Untangling nanostructural patterns of neuromodulation that shape state-dependent visual processing

• Applicant: Dr. Jan Philipp Delling
• Subject Area: Experimental and Theoretical Network Neuroscience ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567204047

The physiological and behavioral state of an animal strongly influences sensory perception. In primary visual cortex (V1), neurons encode signals related to these states, such as arousal or motor movement, affecting how sensory information is processed. The strength of this encoding varies among neurons, but the source of this variability remains unclear. Neuromodulation by cholinergic or noradrenergic input is a potential mechanism, as it strongly affects state-dependent neuronal responses. Current approaches investigating such responses lack the resolution to study subsynaptic organization. Accordingly, whether the nanostructure of neuro-modulatory synapses is linked to state-dependent activity in V1 remains unexplored. How do synaptic signatures of neuromodulation reflect neuronal response variability to state signals and visual stimuli? This proposal aims to address this question by focusing on three objectives integrating in vivo electrophysiology, behavioral analysis, and Expansion Microscopy (ExM). Firstly, the nanostructure of neuro-modulatory synapses will be characterized in layer 5 of V1 ("Objective 1"). Viral sparse labeling will be combined with ExM to categorize neuro-modulatory input of single neurons in V1. I assume that neuronal subpopulations and dendritic subsections show distinct patterns of synaptic diversity or nanostructure related to neuro-modulatory input. Secondly, it will be determined how effectively nanostructural signatures of neuromodulation predict state-dependent activity in layer 5 of V1 ("Objective 2"). In vivo patch-clamp recordings and ExM, will be combined to bridge the scales from behavior and neuronal activity down to subsynaptic protein assemblies. I hypothesize that cellular morphology, synaptic nanostructure, and differential neuro-modulatory input improve predictions of state-dependent neuronal activity patterns. Lastly, the correlation between patterns of neuro-modulatory input and visual processing will be quantified in layer 5 of V1 ("Objective 3"). Visual stimuli will be presented during in vivo patch-clamp recordings to analyze state-dependent visually evoked responses. I anticipate that cellular morphology, synaptic nanostructure, and neuro-modulatory input correlate with the magnitude of such responses. The proposed experiments will enhance our understanding of the neural mechanisms underlying state-dependent visual processing - bridging the scales from subsynaptic protein assemblies to neuronal activity related to behavior and state. Given that sensory processing and neuromodulation are affected in neuropsychiatric disorders like the autism spectrum, further investigation is particularly important to aid future studies developing therapeutic strategies. Conducting this project will support my goal of becoming a principal investigator and clinician scientist enabling multi-disciplinary translational research.

• DFG Programme: WBP Position