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The role of the basal forebrain in attention and learning

Final Report Summary - NBATTENTION (The role of the basal forebrain in attention and learning)

The basal forebrain is thought to play a pivotal role in cognitive functions; yet how it participates in these functions is not well understood. The aim of this project was to elucidate the role of the basal forebrain in attention and learning.
Neurons of the basal forebrain (BF) innervate the entire cortical mantle. Based on the neurotransmitters they release, these projection neurons are cholinergic (releasing the neuromodulatory acetylcholine), GABAergic (releasing the inhibitory gamma-aminobutyric acid) or glutamatergic (releasing the excitatory glutamate). These different cell types are intermixed in the basal forebrain and it is technically challenging to identify these neuron types in vivo. Therefore, no recordings from identified basal forebrain neurons have been conducted from behaving animals. Such recordings are necessary to understand the function of the basal forebrain in cognition, which could eventually lead to more efficient treatments of neurodegenarative dementias like Alzheimer’s disease and Parkinson dementia.
Therefore we recorded identified cholinergic and GABAergic projection neurons from the basal forebrain in an auditory detection task involving sustained attention and reinforcement learning for the first time. Neurons from two different nuclei of the BF, the nucleus basalis and the horizontal limb of the diagonal band of Broca, were identified in transgenic mice by the optogenetic tagging method, applying blue laser light on light-sensitive neurons in vivo. We established the responses of cholinergic and GABAergic neurons in this task and analysed their correlation with attention and learning.
We found that cholinergic neurons of both BF nuclei responded to reward and punishment with surprisingly rapid and temporally precise action potential firing. Furthermore, these responses correlated with the unexpectedness of the behavioral feedback, suggesting that these neurons may encode reinforcement surprise. On the contrary, cholinergic neurons did not show specific activation before the sensory cues. In contrast with cholinergic cells, GABAergic neurons became more active after the presentation of the sensory cues and showed sustained firing rate elevation. On one hand, these results strongly suggest that basal forebrain cholinergic neurons mediate learning by rapidly activating the cortex after behavioral feedback. On the other hand, they do not support the cholinergic system’s hypothesized role in sustained attention.
Since the basal forebrain cholinergic neurons are implicated in Alzheimer’s disease, Parkinson’s dementia and slow cognitive decline in normal aging, these results are expected to have translational potential and possibly far-reaching impact by suggesting new directions in the research of neurodegenerative dementias, including diagnosis and therapy.