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Updated: Sep 24, 2025
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An Appetitive Spatial Working Memory Task for Mice in a Semi-Automated 8-Arm Radial Maze, Reducing Fearful Memory Association in the Maze
Published on: July 29, 2025
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Anterior thalamic circuits crucial for working memory.
Dheeraj S Roy1, Ying Zhang2, Tomomi Aida2
1Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142.
Summary
Activating anterior thalamic nuclei (ATN) circuits, specifically the AV→PaS pathway, rescues spatial working memory deficits in aged mice. This approach shows promise for cognitive aging with fewer side effects than direct prefrontal cortex activation.
Area of Science:
- Neuroscience
- Cognitive Aging
- Systems Neuroscience
Background:
- Aging is associated with cognitive decline, including impaired working memory.
- Alterations in anterior thalamic nuclei (ATN) structure and connectivity are linked to cognitive deficits in aging.
- Specific ATN circuits underlying higher cognitive functions are not well understood.
Purpose of the Study:
- To investigate the role of specific ATN subdivisions and their circuits in spatial working memory during aging.
- To identify potential therapeutic targets within the ATN for mitigating age-related cognitive decline.
Main Methods:
- Utilized a spatial working memory task in aged mice.
- Investigated the anteroventral (AV) subdivision of the ATN and its projections to the parasubiculum (PaS) and entorhinal cortex (EC).
- Employed neuronal activation techniques to assess the rescue of cognitive deficits and impact on neuronal activity in the prefrontal cortex (PFC).
Main Results:
- The AV→PaS→EC circuit is crucial for maintaining spatial working memory.
- Aged mice exhibit spatial working memory deficits linked to reduced AV neuron excitability.
- Activation of AV neurons or the AV→PaS circuit restored working memory in aged mice.
- This restoration was associated with improved neuronal activity in the PFC.
- Direct PFC activation rescued working memory but induced anxiety, unlike AV→PaS circuit activation.
Conclusions:
- The anteroventral (AV) thalamus and its AV→PaS circuit play a critical role in spatial working memory maintenance.
- Targeting the AV thalamus offers a potential therapeutic strategy for age-related cognitive decline.
- AV thalamus-based interventions may provide cognitive benefits with a potentially better side-effect profile compared to direct PFC manipulation.
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