Periodic Reporting for period 1 - RigidPlasticNeurons (Encoding of episodic memory in hippocampal rigid and plastic neurons)
Berichtszeitraum: 2021-04-01 bis 2023-03-31
The ability of the mammalian brain to generate internal representations of the outside world have been extensively studied in the past, yet it is not well understood how a structure central to the formation and recall of memory, the hippocampus, enables both a generalized and yet flexible encoding of external features. In particular, it is not well understood how the encoding properties of neural populations in the hippocampus emerge and refine during early-life brain development.
To overcome this knowledge gap, I sought to investigate the encoding of spatial features in the CA3 region of mouse hippocampus while animals repeatedly explore linear environments. For this, I labelled neural population in CA3 with a fluorescent calcium indicator and trained animals to move head-fixed under a two-photon microscope on a linear treadmill, and to explore familiar and novel haptic environments comprised of distinct tactile cues.
By measuring the activity changes of 100s of cells simultaneously, I could identify a subset of CA3 neurons following a generalized, or rigid, encoding scheme with their spatial activity profile being tuned to the general structure of the treadmill task, while another subset of neurons followed a plastic encoding scheme, showing spatial tuning and activity remapping to specific haptic features on the treadmill. This suggests that both encoding schemes are employed in parallel during explorative behaviors, with rigid neurons encoding task structure and plastic neurons encoding specific features.
Current work focuses on the formation, update, and refinement of rigid–plastic encoding schemes in the developing brain. For this, infant (and adult) mice are trained to move through virtual reality environments, to overcome limitations of movement of very young animals on the haptic treadmill apparatus, and to enable spatial manipulations of the virtual reality environment that are impossible in real-world tasks (e.g. teleportations).
To overcome this knowledge gap, I sought to investigate the encoding of spatial features in the CA3 region of mouse hippocampus while animals repeatedly explore linear environments. For this, I labelled neural population in CA3 with a fluorescent calcium indicator and trained animals to move head-fixed under a two-photon microscope on a linear treadmill, and to explore familiar and novel haptic environments comprised of distinct tactile cues.
By measuring the activity changes of 100s of cells simultaneously, I could identify a subset of CA3 neurons following a generalized, or rigid, encoding scheme with their spatial activity profile being tuned to the general structure of the treadmill task, while another subset of neurons followed a plastic encoding scheme, showing spatial tuning and activity remapping to specific haptic features on the treadmill. This suggests that both encoding schemes are employed in parallel during explorative behaviors, with rigid neurons encoding task structure and plastic neurons encoding specific features.
Current work focuses on the formation, update, and refinement of rigid–plastic encoding schemes in the developing brain. For this, infant (and adult) mice are trained to move through virtual reality environments, to overcome limitations of movement of very young animals on the haptic treadmill apparatus, and to enable spatial manipulations of the virtual reality environment that are impossible in real-world tasks (e.g. teleportations).
During the project, surgical procedures have been implemented to gain optical access to the hippocampal CA3 region for functional calcium imaging in adult and infant mice. In particular, the procedures have been adapted to allow long-term imaging experiments in infant animals, from the time point around eye opening. A head-fixed treadmill navigation assay has been implanted to probe the encoding schemes of CA3 neural populations while animals explore linear corridors. To overcome limitations of the ability of infant animals to move a haptic treadmill, a virtual reality navigation apparatus has been implanted in which animals move head-fixed on a spherical treadmill.
Furthermore, the virtual reality assay allowed for a greater flexibility in the (a) task design and (b) spatial manipulations of the virtual environments. The study found two populations of CA3 neurons that followed either rigid or plastic encoding schemes. Current work is focused on pinpointing the time point of origin of rigid–plastic encoding by imaging CA3 in infant animals moving through virtual reality corridors. Work on a manuscript to be submitted for peer-reviewed publication is expected to commence in autumn of 2023.
Further work has focused on the intrinsically generated activity dynamics, i.e. without pronounced external sensory inputs, in CA3 of infant and adult mice voluntarily moving headfixed on a running wheel in near-darkness. Imaging data from these experiments is currently shared with two theoretical laboratories to collaborate on investigating the underlying dimensionality of the population activity dynamics in the population. Work on a manuscript is expected to start by the end of 2023.
Furthermore, the virtual reality assay allowed for a greater flexibility in the (a) task design and (b) spatial manipulations of the virtual environments. The study found two populations of CA3 neurons that followed either rigid or plastic encoding schemes. Current work is focused on pinpointing the time point of origin of rigid–plastic encoding by imaging CA3 in infant animals moving through virtual reality corridors. Work on a manuscript to be submitted for peer-reviewed publication is expected to commence in autumn of 2023.
Further work has focused on the intrinsically generated activity dynamics, i.e. without pronounced external sensory inputs, in CA3 of infant and adult mice voluntarily moving headfixed on a running wheel in near-darkness. Imaging data from these experiments is currently shared with two theoretical laboratories to collaborate on investigating the underlying dimensionality of the population activity dynamics in the population. Work on a manuscript is expected to start by the end of 2023.
Achieving long-term imaging experiments in infant animals, from a time point early after eye opening and onwards, is a key element to investigate how the developing hippocampus generates internal representations of space. In particular, these ongoing experiments will shed new light on how CA3 population codes emerge and refine during early-life brain development and extend our understanding of how the (infant) brain can maintain a robust and yet flexible internalization of the outside world during explorative and navigational behaviors.