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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - RSCHD (Functional dissection of the head-direction circuit in mouse retrosplenial cortex.)

Teaser

Summary

The brain\'s navigational system, which plays a critical role in survival, is highly preserved among mammalian species including rodents and primates. In order to know where we are, we must be able to discern visual and other sensory aspects of the environment, calculate our body position in absolute and relative terms, and retain a memory of where we have been in the past. Although humans and animals are remarkably adept at handling these complex cognitive tasks, many questions remain as to how the brain accomplishes the sophisticated level of multitasking required to maintain and update our navigational awareness.

One aspect of the navigation system, the head direction system, allows us to perceive the cardinal direction we are facing in space. This ability is thought to be primarily mediated by so-called head-direction cells, which are preferentially active when we are facing a specific direction. Although head direction cells have been described in the scientific literature for decades, and can be found in multiple brain regions, there are many as-yet unanswered questions as to how the property of direction-selective activity is conferred to these cells, and how the function of head-direction cells in different brain regions differs from each other.

The retrosplenial cortex (RSC) is an area of the brain that is highly interconnected with memory-related and sensory-related areas, and contains head-direction cells. Importantly, it is an early target of Alzheimer\'s disease, and this selective degradation of function may underlie the specific deficits in memory and navigation that is a hallmark of Alzheimer\'s. However, surprisingly little is known about how the RSC functions in normal brains, and what the unique circuitry of this brain area accomplishes that is critical for memory and perception.

The RSC is remarkably amenable to neuroscientific studies using state-of-the-art techniques for understanding brain circuitry. This project aimed to investigate the mechanisms of head-direction tuning in the RSC, and how this feature of the navigational system is built up from inputs from other cells and brain regions. We also aimed to understand the individual features of head direction cells, such as their location in the RSC and their molecular characteristics.

As the global population ages, dementia will become a more pressing issue for healthcare systems, societies and families. By applying modern tools to long-standing questions of fundamental brain function, we hope to provide answers that can inform cutting-edge therapeutic avenues for dementia.

Work performed

1. Performing two-photon calcium imaging of head-direction cells in RSC.

A large dataset comprising thousands of cells across mouse RSC was obtained during passive rotation. In this dataset, 5-10% of cells were found to show head direction tuning, and remarkably many of these cells also showed conjunctive tuning to other features such as turn direction, and speed. Summaries of these results were presented in conference abstracts at two major international meetings: (1) European Visual Cortex meeting in London, UK, and (2) Society for Neuroscience meeting in Washington, DC, USA.

2. Computational analysis of head direction tuning in RSC.

In collaboration with a computational neuroscientist, analysis of the dataset from Topic 1 revealed the extent to which individual RSC head direction cells can decode head direction alongside other features of passive rotation. Experimental data also shows the stability of head direction tuning over multiple days of imaging. This analysis will be presented at an international conference for memory research (Spring Hippocampal Research Conference, Taormina, Italy). These results are also being prepared into a manuscript for publication.

3. Development of an active rotation behavioral task to study the causal impact of RSC in head-direction perception.

Since only a minority of cells in the RSC are sensitive to head direction, we developed a task that would allow high-resolution imaging of head direction cell activity during active conditions, as opposed to passive rotation. In the task, mice were trained to orient themselves toward visual or auditory cues and discriminate between the direction of these cues. Therefore, the task required the development of a new behavioral paradigm that can be used to understand how mice used directional information to orient themselves in space. Preliminary experiments also included performance of the task during periods when the RSC was inactivated with a drug, however more experiments are needed to determine the effect of RSC inactivation on behavioral measures.

4. Development of viral-genetic strategies to determine mechanistic underpinnings of RSC head-direction tuning.

Another aspect of the project was to develop viral-genetic strategies to identify how RSC head-direction cells obtain their functional properties. To this end, mouse lines which allowed the study of different neuronal cell types such as inhibitory and excitatory neurons in RSC, and the isolation of specific inputs to RSC from other memory and sensory related areas, were studied under two conditions: (1) passive rotation, and (2) memory consolidation periods in awake and sleeping mice. Cell-type specific responses in both experiments indicate that certain cells mediate different aspects of memory and navigation, and that these cells could be unique therapeutic targets for treatment of memory-related diseases. These results will be presented at two international conferences: (1) The Spring Hippocampal Research Conference (Taormina, Italy), and (2) The Society for Neuroscience Meeting (Chicago, USA). The results are also being prepared into a manuscript for publication.

Final results

The project has covered new ground on multiple levels. It is one of the handful of projects globally that is studying head direction representations in awake mice using high-resolution two-photon calcium imaging. This technique is able to reveal network-, cellular-, and subcellular-level mechanisms of the navigation and memory system. Therefore, these studies can be critical to the development of new understandings of a system that is vulnerable to degradation in old age and during diseases such as Alzheimer\'s. Ours is one of the few studies able to discern new features of the system with tools that have been developed in the past two decades for brain research in mice. Two-photon imaging, combined with the behavioral and viral-genetic strategies described in the project results summary, offer an unprecedented level of specificity and control in experimental investigations of brain function.

One major result of the study is that head-direction cells in the RSC encode multiple features simultaneously, such as turning direction and speed. Therefore, the RSC may be a critical region in the navigation system that allows head direction to be integrated with other relevant aspects of the environment. Further, results show that RSC shows unique activation patterns during periods of memory consolidation, in specific cell types, which implicates the region in processing and storing memories for long-term use. Together, these results provide evidence for potential therapeutic targets within the RSC for treatment of diseases affecting navigation and memory, such as Alzheimer\'s.