We use a combination of egocentric (body-derived) and allocentric (landmark-based) cues to navigate. This ability can become impaired during ageing, leading to spatial disorientation, which an early sign of dementia. Which neural circuits are responsible for disorientation? The anterodorsal nucleus of the thalamus (ADn) contains a high density of head direction (HD) cells that act like a ‘neural compass’. Head direction signals from the ADn are sent to postsynaptic cortical areas such as the retrosplenial cortex, which are important for spatial orientation and navigation. The human ADn is highly susceptible to neurodegeneration in Alzheimer’s disease, the most common form of dementia. We tested the hypothesis that very early pathological changes in the ADn give rise to spatial disorientation. A major pathological hallmark of multiple neurodegenerative diseases, including Alzheimer’s disease, is the presence of amyloid fibrils. Using light and electron microscopy, we detected amyloid fibrils in neuronal cell bodies, dendritic appendages, and axon terminals within post-mortem human ADn, identifying them as aggregates of pathological tau (ptau). We detected ptau in the ADn at all disease stages, including in cases that lacked any known cognitive impairment, cases with mild cognitive impairment, and in Alzheimer’s disease cases. Calretinin-expressing neurons preferentially accumulated ptau. We also localized ptau to large vGLUT2-expressing presynaptic terminals from the mammillary body but not to corticothalamic terminals, suggesting a prime site for the transsynaptic spread of ptau. To test whether ptau affects HD signalling, we virally expressed human tau in the ADn of adult mice (HD-ptau mice). Despite being able to learn spatial memory tasks, HD-ptau mice exhibited looping behaviour when searching for hidden goals in a Morris water maze and made a greater number of head turns during memory recall, suggesting they were disoriented. By recording and labelling single HD cells in awake HD-ptau mice, we found that ADn cells exhibited reduced directionality and altered burst firing patterns. In conclusion, the unusually high vulnerability of this subcortical head direction circuit to tau amyloid fibrils may contribute to disorientation in preclinical Alzheimer’s disease. This information could be used to identify individuals most likely to develop memory impairments, leading to earlier intervention strategies and targeted therapies.
SPEAKER BIOGRAPHY
Dr Viney is a Career Development Fellow in the Department of Pharmacology, University of Oxford, and a Research Fellow at Wolfson College, Oxford. His research group investigates the link between amyloid fibrils and spatial memory in both animal models and post-mortem human brain tissue.
He has a Master of Biology degree in Molecular & Cellular Biology from the University of Bath, UK, and a PhD in Neuroscience from the Friedrich Miescher Institute in Basel, Switzerland. His PhD research, conducted in the group of Dr Botond Roska, focused on defining different types of ganglion cells and amacrine cells in the mammalian retina. He defined the presynaptic inputs to melanopsin-expressing ganglion cells (Viney et al Curr Biol 2007) and demonstrated that ‘approach sensitive’ ganglion cells receive glycinergic inhibition from AII amacrine cells.
After his PhD, Dr Viney joined the group of Professor Peter Somogyi at the MRC Anatomical Neuropharmacology Unit in Oxford where he investigated the spike timing of identified GABAergic neurons and pyramidal cells in the hippocampus of freely moving rats. He discovered a marker for axo-axonic cells and demonstrated that this cell type stops firing during high-frequency ripple oscillations in sleeping rats (Viney et al Nat Neuro 2013). This was followed by research defining GABAergic projection neurons of the mouse basal forebrain. He discovered and defined ‘orchid cells’, which provide theta-rhythmic inhibition to GABAergic interneurons in the presubiculum and entorhinal cortex (Viney et al eLife 2018), and along with his first DPhil student, defined GABAergic projection neurons with low-rhythmic firing that innervated hippocampal CA3 (Salib et al J Neurosci 2019).
In 2019, Dr Viney applied for a competitive Career Development Fellowship in the Department of Pharmacology. He was awarded the fellowship, which started in 2020. Dr Viney’s recent research has involved investigating how amyloid fibrils of tau spread in the human brain (Sarkany et al Acta Neuropathologica 2024) and in mouse models (Viney et al Cell Reports 2022). His group is currently investigating how dysfunction of thalamic head direction cells affects spatial orientation (Jiang and Hijazi et al BioRxiv 2024). As a Research Fellow at Wolfson College, he runs the Mind, Brain & Behaviour Research Cluster. Recent funding sources include the Medical Research Council and the Alzheimer’s Society.
