For most of us, finding our way around (spatial navigation) is a normal part of daily life. It is common to temporarily lose one’s sense of direction, but what if it happens more frequently? Spatial disorientation is an early sign of dementia, but the neural circuit mechanisms remain undefined. The group investigated this by performing a range of immunohistochemical, behavioural, and neurophysiological tests in a new mouse model for spatial disorientation.
The group previously showed that pathological tau, a major hallmark of Alzheimer’s disease (the most common form of dementia), is highly localised to the anterodorsal nucleus (ADn) of the human thalamus at all disease stages. Could tau pathology affect the function of this thalamic nucleus? The ADn contains a high density of head direction (HD) cells, which help provide us with our sense of direction.
The authors modelled the pathology by expressing human tau in the mouse ADn. When they tested the spatial learning strategies of these mice, they found that the mice made an increased number of loops when trying to find a hidden platform. This resembled spatial disorientation. Next, they recorded neuronal activity in the ADn of these mice and found that head direction signals were reduced, and HD cells showed disrupted burst-firing patterns. These findings suggest that dysfunction of HD cells in the thalamus contributes to the symptom of spatial disorientation. Developing tests based on this circuit could lead to earlier detection and more effective treatment strategies to slow cognitive decline.
This study was led by co-first authors Shan Jiang (DPhil student) and Sara Hijazi (UKRI MSCA Fellow), with contributions from Barbara Sarkany (former DPhil student and current MRC postdoctoral scientist), Verena Gautsch (former MSc Pharmacology student), and collaborators David Bannerman (Department of Experimental Psychology), Patrick LaChance and Michael Hasselmo (Boston University, USA).
https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01382-8