Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress

What is it about?

This work uses a novel mouse model of cholinergic dysfunction in the pedunculopontine/laterodorsal (PPT/LDT) tegmental nuclei to dissect the contribution of mesopontine cholinergic signalling to cognition and behaviour. We revealed that mice with long-term dysfunction of mesopontine cholinergic neurons performed normally in tests of attention, visual associative learning, paired associates learning (PAL) and they showed minor deficits in cognitive flexibility. Spatial learning in mutant mice appeared normal when tested on dry mazes. In contrast, these mice showed striking deficits in both spatial and goal-directed learning when tested in water mazes, which are more stressful. Moreover, their performance in the PAL test, while otherwise normal, was affected by a mild sound stressor. Mutant mice also showed disproportionately increased levels a stress-related hormone after swimming in the water maze and they presented altered behavior in tests of anxiety- and depression-related behavior. These results indicate that dysfunction of PPT/LDT cholinergic neurons does not lead to major changes in cognitive function. Instead, it leads to decrease resilience to stress and/or increase anxiety, which can manifest as cognitive performance impairments in some aversive tasks. These results clarify the role of PPT/LDT cholinergic neurons in attention and other forms of higher-level cognition. Also, these data caution for the use of stressful tests to investigate cognition, as it is clear that stress during testing can be a major impediment to the assessment of cognitive function.

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