Dr Lizzie Manning
School of Biomedical Sciences and Pharmacy
- Phone:(02) 4921 7857
The aim of my research is to use basic neuroscience approaches to better understand the neural mechanisms associated with behavioural dysfunction in psychiatric disorders, with the goal that this insight may help guide development of targeted treatments with improved efficacy over existing options.
In 2014 I completed my PhD at the University of Melbourne, completing research at the Florey Institute of Neuroscience and Mental Health with Professor Maarten van den Buuse. My research sought to characterize gene x environment interactions in the development of maladaptive behavioural and neurochemical changes relevant to schizophrenia using a model of adolescent methamphetamine exposure.
For my postdoctoral training, I wanted to both expand my basic neuroscience skills for mechanistic studies of the neural mechanisms underlying maladaptive behaviours, and also enhance the clinical relevance of my approach to research. The translational neuroscience program in the department of psychiatry at the University of Pittsburgh was an excellent environment to achieve these goals. I am incredibly lucky to have worked so closely with an outstanding clinician scientist in my postdoc mentor Associate Professor Susanne Ahmari, which has given me great insight into effective strategies for developing and executing translationally relevant research in animal model systems.
My recent work in the Ahmari lab has used in vivocalcium imaging using Inscopix miniature microscopes to characterize neural activity patterns in prefrontal cortex (PFC) and striatum that are associated with disruption of flexible behaviour relevant to obsessive compulsive disorder (OCD). Currently I am completing analysis and preparing manuscripts related to an NIH R21 grant that I co-authored with Dr Ahmari, where I am comparing neural patterns in PFC associated with compulsive grooming and impaired reversal learning in a mouse model relevant to OCD. Following my work demonstrating individual differences in these distinct OCD-relevant phenotypes in the sapap3 knockout mouse model (Manning et al., 2019 https://doi.org/10.1038/s41386-018-0307-2), my recent imaging studies have identified specific neural changes in PFC associated with heterogeneity in these different behaviours.
In June 2020 I commenced a new position as a Research Associate at the University of Newcastle. With funding I was recently awarded from the Rebecca L Cooper medical research foundation, I will begin to establish my independent research program under the mentorship of Professor Chris Dayas in the school of Biomedical Sciences and Pharmacy. This new project will examine neural activity associated with disturbances in motivation and the effects of new drug candidates on neural activity and behaviour in a preclinical model relevant to schizophrenia, linking my PhD and postgraduate training experiences. I will continue to leverage longitudinal optical imaging using the Inscopix miniature microscope technology to examine activity patterns across distinct behaviours and drug treatment conditions, to better understand neural encoding of motivation that is relevant to cognitive deficits and negative symptoms in Schizophrenia. Using cell-type and circuit-specific imaging approaches will help guide future mechanistic studies to identify the precise activity patterns associated with maladaptive behaviours (e.g. using optogenetics and chemogenetics). Alongside Professor Dayas I will also lead new studies examining interactions between hypothalamic stress systems and basal ganglia control of behaviour in the development of maladaptive responses following chronic stress, bridging my new mentor’s interests with that of my postdoc work.
- Doctor of Philosophy, University of Melbourne
- calcium imaging
- obsessive compulsive disorder
- English (Mother)
Fields of Research
|170101||Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)||50|
|110999||Neurosciences not elsewhere classified||50|
|Title||Organisation / Department|
|Dates||Title||Organisation / Department|
|1/8/2014 - 31/5/2020||
Working in the lab of Susanne Ahmari (MD, PhD), I studied changes in cortico-striatal circuit function that contribute to the development of behavioural disturbances observed in OCD
|University of Pittsburgh
|1/7/2010 - 6/6/2014||
Working in the lab of Maarten van den Buuse (PhD), I studied gene x environment interactions in the context of development of behavioural disturbances relevant to schizophrenia following adolescent exposure to methamphetamine
|The Florey Institute of Neuroscience and Mental Health
Trainee Professional Development Award (SfN)
Society for Neuroscience
Travel Award, Schizophrenia International Research Society (SIRS) biennial meeting
Schizophrenia International Research Society
Best Poster Award, Schizophrenia International Research Society (SIRS) biennial meeting
Schizophrenia International Research Society
International Behavioral Neuroscience Society
Jared Franklin Purton Travel award
The Florey Institute of Neuroscience and Mental Health
Travel Award Neuro 2013
The Miller Travel Fellowship
The Florey Institute of Neuroscience and Mental Health
Lavarack Prize for Developmental Biology
The University of Melbourne
For publications that are currently unpublished or in-press, details are shown in italics.
