Identification of anterodorsal thalamic head direction cell types and their role in spatial disorientation

Thesis

Head direction signalling is fundamental for spatial orientation and navigation. The anterodorsal nucleus of the thalamus (ADn) contains a high density of head direction (HD) cells. This hub of HD cells is acting as a neural compass. The first part of the thesis tests this dogma and defines the diversity of ADn HD cells based on the combination of neurochemical identity, firing patterns, and connectivity. Using in vivo extracellular recordings and juxtacellular labelling, I observed HD cells exhibiting different response profiles to light pulses, sound, and movement, whereas others remained unresponsive. I identified a mediolateral gradient of calretinin-expressing (CR+) ADn cells, with CR+ HD cells having narrower tuning widths, lower peak and maximal firing rates compared to CR- cells. By examining the connectivity of ADn HD cells, I identified 3 projection patterns: type I cells followed the ‘typical’ route via the thalamic reticular nucleus (TRN) and dorsomedial striatum (DMS) to enter the cingulum bundle; type II cells formed additional collaterals in the DMS; and type III cells avoided the TRN and had descending axons. These data suggest that ADn HD cells formed of distinct cell types. Given the crucial role of the ADn in spatial navigation and its early vulnerability to pathological forms of tau – a hallmark of Alzheimer’s disease and ageing – the second part of the thesis addresses how tau pathology in the HD network promotes spatial disorientation. I virally expressed human mutant tau in the mouse ADn (HD-tau mice) and observed phosphorylated and oligomeric forms of tau in ADn somata and axon terminals. During initial spatial learning in the Morris water maze, HD-tau mice exhibited increased looping behaviour, indicative of spatial disorientation. Furthermore, I found that ADn cells from HD-tau mice had reduced directionality and altered burst firing. These findings provide evidence that pathological human tau alters HD signalling, leading to impairments in spatial orientation. Overall, this thesis demonstrates the existence of a diverse anterodorsal thalamic head direction neuronal population and their dysfunction promotes spatial disorientation.

Authors: Jiang, S

• DOI: 10.5287/ora-yejgbzdaj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: tau pathology; spatial disorientation; Head direction cells; spatial navigation
• Subjects: Neurosciences