New Discovery in Neuron︱Nobel Prize Lab!

Source︱Taobo Biological Editor︱Wang Sizhen Path integration is a navigation strategy that allows animals to form an estimate of their internal position relative to external signposts
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Path integration relies on brain (autonomous movement) signals from the vestibule, proprioception, visual flow, and movement sources, which provide imperfect estimates of movement
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The cumulative error in the internal position estimation must be corrected by external road signs
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The convergence of path integration and external landmarks expands the scope of accurate animal navigation
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The identification of landmarks raises an interesting conceptual question
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The sensory characteristics of landmarks have no inherent spatial significance, and are valuable only when they are considered fixed in space, and this determination may require path integration
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If the same sensory characteristics are encountered in different locations, further disambiguation problems will occur
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Path integration and the fusion of sensory features create a cognitive spatial map that can impose unique spatial meaning on these features, thereby creating landmarks
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Smell is the main source of sensory information.
If fixed in space, smell can be used as a navigation sign
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The hippocampus receives olfactory information from the lateral entorhinal cortex (LEC)
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LEC accepts direct input from the olfactory bulb and the pear-shaped cortex, two structures responsible for encoding odor identity
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The effect of odor on hippocampal activity has been observed in both spatial and non-spatial environments
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The mesh, head orientation, and velocity cells of the medial entorhinal cortex (MEC) are driven by internal pathway integration signals to provide position and self-motion information to the hippocampus
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In the dark, these internal pathways integrate signals, combined with olfactory and/or tactile cues, to support a stable spatial representation in the hippocampus
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Therefore, the hippocampus is a potential convergence point for internal pathway integration and external sensory signs
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On October 27, 2021, the Richard Axel group of Columbia University and the LF Abbott group jointly published an article entitled "Olfactory landmarks and path integration converge to form a cognitive spatial map" on Neuron
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Richard Axel won the 2004 Nobel Prize in Physiology or Medicine together with Linda B.
Buck for his outstanding research on smell
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In this study, the authors showed how the activity of hippocampal neurons can recognize location information through sensory features when mice use odor cues to navigate in the dark
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They used the Inscopix free activity calcium imaging microscope to record the neural activity of the hippocampus CA1 and found that path integration imposes spatial meaning on odor cues, thereby creating new location markers, greatly improving navigation capabilities, and the same odor appears in different locations It also produced the characterization of different Place Cells
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The results of this study show that odor can be used as a location marker and activate the interaction model of path integration and odor cues in sequence, thereby forming a long-distance cognitive spatial map
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 In this study, the author detected the activity of mouse hippocampal neurons, and only relied on path integration and sparse olfactory sensory cues when performing navigational behaviors
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These experimental results show that path integration and landmarks have convergence in the formation of the hippocampus cognitive space map
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These observations led to the formation of a theoretical model to describe how path integration and olfactory landmarks interact in an iterative process to form a cognitive spatial map
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 1.
Precise navigation behavior under olfactory signs The author designed a series of experiments to allow mice to navigate to a virtual target location in the dark based on path integration and olfactory landmarks
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Initially, mice trained with fixed heads walked 4 meters on a spherical treadmill, reached an unmarked target location in complete darkness, and were rewarded with drinking water (Figure 1A)
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Initially, this task required mice to estimate the location of themselves and their target using only path integration based on internal unique signals
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In the absence of odor, the behavioral performance stabilized after 1-2 weeks (n = 5 mice)
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The mice began to lick after moving only about 2 meters along the 4-meter track and reduced their running speed (Figure 1 BD)
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Therefore, in this experiment, it is impossible to accurately measure distances greater than 2 meters relying on path integration
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 Next, when the mice reached positions 1 meter and 3 meters, the author introduced two brief pulses of the same smell (Figure 1E)
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The measurement result of the photoionization detector (PID) showed that the odor concentration generated by the 1-m and 3-m pulses only differed by 1% (Figure 1F)
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The experiment uses two neutral odors, limonene or pinene, and carries out a random crossover experiment
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After four days of odor reminder training, all mice inhibited licking and kept running at a high speed of 3.