Journal article (13 outputs)
Manning EE, Bradfield LA, Iordanova MD, 'Adaptive behaviour under conflict: Deconstructing extinction, reversal, and active avoidance learning.', Neurosci Biobehav Rev, (2020)
Corbit VL, Manning EE, Gittis AH, Ahmari SE, 'Strengthened inputs from secondary motor cortex to striatum in a mouse model of compulsive behavior', Journal of Neuroscience, 39 2965-2975 (2019)
© 2019 the authors. Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this ... [more]
© 2019 the authors. Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (~3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (~6-fold) in strength and reliability inKOsrelative to WTs. These results suggest that increased M2-striatal drivemaycontribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.
Manning EE, Dombrovski AY, Torregrossa MM, Ahmari SE, 'Impaired instrumental reversal learning is associated with increased medial prefrontal cortex activity in Sapap3 knockout mouse model of compulsive behavior', Neuropsychopharmacology, 44 1494-1504 (2019)
© 2019, American College of Neuropsychopharmacology. Convergent functional neuroimaging findings implicate hyperactivity across the prefrontal cortex (PFC) and striatum in the neu... [more]
© 2019, American College of Neuropsychopharmacology. Convergent functional neuroimaging findings implicate hyperactivity across the prefrontal cortex (PFC) and striatum in the neuropathology of obsessive compulsive disorder (OCD). The impact of cortico-striatal circuit hyperactivity on executive functions subserved by these circuits is unclear, because impaired recruitment of PFC has also been observed in OCD patients during paradigms assessing cognitive flexibility. To investigate the relationship between cortico-striatal circuit disturbances and cognitive functioning relevant to OCD, Sapap3 knockout mice (KOs) and littermate controls were tested in an instrumental reversal-learning paradigm to assess cognitive flexibility. Cortical and striatal activation associated with reversal learning was assessed via quantitative analysis of expression of the immediate early gene cFos and generalized linear mixed-effects models. Sapap3-KOs displayed heterogeneous reversal-learning performance, with almost half (n = 13/28) failing to acquire the reversed contingency, while the other 15/28 had similar acquisition as controls. Notably, reversal impairments were not correlated with compulsive grooming severity. cFos analysis revealed that reversal performance declined as medial PFC (mPFC) activity increased in Sapap3-KOs. No such relationship was observed in controls. Our studies are among the first to describe cognitive impairments in a transgenic OCD-relevant model, and demonstrate pronounced heterogeneity among Sapap3-KOs. These findings suggest that increased neural activity in mPFC is associated with impaired reversal learning in Sapap3-KOs, providing a likely neural basis for this observed heterogeneity. The Sapap3-KO model is thus a useful tool for future mechanistic studies to determine how mPFC hyperactivity contributes to OCD-relevant cognitive dysfunction.
