Neuropsychiatry and Stress Biology
A model of functional disconnections to study the pathophysiology of psychosis and epilepsy
Supervisor: Dr Nigel Jones and Prof Terence J O’Brien.
Location: Department of Medicine (RMH)
Contact details: Dr Nigel Jones 8344 3273 Email: ncjones@unimelb.edu.au
Functional disconnections in cortico-thalamo-cortical (CTC) systems, the neuronal circuits of attention, cognition and perception, are thought to underlie dysfunctions of conscious integration such as those seen in schizophrenia. More than 80% of the neurons that make up the CTC systems are glutamatergic. There is considerable evidence to suggest that NMDA-type glutamate receptors are implicated in the pathophysiology of schizophrenia. Non-competitive NMDA receptor antagonists (PCP, ketamine, MK-801), at subanaesthetic doses, induce cognition impairment, schizophreniform psychosis, hallucinations, and exacerbate both positive and negative symptoms in schizophrenic patients. In rodents, ketamine produces a wide spectrum of abnormal behaviour relevant to schizophrenia. The neuronal mechanisms underlying transient disruption in NMDA receptor function remain to be determined. CTC circuits generate coherent synchronized gamma frequency (30-80 Hz) oscillations during conscious brain operations. Disruption of cognition-related coherences of gamma oscillations between cortical areas is a major functional abnormality in schizophrenic patients.
It has been shown that patients with generalised epilepsy have increased baseline (i.e. between seizures) gamma activity on the EEG compared to non-epileptic control subjects. Work in our laboratory in the Department of Medicine has demonstrated that the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well validated animal model of genetic generalized epilepsy, display a range of behavioural and emotional abnormalities that are consistent with those seen in models of schizophrenia-like psychosis. These rats, and their non-epileptic counterparts (NEC rats), have been respectively selectively breed for the presence or absence of the epileptic phenotype. The co-segregation of the psychiatric behavioral and epileptic phenotypes over more than 60 generations suggests an aetiological link between the two. This project will also explore the hypothesis that GAERS have an abnormal response of cortical gamma activity to the administration of NMDA antagonists. If true, this would provide a neurophysiological correlate for the link between the epilepsy and schizophrenic like phenotypes in GAERS.
Note: this project is also listed under Epilepsy and Neuropharmacology
Temporal lobe epilepsy, the HPA axis and depression
Supervisors: Dr Mike Salzberg (michael.salzberg@svhm.org.au), Phone:0417357205, Prof Terry O’Brien. University of Melbourne, Departments of Psychiatry and Medicine
The key structures involved in mesial temporal lobe epilepsy – the hippocampus and amygdala – are critical components in the central regulation of the HPA axis. The implications of this have hardly been studied at all. Does the HPA axis function normally when someone has mesial temporal sclerosis (the usual pathology underlying TLE)? What happens to HPA axis function when a temporal lobe is excised to treat intractable TLE (temporal lobectomy)? There are good reasons to think the answers to these questions are very important for several reasons, e.g., glucocorticoids and stress have been shown in animal models of this kind of epilepsy to aggravate the disorder, to speed up its rate of development.
Does stress contribute to epilepsy?
Supervisor: Dr Nigel Jones and Prof Terence O’Brien
Location: Department of Medicine, (RMH)
Contact: Dr Nigel Jones T: 8344 6729 E : ncjones@unimelb.edu.au
- Chronic stress is strongly linked to the development of psychiatric disturbances, such as depression and anxiety disorders. Interestingly, these disorders are prevalent in a high proportion of people suffering from epilepsy.
- Recent literature suggests that environmental exposures such as stress may also contribute to the development of epilepsy. This project aims to investigate this hypothesis, with a parallel focus on anxiety and depression-like behaviour.
- Using rat models, this study will determine whether exposure to repeated stressful situations leads to a vulnerability to limbic epilepsy. It will also study whether psychiatric disturbances are enhanced in subjects who have experienced the stress.
- The second stage of the project will investigate molecular and plasticity changes which occur after epilepsy to determine whether the stress can influence such parameters as stress receptor expression and neurogenesis.
Skills: Small animal handling and neurosurgery (electrode implantations), neurobehavioural testing and analysis, post-mortem stereology.
Altered social behaviour in a mouse model of Autism
Supervisors: Dr Elisa Hill and Assoc. Prof Anthony Hannan
Location: Howard Florey Institute, florey Neuroscience Institutes
Contact: Dr Elisa Hill T: 8344 1954 E: elisa.hill@florey.edu.au
Web: www.brainsrus.org.
Aim of Project: This project involves the study of altered behavioural characteristics in the (R451C)NL3 mouse model of Autism Spectrum Disorder.
Specifically, the project will investigate:
- altered social behaviour, and
- the effect of environmental enrichment paradigms on (R451C)NL3 mice.
Autism Spectrum Disorder (ASD) is a highly prevalent neurological disorder characterised by impairments in social interactions, communication, and repetitive behaviour. Autism includes Asperger’s Syndrome, Rett’s syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and affects approximately 1 in 150 children in Australia. Intensive educational and behavioural intervention therapies have produced positive outcomes for children with autism. These methods include exposing children with ASD to highly stimulating environments to improve social interaction.
Standard housed (R451C)NL3 mice show decreased social tendencies in keeping with ASD symptoms. In this project, we wish to investigate the effect of environmental enrichment on these behavioural profiles. Social interaction by standard housed mice will be assessed by time spent interacting with novel and inanimate objects and caged target mice. Subsequent analysis will assess social behaviour in (R451C)NL3 and wild type littermate mice housed in environmentally enriched paradigms (e.g. these mice will be housed in larger cages, with exposure to a variety of different enrichment objects and activities such as tunnels and running wheels). Additional behavioural testing will be conducted to assess levels of anxiety, alterations in communication and sensory modulation to further characterise the mouse model.
Skills: Mouse behavioural analysis (motor, cognitive and affective test batteries), Environmental manipulations in wild-type and mutant mice.
Altered cortical inhibition in a mouse model of Autism
Supervisors: Dr Elisa Hill
Location: Howard Florey Institute, florey Neuroscience Institutes
Contact: Dr Elisa Hill T: 8344 1954 E: elisa.hill@florey.edu.au
Web: www.brainsrus.org.
Aim of Project: This proposal aims to examine synaptic activity in the somatosensory cortex of the (R451C)NL3 mouse model of Autism Spectrum Disorder.
Autism Spectrum Disorder (ASD) is a highly prevalent neurological disorder characterised by impairments in communication, socialisation, restricted patterns of interests and behaviours. Autism includes Asperger’s Syndrome, Rett’s syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and affects approximately 1 in 150 children in Australia. As many as 30% of people with ASD also experience seizures, suggesting alterations in neuronal network function.
(R451C)NL3 mice show decreased social tendencies in keeping with ASD symptomsalong with an increase in the frequency of inhibitory synaptic events in the somatosensory cortex. The observed alterations in inhibitory synapse activity may reflect changes in physiologicalproperties of inhibitory neurons to cause subtle alterations in cortical function. Inhibitory neurons comprise aheterogeneous population and it has been suggested that a deficit in even a single subset of inhibitory neuronsmay contribute to the specific symptoms observed in ASD.
Skills: This project will involve the characterisation of cortical inhibitory neurons in the (R451C)NL3 mouse based on physiological and morphological properties using patch clamp electrophysiology in acute slices, biocytin labelling (histochemistry) and 3D neuronal reconstruction software.