A07
We all know it – too little sleep or jet lag after a flight impairs our ability to think and remember because the internal rhythm of our brain gets confused. We are investigating how this inner rhythm and an important messenger substance for these processes, orexin, can be used to restore cognitive performance.
Principal Investigators
Prof. Dr. Dr. med. Anne Albrecht
Prof. Dr. Oliver Stork
Co-Workers
Lara Chirich Barreira
Dr. Gürsel Caliskan
Dr. Yunus Demiray
Hannah Gapp
Dr. Aliće Grünig
Harini Srinivasan
What is the orexin?
Orexin is a small neuropeptide. It is produced in a few cells in the hypothalamus, our control center in the brain for autonomic functions such as sleeping, eating and reproduction. Orexin acts there as the most important wake promoting factor. Orexin may also affect memory formation and cognitive flexibility by connecting the hypothalamus to other brain areas such as the hippocampus and the prefrontal cortex in the frontal lobe.
What is the joint function of the hippocampus and prefrontal cortex?
Both brain areas work closely together to retrieve memory content or to apply what has already been learned in a new context (cognitive flexibility). While the hippocampus sends direct neuronal connections to the prefrontal cortex, further intermediate stations are switched on in the “return path”, such as the so-called supramammillary nucleus (Vertes, 2015). Information processing also takes place in these intermediate stations (Hashimotondani et al., 2018), but it is not yet clear how orexin influences the flow of information between all these brain areas.
How does orexin work in the hippocampus and prefrontal cortex?
The hippocampus, supramammillary nuclei, and prefrontal cortex receive orexin signals from the hypothalamus and sense them with receptors for orexin on their cells. Pharmacological studies have shown that the stimulation of such orexin receptors supports neuronal plasticity and spatial memory formation (Akbari et al., 2010; Dang et al., 2018). The stimulation of the orexin receptors can trigger molecular changes in these cells and thereby support their permanent connection. This contributes to the formation of a kind of memory trace in the brain.
The goals of our project
We will investigate how disturbances of the circadian rhythm affect the information flow between the prefrontal cortex and the hippocampus influences it and will analyse the role orexin and its receptors play in these processes. We are also interested in how orexin influences the cellular and molecular processes in the hippocampus that enable neuronal cells to be linked to memory traces.
Orexin in cognition circuits
We use viral neuronal tracers to map connections between the prefrontal cortex, supramammillary nucleus, and hippocampus. In order to find out whether the interconnected nerve cells contain orexin receptors, they are isolated using laser microdissection and their mRNA profile is examined. In addition, we use the RNAScope technique to display the expression of orexin receptors in the individual brain areas with high spatial resolution.
Orexin action in the hippocampus
We will investigate how a disruption of the circadian rhythm (disrupted sleep, jet lag) affects learning and memory and which role the hippocampus, supramammillary nuclei and prefrontal cortex play in these processes. We will also evaluate the impact of the local reduction of orexin receptors on learning and memory. Then we will test how the intranasal application of orexin and, as a complement, a blockade of orexin receptors affects cognitive performance and the formation of cellular memory traces in the hippocampus.
A glimpse into the future
We expect, together with other SFB projects, to gain insights into neuronal circuits and cellular mechanisms that can counteract cognitive decline. Orexin has great potential not only to improve cognitive performance after circadian rhythm disturbances, but also to counteract the loss of such neuronal resources during stress or aging processes. Since orexin can also be used in humans as a nasal spray or orexin blocker as a sleeping pill, new therapeutic approaches for patient groups with sleep disorders, anxiety disorders or various forms of dementia can arise in the long run.