Periodic Reporting for period 1 - FLEXIN (Context-dependent flexibility in innate behaviours and their underlying neural circuitry)
Reporting period: 2023-02-01 to 2025-07-31
Imagine you are cycling through your town and a car door suddenly opens in front of you. You might react by hitting the breaks or by dodging the door and cycling around it. Which reaction is induced depends on external and internal factors – the traffic next to you, your stress level because of the meeting you are cycling to and many more. To ensure your survival, your reactions to the car door need to be reflex-like, fast and reliable; but also flexible to account for the particular situation. The innate reaction of avoiding danger is one of the most essential and conserved set of behaviours, observed in most species from crabs to primates. Like in the case of a cyclist avoiding a car door, other animals as well need to adapt their avoidance responses to optimize their survival. However, how the brain is able to integrate contextual information to adjust innate behaviours to each situation remains an open fundamental question.
In this project, we perform experiments that dissect how neural circuits in the brain mediate context-specific reactions to survival-critical cues. A unique combination of viral tools, high-throughput neural recording techniques, and quantification of behaviour in different rodent species, will reveal how neural circuits can encode changes in the animal’s context and adjust to different situations. The strengths of this proposal are twofold: First, this research will make use of the reliable framework of innate behaviours that do not require learning, and which can be elicited with simple visual stimuli to assess flexibility. Second, I will compare the impact of three different contexts on these behaviours and their underlying circuits: How does ambient light affect innate reactions? How do animals respond to threat at different times of the day? How have species that evolved in different ecological niches developed distinct avoidance behaviours? Comparing the impact of these internal and external, transient and permanent contexts on the same, well-defined circuits and behaviours will, first, reveal general principles of context-specific flexibility; second, dissect whether neural circuits that underly similar behaviours are conserved across species; and third, determine which parts of the brain are most likely to adjust when changes in the environment requires behavioural flexibility. Together, this work will reveal how flexible behaviours are created in the brain and may provide a framework to assess cause and treatment of lack of such flexibility, e.g. in anxiety disorders.
In this project, we perform experiments that dissect how neural circuits in the brain mediate context-specific reactions to survival-critical cues. A unique combination of viral tools, high-throughput neural recording techniques, and quantification of behaviour in different rodent species, will reveal how neural circuits can encode changes in the animal’s context and adjust to different situations. The strengths of this proposal are twofold: First, this research will make use of the reliable framework of innate behaviours that do not require learning, and which can be elicited with simple visual stimuli to assess flexibility. Second, I will compare the impact of three different contexts on these behaviours and their underlying circuits: How does ambient light affect innate reactions? How do animals respond to threat at different times of the day? How have species that evolved in different ecological niches developed distinct avoidance behaviours? Comparing the impact of these internal and external, transient and permanent contexts on the same, well-defined circuits and behaviours will, first, reveal general principles of context-specific flexibility; second, dissect whether neural circuits that underly similar behaviours are conserved across species; and third, determine which parts of the brain are most likely to adjust when changes in the environment requires behavioural flexibility. Together, this work will reveal how flexible behaviours are created in the brain and may provide a framework to assess cause and treatment of lack of such flexibility, e.g. in anxiety disorders.
Since the start of the project, we have built and tested the experimental setups to perform our experiments, including highly controlled behaviour assays, in-vivo brain recordings in behaving animals, and precise expression of viral tools in selected brain areas. This allowed us to make several important advances:
We started by systematically evaluating the number of experimental sessions we can perform in a mouse without losing its responses to visual threat stimuli, and found that more than 4-5 sessions leads to permanent habituation. These are crucial data for all behaviour experiments of this project.
