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bioRxiv · 10.64898/2026.02.16.706106

Noradrenergic administration improves cognitive flexibility even after glutamatergic damage in rat mediodorsal thalamus or thalamic nucleus reuniens

Hamilton, J. J.·Berriman, L.·Harrison-Best, S.·Dalrymple-Alford, J. C.·Mitchell, A. S.
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Abstract

Cognitive flexibility, switching behaviour responses to changing task demands, is classically attributed to the prefrontal cortex. Prefrontal thalamocortical circuits from mediodorsal thalamus (MD) or thalamic nucleus reuniens (RE) are altered in neurological conditions with cognitive flexibility deficits. Interventions targeting thalamocortical interactions may offer therapeutic benefits. Using the attentional set-shifting task, we showed in rats that permanent lesions of MD or RE glutamatergic neurons caused dissociable cognitive flexibility deficits and that the selective 2-adrenoceptor antagonist, atipamezole improved cognitive flexibility. RE damaged rats were impaired on the first of three intradimensional shift (ID) subtasks involving responding to novel stimuli pairings linked to the sensory dimension that reliably predicts reward. In contrast, MD damaged rats had intact ID performance but were impaired in the extradimensional shift (ED) subtask, whereby after task demands change rats are required to make a rapid shift in attending to and adapting choice responses to novel stimuli pairings linked to the previously irrelevant sensory dimension. RE damage did not disrupt ED performance. Intraperitoneal injections of atipamezole (1mg/kg), given 30-min prior to retesting with novel stimuli pairings improved cognitive flexibility despite permanent thalamic damage. VGluT2 labelling in the anterior cingulate cortex indicated neural network downstream effects with MD damage producing increased labelling relative to Sham operated controls, while RE damage showed decreased labelling. These findings demonstrate the dissociable influence of MD and RE during cognitive flexibility and suggest the use of noradrenergic regulation as a potential therapeutic option to reduce this cognitive dysfunction.

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Hamilton, J. J., Berriman, L., Harrison-Best, S., Dalrymple-Alford, J. C., Mitchell, A. S.. 2026-02-18. Noradrenergic administration improves cognitive flexibility even after glutamatergic damage in rat mediodorsal thalamus or thalamic nucleus reuniens. https://doi.org/10.64898/2026.02.16.706106

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