Periodic Reporting for period 2 - HippoFronThal (Role of midline thalamic neurons during memory related hippocampal and cortical network activity)
Reporting period: 2023-01-20 to 2024-01-19
In everyday life, our behavior is primarily driven by our motivation and need. Yet, at the same time, it is constrained by external conditions, like the presence of a threat. Our brain has to make decisions in many conflicting situations throughout our life and it constantly learns and re-evaluates what kind of behavior would be the best for us. Research in mice revealed an evolutionary conserved system of interconnected brain regions that is responsible for motivated behavior. A key component of this system is the midline thalamus, that collect information about the internal states and needs of the organism - like pain, hunger or fear -, but also communicates with brain areas that form memories and organize behavior. The aim of HippoFronThal is to understand how the midline thalamus contributes to motivated behavior. We particularly focus on how neurons in the midline thalamus cooperate and communicate with neurons in other parts of the brain. To explore this question, we combined multiple cutting-edge techniques to identify and monitor the activity of midline thalamic neurons in freely behaving mice during various types of behavior. The significance of this work would be to help better understand how the brain processes information coming from the body and from the environment and how it integrates them with existing memories in order to select appropriate behavior.
To investigate the role of midline thalamus and its communication with other brain regions we used mice to record brain activity at multiple brain areas at the same time, while mice were exploring a familiar environment for food, running on a wheel, or just sleeping. During sleep the brain is detached from its environment and generates its own internal activity patterns with minimal sensory influence. Therefore, sleep can be considered as a default state of the brain where one can investigate the basic functional connections and relationships between brain areas.
It is technically challenging to monitor neuronal activity at multiple locations of the brain in a freely moving mouse. We designed a recording configuration, where we implanted three electrode arrays into the brain in order to monitor neuronal electrical activity within the midline thalamus and in two other connected brain areas relevant for memory formation and for organizing behavior: the hippocampus and the prefrontal cortex, respectively. The challenge, on the one hand, was to miniaturize the holding components of electrode arrays to be able to fit them onto the small skull of a mouse. For that we used the most sophisticated commercially available electrode arrays and designed high quality 3D printed materials to position them. On the other hand, we needed to discriminate midline thalamic neurons from surrounding neurons. Midline thalamic neurons express a protein, called Calretinin, which neighboring neurons lack. Taking advantage of advanced genetic techniques (transgenic mice, optogenetics), we were able to turn these Calretinin containing neurons light sensitive: by shining brief light pulses into the thalamus, we were able to temporarily activate these neurons, hence we could tell which neurons belonged to the midline thalamus and which didn’t.
The brain generates different electrical activity patterns in different brain states (like slow oscillation during sleep but much faster oscillations during wakefulness), which suggests that the brain performs different computations in these states. Once we identified midline thalamic neurons with our electrodes, we monitored their activity in various brain states and across multiple behavioral conditions. We were curious how different the activity of midline thalamic neurons was during sleep and during exploration and how their activity coupled to the neuronal activity of the cortex and hippocampus. Our experiments revealed a strongly interconnected tripartite circuit, where the midline thalamic activity is strongly coupled to the cortical and hippocampal activity during sleep and wakefulness. While our experiments are still ongoing, our results clearly suggest that the midline thalamus is extensively but differentially communicate with the hippocampus and cortex in multiple brain and behavioral states. We presented our results in several international conferences both within Europe and in the United States.
It is technically challenging to monitor neuronal activity at multiple locations of the brain in a freely moving mouse. We designed a recording configuration, where we implanted three electrode arrays into the brain in order to monitor neuronal electrical activity within the midline thalamus and in two other connected brain areas relevant for memory formation and for organizing behavior: the hippocampus and the prefrontal cortex, respectively. The challenge, on the one hand, was to miniaturize the holding components of electrode arrays to be able to fit them onto the small skull of a mouse. For that we used the most sophisticated commercially available electrode arrays and designed high quality 3D printed materials to position them. On the other hand, we needed to discriminate midline thalamic neurons from surrounding neurons. Midline thalamic neurons express a protein, called Calretinin, which neighboring neurons lack. Taking advantage of advanced genetic techniques (transgenic mice, optogenetics), we were able to turn these Calretinin containing neurons light sensitive: by shining brief light pulses into the thalamus, we were able to temporarily activate these neurons, hence we could tell which neurons belonged to the midline thalamus and which didn’t.
The brain generates different electrical activity patterns in different brain states (like slow oscillation during sleep but much faster oscillations during wakefulness), which suggests that the brain performs different computations in these states. Once we identified midline thalamic neurons with our electrodes, we monitored their activity in various brain states and across multiple behavioral conditions. We were curious how different the activity of midline thalamic neurons was during sleep and during exploration and how their activity coupled to the neuronal activity of the cortex and hippocampus. Our experiments revealed a strongly interconnected tripartite circuit, where the midline thalamic activity is strongly coupled to the cortical and hippocampal activity during sleep and wakefulness. While our experiments are still ongoing, our results clearly suggest that the midline thalamus is extensively but differentially communicate with the hippocampus and cortex in multiple brain and behavioral states. We presented our results in several international conferences both within Europe and in the United States.
We recorded an unprecedentedly rich dataset of midline thalamic activity (several thousands of neurons) in freely behaving mice. Our recording configuration allowed us to relate thalamic activity to multiple brain activity simultaneously and across various brain states. We provide the first dataset that functionally describes how the midline thalamus interacts with the hippocampus at the neuronal level. So far, we focused on to describe the activity of midline thalamic neurons during sleep and exploration. In the remaining part of the fellowship, we will focus on how the midline thalamic neurons respond to the presence of an aversive stimulus when the animal is exploring for food. We would like to know how the sudden appearance of a threat changes the behavior of the mouse and the communication of the midline thalamus with the cortex and hippocampus. Our findings will provide not just a better understanding of the midline thalamus at the neurophysiological level but also might provide a foundation for future translational research to help understand human conditions with motivational deficits.