Applying these insights, we discovered astonishing effects of time and light on behaviour with three main findings: First, the main modulator of escape behaviour is ambient light. Second, the circadian clock only affects behaviour if it mismatches the light conditions (e.g. daylight at night), leading to weaker behaviour whenever there is a mismatch. Third, light history plays an important role and can either counteract or enhance the mismatch effect. If 2-3 of these aspects mismatch, it can have detrimental effects on innate behaviours. Ongoing tests using tools that allow us to specifically inhibit or activate selected neuronal circuits, suggest that direct connections from the “master clock” of the brain to the brain nuclei that mediate innate behaviours are responsible for time-specific reactions to danger. In the meantime, we have prepared everything to start experiments with Rhabdomys pumilio, a diurnal close relative of mice. It will be exciting to see if diurnal species react the same or in an opposite way to changes in time and light.
Furthermore, we have built on preliminary data on how ecological niches affect behaviour and found that two sister-species of Peromyscus (North American deer mice), originating from very different habitats, react differently to approaching danger. Animals that live in vegetated areas with many hiding spots tend to escape from approaching danger, while those that live in empty sand dunes tend to freeze. We could pinpoint the source of these differences to a specific brain nucleus that induces escaping behaviour in one species, but not in the other. Such drastic remodeling in an evolutionary speaking short time has been very surprising. This reinforces additional questions that we have planned to address, such as how similar the brain circuits that mediate essential behaviours are across species.
Finally, we have started experiments to dive deeper into a mechanistic understanding of how time, light and ecological changes precisely impact neural circuits, and how the resulting changes in behaviour are encoded.
We started by systematically evaluating the number of experimental sessions we can perform in a mouse without losing its responses to visual threat stimuli, and found that more than 4-5 sessions leads to permanent habituation. These are crucial data for all behaviour experiments of this project.
Applying these insights, we discovered astonishing effects of time and light on behaviour with three main findings: First, the main modulator of escape behaviour is ambient light. Second, the circadian clock only affects behaviour if it mismatches the light conditions (e.g. daylight at night), leading to weaker behaviour whenever there is a mismatch. Third, light history plays an important role and can either counteract or enhance the mismatch effect. If 2-3 of these aspects mismatch, it can have detrimental effects on innate behaviours. Ongoing tests using tools that allow us to specifically inhibit or activate selected neuronal circuits, suggest that direct connections from the “master clock” of the brain to the brain nuclei that mediate innate behaviours are responsible for time-specific reactions to danger. In the meantime, we have prepared everything to start experiments with Rhabdomys pumilio, a diurnal close relative of mice. It will be exciting to see if diurnal species react the same or in an opposite way to changes in time and light.
Furthermore, we have built on preliminary data on how ecological niches affect behaviour and found that two sister-species of Peromyscus (North American deer mice), originating from very different habitats, react differently to approaching danger. Animals that live in vegetated areas with many hiding spots tend to escape from approaching danger, while those that live in empty sand dunes tend to freeze. We could pinpoint the source of these differences to a specific brain nucleus that induces escaping behaviour in one species, but not in the other. Such drastic remodeling in an evolutionary speaking short time has been very surprising. This reinforces additional questions that we have planned to address, such as how similar the brain circuits that mediate essential behaviours are across species.
Finally, we have started experiments to dive deeper into a mechanistic understanding of how time, light and ecological changes precisely impact neural circuits, and how the resulting changes in behaviour are encoded.
Especially our findings of how circadian rhythm and ambient light changes innate reactions to threat were very unexpected and have a potentially big impact. Until now, chronobiologists tested the interplay of these two parameters mostly with very strong interventions, e.g. very bright light at night; and researchers have focused on the impact of time and light on “steady-states” (sleep, anxiety etc.). We were very surprised to find that we could almost completely abolish essential innate reactions just by mismatching circadian time points and ambient light levels during the experiment. We consider this a breakthrough because until now there has been very little knowledge on how disturbances in circadian rhythm affect evoked behaviours (i.e. reactions to a stimulus, rather than steady-states). Here we show massive effects of such disturbances on evoked and directed survival-critical behaviours. (2) This is relevant for species conservation as many animals are exposed to mismatching time/light conditions (e.g. light pollution at night). And (3), this suggests a more direct effect of jetlag, device use at night, artificial light conditions etc. on subconscious behaviours, not just because of tiredness.