Connecting Nerves

If we were mere stimulus-response machines, our lives would be quite boring, predictable, and devoid of purpose. Imagine, for example, if we always pounced on food the moment we saw it – even when we weren’t hungry at all. Fortunately, however, we are generally quite flexible in our behavior. This is made possible by the interconnection of nerve cells via synapses. ▸ Synapses: Interfaces of Learning

Ilona Grunwald Kadow has been closely examining how the connections between our brain cells affect our behavior for years. “Our decisions are based on how we assess situations,” says the neuroscientist, formerly at the Technical University of Munich and now at the University Hospital Bonn. “This assessment, in turn, is determined by our experience, our current needs, and what our sensory Perception is presenting to us at that moment.” For example, it makes a big difference whether an organism is hungry or not. Hungry animals place a higher value on smells and tastes than usual. This is because, in such cases, the “reward hormone” Dopamine is released in greater quantities at the synapses in various regions of the brain. “Neurons that produce dopamine influence sensory perception and thus allow behavior to be flexibly adapted to current situations,” says Grunwald Kadow. 

In a study published 2020, she examined the response of all dopamine-producing neurons in over 400 living fruit flies when exposed to Taste and smell stimuli. The result: Certain neurons appear, for example, to detect whether the fly is currently moving, resting, or grooming itself. If the fly smells something enticing and the pleasant scent intensifies when the fly moves, the signal is: Keep moving in this direction. Grunwald is not studying the cell bodies, but rather the synapses. Upstream neurons send information – such as odors – to downstream neurons, which then control whether the organism moves or not. 

Kadow has already shed light on what such communication might look like in a study published in 2015. Together with colleagues, she exposed fruit flies to two odors that trigger conflicting “emotions” in the animals: the enticing food odor of vinegar, and CO₂ which can signal danger. When the flies detect CO₂, an innate flight response is triggered. However, this does not exactly make decision-making any easier for the flies: CO₂ is also produced – in a rather tricky twist – by overripe fruit, a coveted food source for many insects. In such cases, foraging flies must therefore be able to ignore their innate aversion to CO₂. The study revealed that the smell of vinegar did indeed activate certain dopaminergic neurons. These, in turn, suppressed activity in synapses that respond to negative odors such as CO₂. As a result, the hungry flies were less responsive to the potential danger and were able to focus on the source of the enticing scent.
 

“Some activity of dopaminergic synapses alters the response of downstream neurons only briefly, thereby influencing an immediate decision,” says Kadow. “But above all, recurring activity can lead to long-term changes in communication between neurons.” This is how living organisms learn. During learning, tiny extensions form on nerve cells. To establish a synaptic connection, these extensions on opposing nerve cells grow into mushroom-like structures. On the upstream side of the Neuron – where the stimulus originates – axonal terminals form. On the opposite, receiving side, so-called Dendritic spines develop. The interaction between these two projections enables the exchange of information between different nerve cells. The rule of learning is: Neurons that fire together wire themselves together. ▸ The Nervous System – A Master of Transformation.

To observe new connections forming in real time, Mark Hübener relies on two-photon microscopy. “It allows us to examine even very fine structures in the intact nervous system,” says the neurobiologist at the Max Planck Institute for Biological Intelligence in Martinsried, near Munich. “The advantage is that you can look deeper into the tissue than with a normal microscope – up to one millimeter.” This is because two-photon microscopy uses light with a long wavelength – namely, infrared light. It penetrates tissue more easily than shorter-wavelength light. Furthermore, it is much less harmful to the tissue than, for example, UV light.

“This method is particularly well-suited for our research into synaptic Plasticity because synapses are very small structures and are often located deep within the brain.” Both axonal terminals and Dendritic spines are only two-to-three-thousandths of a millimeter in size. In his experiments, Hübener, for example, exposes mice to a new experience. Over the course of days or weeks, he can then repeatedly check whether this is accompanied by the formation of dendritic spines. “If, for example, a dendritic spine on the downstream side of the Synapse grows larger or forms for the first time, then we know that synaptic connections have become stronger or have formed anew.” A change has thus taken place that underlies learning. In the same way, two-photon microscopy can be used to examine changes in the axonal terminals on the presynaptic side of the synapse. 

When a Synapse is learning and needs to be restructured for that purpose, various molecular processes come into play. In nerve cells, a portion of the RNA – the transcript of DNA – is translated into new proteins not only in the cell body but also locally at the dendrites. To achieve this, the transcript must be transported specifically to the synapses. However, how the cell ensures that the correct blueprint is delivered to the right address has remained largely unknown until now. Using fluorescence microscopy, Michael Kiebler from the Biomedical Center at Ludwig Maximilian University of Munich examined cell cultures from the rat Hippocampus. As it turned out, the same RNA circulated repeatedly from the cell body to the processes and back until it was needed by a synapse. In this process, specific recognition sequences in the RNA serve as a kind of “postmark” for transport and ensure that the transcript reaches the correct locations within the cell. The transcript can then be translated into proteins for the necessary remodeling of the synapse.

In addition to experiments, computer models also help researchers get to the bottom of the intricate mechanisms at the synapses. Christian Leibold – now at the University of Freiburg – was investigating what happens between the two ears: “Sound takes different amounts of time to reach the left and right ears,” says the neurobiologist. “The brain can localize the sound based on this time difference.” Neurons in the medial superior olive (MSO) use their sensitivity to these time differences to generate a neural map of the acoustic space. Using computer models, Leibold simulated the sound processing of MSO neurons. These nerve cells have four input pathways at the synapse. Two excitatory pathways from the right and left ears, respectively. These increase the likelihood that the Neuron will fire. In addition, there are two inhibitory pathways that have the opposite effect. In the computer model, Leibold and his colleagues then investigated how fast these excitatory and inhibitory potentials must be at the Synapse to explain the neurons’ sensitivity to time differences, as demonstrated in experiments. A similar problem arises for the nerve cells in the midbrain, which process the MSO’s activity to resolve complex sound situations – for example, multiple speakers. In their models, the researchers need only adjust a few parameters, such as changing the ratio of excitatory to inhibitory potentials. “In fact, it’s enough to tweak just a few parameters to explain all the cell’s responses observed in the experiment,” says Leibold. The researchers are like the synapses themselves: they are constantly learning.

Further reading

• Siju, K.P et al.: Valence and State-Dependent Population Coding in Dopaminergic Neurons in the Fly Mushroom Body. In: Current Biology, Volume 30 (11), P2104-2115.e4, June 08, 2020. doi: https://doi.org/10.1016/j.cub.2020.04.037
• Bauer, K.E. et al.: Live cell imaging reveals 3'-UTR dependent mRNA sorting to synapses. Nat Commun. 2019 Jul 18;10(1):3178. doi: 10.1038/s41467-019-11123-x. 

First published on December 1, 2020
Last updated on May 5, 2026