The cognitive mapping of uncertainty by integrated neuromodulation in the hippocampus

In a constantly changing environment, the brain must store and update information in a way that depends on uncertainty. The hippocampus is central to this continual process but relies on inputs that signpost new information and regulate the extent to which it is incorporated in future estimates. Our central hypothesis proposes that this signposting is performed by functionally overlapping neuromodulator systems interacting in an integrated fashion to signal different types of error and uncertainty. This signal enables appropriate updating of memories stored in the hippocampus providing realistic expectations on which to base decision making in uncertain situations, a fundamental process whose disruption is a core feature of multiple psychiatric disorders. To test these models, we will measure where and when neuromodulation by acetylcholine, dopamine, noradrenaline and serotonin occurs in the hippocampus during spatial navigation tasks in mice designed to manipulate the type and degree of error and uncertainty. These findings will inform a novel theoretical framework which will be iteratively refined by experiments to selectively manipulate neuromodulator release and downstream targets, providing mechanisms for how neuromodulators integrate to modify observable hippocampal representations of space. Ultimately this project will fundamentally reappraise the principles of neuromodulation and its therapeutic potential.