A08
The integrity of the locus coeruleus- noradrenergic system (LC-NA) is important in determining late-life cognitive abilities. However it has yet to be investigated whether pharmacological modulation of the LC-NA system or cognitive training interventions tailored to boost noradrenaline (NA) function may prevent cognitive decline in old age. The proposed project examines whether the LC-NA system offers hidden potential in boosting neural resource in ageing. This will be done by increasing NA function pharmacologically as well as by training particular cognitive functions known to recruit the LC-NA system.
Principal Investigators
Dr. Matthew Betts
Prof. Dr. Dorothea Hämmerer
Co-Workers
Guruprasath Gurusamy
Marina Leimann
Dr. Hartmut Schütze
What is the locus coeruleus?
The locus coeruleus (LC), a small nucleus located deep in the brainstem, is the major source of noradrenaline (NA) modulation in the brain and has been shown to be involved in regulating a wide range of higher cognitive functions including working memory, learning and attention, memory consolidation and retrieval vigilance and arousal/wakefulness (for reviews see Sara, 2009; Mather & Harley, 2016; Betts et al. 2019).
What do we know about the role of the locus coeruleus in cognition and brain health?
A core function of the LC is to support the encoding or processing of (emotionally) salient events (Arnsten, 1998; Luo et al., 2015). Within this saliency network, increases in extracellular NA through LC activation may increase neural resources via activation of α and ß-adrenoreceptors in the prefrontal cortex and hippocampus to enhance working memory (Ramos & Arnsten, 2007) and episodic memory (Luo et al., 2015), respectively. It has been shown that boosting the LC-NA system may also increase cognitive performance by reorganizing functional connectivity of brain regions that are implicated in particular cognitive processes. For instance, pharmacological increases in NA have been shown to increase connectivity between frontal and parietal regions during a visual attention task via enhancing the influence of LC inputs − the principle source of NA in these regions (Coull et al., 1999). Moreover, recent evidence indicates that age-related differences in the LC-NA are associated with reduced cognitive abilities relating to episodic memory (Hämmerer et al., 2018; Dahl et al., 2019) and cognitive reserve (Robertson, 2013; Wilson et al., 2013; Clewett et al., 2016).
NA modulation is also important for preserving long-term brain health due to its anti-inflammatory properties and role in supporting local vascular function (Satoh & Iijima, 2017). This is particularly relevant for brain health in ageing as animal studies show that the combination of lower NA levels and higher age-related pathologies such as amyloid-beta (Aß) or neurofibrillary tangles (NTF) accelerate the decline in brain health by increasing the spread of protein pathologies and increases microglial and neurovascular dysfunction (Chalermpalanupap et al., 2017; Satoh & Iijima, 2017; Weinshenker, 2018)
The goals of our project
The integrity of the LC-NA system is important in determining late-life cognitive abilities. However it has yet to be investigated whether pharmacological modulation of the LC-NA system or cognitive training interventions tailored to boost NA function may prevent cognitive decline in old age. The proposed project aims to examine whether the NA system offers hidden potential in boosting neural resource in ageing. This will be achieved by increasing NA function pharmacologically as well as by training particular cognitive functions known to recruit the LC-NA system. We aim to tailor the assessment of cognitive and physiological changes according to known neurophysiological effects of increases in NA function (e.g. with respect to increased functional activity/connectivity) and to examine the functional effects of boosting NA levels pharmacologically or via cognitive training in the context of a multi-faceted assessment of interindividual differences in the integrity of the LC-NA system. We will also examine whether so called ‘super agers’, octogenarians which show far above average cognitive performance, have a particularly intact noradrenergic system.
Towards the future
The long-term perspective of this project is to assess whether in vivo assessment of the LC-NA system can identify individuals with hidden neural resource in older age and whether interventions aimed at increasing NA levels may benefit clinical or at-risk populations in ageing. In the future, we aim to broaden our understanding of LC-mediated plasticity in target areas of LC projections including understanding the role of LC-mediated dopamine release and the mechanisms regulating LC activation. We also aim to explore how boosting noradrenergic modulation affects cortical layer activation using ultra high-field MRI. Animal studies suggest that noradrenergic projections exert their cognitive effects by altering the signal to noise level of neurons particularly in layer 4 of the cortex (Berridge & Waterhouse), however this remains to be explored in humans.