Dr. Colm Cunningham

Systemic inflammation, which arises outside the brain, can cause inflammatory changes inside the brain and these can trigger acute and lasting neuropsychiatric deficits. Delirium is a highly prevalent complication of systemic inflammation in the elderly which is characterised by acute disturbance of attention, thinking and memory and causes significant confusion and distress. Significantly, these episodes also accelerate the onset and progression of dementia. Despite the public health and economic imperatives, the mechanisms by which inflammation causes these acute and lasting outcomes are poorly understood. Tumour necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is elevated in blood during a wide range of clinical conditions including infection, sepsis, COVID19, surgery, injury and many chronic conditions and is, thus, elevated many times across the lifetime. This project will investigate how episodic peripheral administration of TNF-alpha, induces delirium-like episodes and how it exacerbates underlying neurodegeneration in mice. Supported by strong preliminary data, we will test the hypothesis that repeated exposures to systemic TNF-alpha reprogramme the phenotype of brain glial cell populations (microglia and astrocytes) and directly affect electrical activity of neurons, producing acute 'delirium-like' episodes and leading to long-term impairment of cognitive function. Using episodic systemic TNF-alpha challenges we will test the hypothesis that, regarding glial phenotypes and cognitive function, that prior TNF exposures influence the magnitude of responses to subsequent TNF exposures. We further hypothesise that dynamic disruption of brain energy metabolism, with changes in glucose metabolism and changes in levels of the excitatory neurotransmitter glutamate, will contribute to cognitive dysfunction. We will use real-time brain bioenergetic analysis using implantable electrochemical sensors for glucose, lactate and glutamate, time-synchronised with behavioural analysis to elucidate this. These data will contribute to our understanding of how episodic systemic inflammation contributes to acute neuropsychiatric symptoms and to the progression of dementias like Alzheimer"s disease.

Systemic inflammation can trigger acute cognitive dysfunction (including delirium) as well as accelerating long-term cognitive decline (including dementia) and this occurs with high prevalence in the aging population. It is accepted that prior neurodegeneration increases the risk of these adverse health outcomes but this is poorly understood and we now propose that loss of anti-inflammatory acetylcholinergic tone predisposes to exaggerated brain inflammatory responses to systemic inflammatory insults, resulting in excessive inflammatory mediator release and contributing to acute cognitive dysfunction and lasting brain injury. In the current proposal we will use p75NTR-saporin to produce partial and selective degeneration of basal forebrain cholinergic neurons, and will induce systemic inflammation with bacterial endotoxin or polymicrobial sepsis, in order to study the influence of pre-existing hypocholinergia on acute illness-induced brain inflammation, changes in brain energy metabolism and neurophysiology (time-synchronized to behaviour) and new brain injury leading to long-term cognitive decline.

1) Reconciling inflammatory and cholinergic mechanisms of delirium. I propose that prior pathology in the basal forebrain cholinergic nuclei (BFCN) predisposes individuals to systemic inflammation-induced acute cognitive impairments. I will produce selective and limited lesions of the BFCN, with p75NTR-saporin that do not cause significant cognitive impairment. I predict that superimposed systemic inflammation will then induce acute cholinergic dysfunction specifically in lesioned animals. This will be a valuable model system with which to study aspects of cholinergic hypofunction-associated delirium and I will study inflammatory, behavioural and neurochemical aspects of this system. 2) Mechanisms of long-term decline. Using both the "ME7+systemic inflammation" and p75-saporin models of delirium during dementia I will study potential mechanisms of acute impairments and long-term decline resulting from inflammatory challenges. In so doing I will examine the idea that the acute cognitive dysfunction and the subsequent long-term cognitive impairment associated with delirium are two distinct processes: an acute neurochemical change and an acute pathological change that is superimposed on the existing pathological state. 3) Microglial priming. I predict that primed microglia have a role in both acute and long-term consequences of acute inflammatory episodes. I propose that priming of these CNS macrophages consists of hyper-responsiveness to a variety of inflammatory stimuli and I will investigate this with respect to receptor expression, cytosolic levels of key transcription factors and nuclear localization of these in response to inflammatory stimulation.