Manning EE, Ahmari SE, 'How can preclinical mouse models be used to gain insight into prefrontal cortex dysfunction in obsessive-compulsive disorder?', Brain Neurosci Adv, 2 2398212818783896 (2018)
Jones NC, Hudson M, Foreman J, Rind G, Hill R, Manning EE, van den Buuse M, 'Brain-derived neurotrophic factor haploinsufficiency impairs high-frequency cortical oscillations in mice', European Journal of Neuroscience, 48 2816-2825 (2018)
© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd Schizophrenia is a complex psychiatric disorder with a heterogeneous aetiology involving genet... [more]
© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd Schizophrenia is a complex psychiatric disorder with a heterogeneous aetiology involving genetic and environmental factors. Deficiencies in both brain-derived neurotrophic factor (BDNF) and NMDA receptor function have been implicated in the disorder and may play causal and synergistic roles. Perturbations in the regulation of electrophysiological signals, including high-frequency (¿: 30¿80¿Hz and ß: 20¿30¿Hz) neuronal oscillations, are also associated with the disorder. This study investigated the influence of BDNF deficiency and NMDA receptor hypofunction on electrophysiological responses to brief acoustic stimuli. Adult BDNF heterozygote (BDNF+/-) and wild-type littermate C57Bl/6J mice were surgically implanted with EEG recording electrodes. All mice underwent EEG recording sessions to measure ongoing and auditory-evoked electrophysiological responses following treatment with MK-801 (0.3¿mg/kg ip) or vehicle. Western blotting on post-mortem cortical tissue assessed parvalbumin and GAD67 expression ¿ markers of interneurons which are involved in the generation of gamma oscillations. Compared with wild-type controls, BDNF+/- mice exhibited markedly dampened electrophysiological responses to auditory stimuli, including reductions in the amplitude of multiple components of the event-related potential and auditory-evoked oscillations, as well as reduced ongoing cortical gamma oscillations. MK-801 elevated ongoing gamma power but suppressed evoked gamma power, and this was observed equally across genotypes. BDNF+/- mice also displayed reductions in parvalbumin, but not GAD67 expression. We conclude that reduced BDNF expression leads to impairments in the generation of high-frequency neural oscillations, but this is not synergistic with NMDA receptor hypofunction. Reduced parvalbumin expression associated with BDNF haploinsufficiency may provide a molecular explanation for these electrophysiological deficits.
Manning EE, 'There is much to be learned from animal models of obsessive-compulsive disorder', Biological Psychiatry, 79 e1-e3 (2016)
Manning EE, van den Buuse M, 'Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure', Behavioural Brain Research, 305 181-185 (2016)
© 2016 Elsevier B.V. Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical s... [more]
© 2016 Elsevier B.V. Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia.
Manning EE, Halberstadt AL, Van Den Buuse M, 'BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine', International Journal of Neuropsychopharmacology, 19 (2016)
© The Author 2015. Published by Oxford University Press on behalf of CINP. Background: One of the most devastating consequences of methamphetamine abuse is increased risk of psych... [more]
© The Author 2015. Published by Oxford University Press on behalf of CINP. Background: One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Methods: Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Results: Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Conclusions: Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users.
Abayomi O, Amato D, Bailey C, Bitanihirwe B, Bowen L, Burshtein S, et al., 'The 4th Schizophrenia International Research Society Conference, 5-9 April 2014, Florence, Italy: A summary of topics and trends', SCHIZOPHRENIA RESEARCH, 159 E1-E22 (2014)
Manning EE, van den Buuse M, 'BDNF deficiency and young-adult methamphetamine induce sex-specific effects on prepulse inhibition regulation', Frontiers in Cellular Neuroscience, (2013)
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetam... [more]
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH) users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous mutant mice (HET) has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and WT littermates were treated during young-adulthood with METH and, following a two-week break, prepulse inhibition (PPI) was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH) disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioural endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behaviour. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the disorder. © 2013 Manning and Van_den_buuse.
|Show 10 more journal articles|
Grants and Funding
|Number of grants||1|
Click on a grant title below to expand the full details for that specific grant.
20201 grants / $100,000
Visualizing neuronal activity patterns associated with cognitive symptoms relevant to schizophrenia using in vivo microscopy$100,000
Funding body: Rebecca L Cooper Medical Research Foundation Ltd
|Funding body||Rebecca L Cooper Medical Research Foundation Ltd|
|Project Team||Doctor Lizzie Manning|
|Type Of Funding||C1700 - Aust Competitive - Other|