Dendritic integration in human cortical neurons under natural conditions in human cerebrospinal fluid (hCSF)

• Applicants: Professor Dr. Björn Michael Kampa; Henner Koch, Ph.D.
• Subject Area: Experimental and Theoretical Network Neuroscience
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554040784

The human brain is constantly active and capable of switching between several states, which is the basis of many essential processes, including information processing and memory formation. Understanding the mechanisms that enable neurons to generate complex patterns of activity depends on investigations on the level of single cells, their dendritic properties and the integration of their synaptic signals. Many elegant neuroscience studies have used animal models to investigate these cellular and dendritic mechanisms of cortical cells. However, it remains uncertain how far these results can be directly translated to the human brain. This problem has led to a strong effort of the research community to investigate fundamental properties in cells and circuits of humans directly. In addition, it is now recognized that human cerebrospinal fluid (hCSF) can significantly influence the activity and properties of neurons and might unmask mechanisms of the human brain that might stay hidden when investigated in artificial cerebrospinal fluid (aCSF). Therefore, we propose to investigate human cortex samples (acute and organotypic slices) and decipher the effects of hCSF on cortical pyramidal cells, investigate their dendritic properties and test how ensembles of neurons are connected In detail, we intend to investigate human neurons and networks with three independent but interacting aims: 1. We plan to measure somato-dendritic coupling in human slice cultures of the cortex using intracellular recordings and perform a pharmacological screening to unravel the potential molecular mediator of the effects of hCSF. 2. We aim to investigate the supralinear dendritic integration properties of human cells in the presence of hCSF compared to aCSF using two-photon calcium imaging of human pyramidal neurons. 3. We utilize optogenetic strategies to investigate the dendritic integration of local network connections in cortical microcircuits between aCSF and hCSF, transducing newly designed opsins (ChroME) to allow two-photon activation of small ensembles. Our study's results will help to narrow the translational gap between animal studies and humans and improve the design of therapy approaches for neurological diseases.

• DFG Programme: Research Grants