos, A. & van den Buuse, M., 24 Mar 2013, In : Journal of Neurochemistry. 126, 3, p. 389-99 10 p.

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Sex differences and the role of estrogen in animal models of schizophrenia: interaction with BDNF

Wu, Y. C., Hill, R. A., Gogos, A. & van den Buuse, M., 22 Oct 2013, In : Neuroscience. 239, p. 67-83 6 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

53 Citations (Scopus)
2012

Altered N-methyl-D-aspartate receptor function in reelin heterozygous mice: male-female differences and comparison with dopaminergic activity

van den Buuse, M., Hill, R. A., Halley, P. & Martin, S., 1 Jun 2012, In : Progress in Neuro-Psychopharmacology and Biological Psychiatry. 37, 2, p. 237-246 9 p.

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Interaction of sex steroid hormones and brain-derived neurotrophic factor-tyrosine kinase B signalling: relevance to schizophrenia and depression.

Hill, R. A., Dec 2012, In : Journal of Neuroendocrinology. 24, 12, p. 1553-61 8 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

22 Citations (Scopus)

Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice

Klug, M., Hill, R. A., Choy, K. H. C., Kyrios, M., Hannan, A. J. & van den Buuse, M., Jun 2012, In : Neurobiology of Disease. 46, 3, p. 722 - 731 10 p.

Research output: Contribution to journalArticleResearchpeer-review

46 Citations (Scopus)

Modulatory effects of sex steroid hormones on brain-derived neurotrophic factor-tyrosine kinase B expression during adolescent development in C57Bl/6 mice.

Hill, R. A., Wu, Y. C., Kwek, P. & van den Buuse, M., May 2012, In : Journal of Neuroendocrinology. 24, 5, p. 774-88 14 p.

Research output: Contribution to journalArticleResearchpeer-review

61 Citations (Scopus)

Sex-specific and region-specific changes in BDNF-TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice.

Wu, Y. W. C., Hill, R. A., Klug, M. & van den Buuse, M., 3 May 2012, In : Brain Research. 1452, p. 10-7 7 p.

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)
2011

Brain-derived neurotrophic factor expression is increased in the hippocampus of 5-HT(2C) receptor knockout mice.

Hill, R. A., Murray, S., Halley, P., Binder, M., Martin, S. & van den Buuse, M., Apr 2011, In : Hippocampus. 21, 4, p. 434-45 11 p.

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Differential effect of amphetamine on c-fos expression in female aromatase knockout (ArKO) mice compared to wildtype controls

Chavez, C., Gogos, A., Hill, R., Van Sinderen, M. L., Simpson, E. R., Boon, W. C. & van den Buuse, M., 2011, In : Psychoneuroendocrinology. 36, p. 761 - 768 7 p.

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice.

Hill, R. A. & van den Buuse, M., 12 Apr 2011, In : Brain Research. 1384, p. 51-60 9 p.

Research output: Contribution to journalArticleResearchpeer-review

50 Citations (Scopus)
2010

Modulatory effects of estrogens on grooming and related behaviors

Hill, R. A. & Boon, W. C., 1 Jan 2010, Neurobiology of Grooming Behavior. Cambridge University Press (Anthem Press), p. 108-130 23 p.

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review

1 Citation (Scopus)
2009

Estrogen deficiency results in apoptosis in the frontal cortex of adult female aromatase knockout mice

Hill, R. A., Chua, H. K., Jones, M. E., Simpson, E. R. & Boon, W. C., 2009, In : Molecular and Cellular Neuroscience. 41, 1, p. 1 - 7 7 p.

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)

Estrogen Deficient Mouse Models in the Study of Brain Injury and Disease

Hill, R. A. & Boon, W. C., 24 Nov 2009, Mutant and Transgenic tools in modeling brain disorders, Neuromethods. Vol. 44. p. 113-136 23 p. (Neuromethods; vol. 44).

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review

Estrogens, brain, and behavior: Lessons from knockout mouse models

Hill, R. A. & Wah, C. B., 1 May 2009, In : Seminars in Reproductive Medicine. 27, 3, p. 218-228 11 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

28 Citations (Scopus)

Estrogens, Brain and Behavior:Lessons from mouse models

Hill, R. A. & Boon, W. C., 2009, In : Seminars in Reproductive Medicine. 27, 3, p. 218-228

Research output: Contribution to journalReview ArticleResearchpeer-review