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• neuroscience and mental health

• Medicine
• Surgery
• Psychiatry
• Anaesthetics
• Emergency Medicine

• Dementia
• Geriatric Medicine
• Immunology
• Neurology
• Orthopaedic surgery
• Pharmacology
• Physiology
• Psychiatry

My main research interests are in neurodegeneration and neuroinflammation and in the role of microglia and astrocytes in these processes. I am particularly interested in how systemic insults like infection, inflammation and injury interact with, and influence, ongoing neurodegeneration. Our work has shown exaggerated responses to systemic inflammation in animals/persons with existing brain pathology. Our laboratory is one of the few, worldwide, performing basic research in delirium and we've developed the first animal models to study delirium during dementia, combining molecular, histological and behavioural approaches with validation of findings in clinical populations.

Relevant Publications
Hennessy et al., (2015) Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNF-a. Journal of Neuroscience. Jun 3;35(22):8411-22
Davis et al., (2015) Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium. Am J Geriatric Psychiatry. Apr 23(4): 403-415
Field et al, (2012) Prior pathology in the basal forebrain cholinergic system predisposes to inflammation induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium. Journal of Neuroscience 32(12):6288-6294.
Cunningham et al., (2009) Systemic inflammation superimposed on chronic neurodegeneration induces acute behavioural and cognitive changes and accelerates neurological decline. Biological Psychiatry 65(4):304-12.

Mechanisms by which systemic inflammation induces delirium and brain injury: Using mouse models of dementia, we are studying the acute CNS inflammatory and behavioural consequences (affective, cognitive, motor) of systemic infection/inflammation in mice and their mechanistic bases. Current potential projects will likely use the APP/PS1 double transgenic model of Alzheimer's disease to examine the mechanistic basis of acute cognitive dysfunction and brain injury arising from acute illness.

1) Direct production of cytokines and chemokines at brain endothelium and choroidal epithelium may drive neuronal dysfunction after systemic inflammation. We will intrathecally inject chemokines including CXCL1, CCL2, CXCL10, CCL11 into APP/PS1 and WT mice to examine acute behavioural dysfunction, patterns of neuronal immediate early gene expression (IEG) and induction of acute neuronal injury and death.

2) Delirium can occur in both hyper- and hypo-active forms and it is not clear whether inflammatory mechanisms underpin both and to what extent mechanisms are overlapping. We have been developing models of acute illness using inflammogens producing dissociable arousal levels (hypoactive: Gram negative bacterial endotoxin (LPS) vs hyperactive: Staphylococcal enterotoxin A (SEA)) and examining the roles of IL-1β (hypo) and IL-2 (hyper), and of differential glycemic control in driving these divergent phenotypes.

3) We have recently demonstrated that astrocytes are primed by primary pathology in the degenerating brain to produce exaggerated chemokine responses to secondary inflammatory stimulation. It is now a priority to study the mechanisms of priming of astrocytes and the consequences of further stimulation of primed astrocytes for inflammatory cell infiltration and brain pathology in the context of dementia.

Human validation may be sought using specimens from the Dublin Brain Bank (Beaumont Hospital) or using patient samples from St James and/or Tallaght hospitals as may arise through collaborations with clinical researchers in those locations and contingent on the clinical specialisation/motivation of the candidate.