Neurochemistry

Cholinergic Mechanisms of Learning and Cognition

The brain is the most complex organ of our body. It enables us to do complex behavioral tasks and find ready-to-go solutions for abstract problems. The brain uses many different subsystems to respond in an adequate manner to a stimulus from the environment. One of these systems is the cholinergic network located in the basal forebrain and extending from there through the entire cortex. Learning and cognition heavily depend on an intact cholinergic system, which guarantees attention to important and relevant cues from the outside world and also insures subsequent memory formation of these cues to create an integrated and reliable experience for adequate behavior in later life. The importance of the cholinergic system becomes dramatically evident in the devastating effects of progressive Alzheimer disease.

In one project we investigate the effect of different drugs (antagonists and agonists of cholinergic release) on the BOLD and on the neuronal signal. To improve the predictive power of the BOLD and the neuronal signal after drug application we are applying machine learning methods to allow for near real-time analysis of the two signals.

In a second project we take advantage of the fact that the extracellular space is an integrated functional part of information processing in the brain. The release of chemical substances into the extracellular space for signaling provides an interesting opportunity for monitoring signal transduction in the living brain. We are monitoring the cholinergic effect on the dynamics of the neurotransmitters glutamate and GABA and of the neuromodulators serotonin and dopamine. We are also able to monitor metabolites such as lactate which are linked to the neurovascular coupling process. The neurochemical monitoring of these compounds is performed while simultaneously measuring the BOLD signal. In this way we can see how the neurochemical dynamics interacts with the BOLD signal and gain additional insight into the neurovascular coupling process. In a second project we take advantage of the fact that the extracellular space is an integrated functional part of information processing in the brain. The release of chemical substances into the extracellular space for signaling provides an interesting opportunity for monitoring signal transduction in the living brain. We are monitoring the cholinergic effect on the dynamics of the neurotransmitters glutamate and GABA and of the neuromodulators serotonin and dopamine. We are also able to monitor metabolites such as lactate which are linked to the neurovascular coupling process. The neurochemical monitoring of these compounds is performed while simultaneously measuring the BOLD signal. In this way we can see how the neurochemical dynamics interacts with the BOLD signal and gain additional insight into the neurovascular coupling process.

By combining the three methods we are also in a strong position to elucidate the mechanism of neurovascular coupling itself. These studies are carried out in anesthetized monkeys and focus on the effects of neuromodulators on the neural and BOLD fMRI signals. By combining the three methods we are also in a strong position to elucidate the mechanism of neurovascular coupling itself. These studies are carried out in anesthetized monkeys and focus on the effects of neuromodulators on the neural and BOLD fMRI signals.

We are working with endogenous neuromodulators or with subreceptor agonists (1) to facilitate translation of our findings to later stages when physiological manipulations are used to trigger the release of neuromodulators, for example in an attentional task in an awake monkey. A close understanding of the neuromodulators’ influence on neurovascular coupling is important because many important neuromodulatory systems are involved in disabling human diseases. In this context fMRI has great diagnostic potential due to its non-invasiveness.

Literature

1. Rauch A., G. Rainer, N. K. Logothetis: The Effect of a Serotonininduced Dissociation between Spiking and Perisynaptic Activity on BOLD functional MRI. Proc. Natl. Acad. Sci. USA 6, 105(18), 6759 – 6764 (2008).