5 meters before they started licking, and quickly slowed down their running at a distance of 0.
5 meters from the reward point.
Speed ​​(Figure 1 C, D, G)
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This shows that the mice recognize odors as spatial landmarks and use these landmarks to improve navigation
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Figure 1 Precise navigation behavior under olfactory signs (source: Fischler-Ruiz et al.
, Neuron, 2021) 2.
Olfactory signs enhance the activity level of positional cells in CA1 The author uses microscopic microscopes (nVista, Inscopix) and The genetically encoded fluorescent Ca2+ indicator GCamp6f imaged ~3000 CA1 pyramidal neurons in each experiment
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Use Inscopix Data Processing Software (IDPS) to identify individual neurons and their Ca2+ traces, and record their activities on the trajectory of the mouse on the virtual track
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The neurological and behavioral data were averaged in a behavioral window of 100 mm for analysis
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Neurons with consistent location selection activity are classified as location cells
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After 1-2 weeks of training without odor cues, 5.
8% of imaging neurons were classified as positional cells (Figure 2 AC)
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The spatial density of the cells is the largest at the starting position, and rapidly decays with distance (Figure 2D)
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The reliability of the position field decreases as the distance from the starting position increases, while the jitter and width of the position field increase as the mouse crosses the trajectory (Figure 2E)
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At the population level, the cross-test stability of the population activity carrier decreases with the increase of distance (Figure 2F)
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These results indicate that in this mode, path integration alone cannot support cell viability at locations exceeding ~2 m
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Neural representations in the space above ~2 m are sparse and unreliable, consistent with the observation of mice starting to lick at ~2 m, and may reflect the accumulation of errors in path integration
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Figure 2 Olfactory markers enhance the activity level of location cells in CA1 (Source: Fischler-Ruiz et al.
, Neuron, 2021) Next, the authors investigated whether spatially located odor cues would enhance the characterization of location cells
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After the mice completed the task for 4 consecutive days under the odor prompts of 1 meter and 3 meters, the percentage of location cells increased from 5.
8% to 35% (Figure 2 GI)
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The density of location cells increases with the length of the trajectory, but it is most obvious after 1 m and 3 m, and the location of the odor is certain (Figure 2D)
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Importantly, despite being exposed to the same odor in these two places, the cells in the different groups were still active at 1m and 3m
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The author also observed that there were relatively few neurons (2.
4%) that responded in both parts of the odor presentation (Figure 2J)
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The presence of three interval peaks (at the starting point and two odor points) keeps the location cell density at a high level throughout the trajectory, despite the attenuation between the peaks
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After odor training, the reliability of the position field increases, while the jitter of the position field tends to decrease (Figure 2E)
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At the population level, the cross-test stability of the population activity carrier increases after odor training (Figure 2F)
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The increase in location cell density and the increase in reliability are consistent with the animal’s ability to inhibit licking and keep running towards the reward zone during odor cueing
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The peak of the location cell at the 3m odor cue and the rising location cell density all the way to the reward location, which is consistent with the use of cognitive space maps to support navigation
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 Analysis of the cell viability of a single experiment showed that there was a significant correlation between the number of cells in the active positions at the 1-m and 3-m odor cues (Figure 2K)
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This indicates that the density of cells near landmarks will affect the density of cells at far landmarks during spatial navigation
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 After decoding the location of CA1 population activity, the authors observed that the mice adjusted the distance estimation and licking behavior to a large extent in response to the speed deviation time and time again, showing the gap between CA1 neural activity and navigation behavior.
Link
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Importantly, this shows that animals use path integration when performing tasks to identify odor cues as spatial landmarks, rather than using elapsed time estimates
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In summary, these results indicate that odor cues can be used as road signs to integrate and integrate with paths to generate strong spatially dependent neural activities and support accurate navigation behavior
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 3.
Olfactory markers induce positional cells to relocate and produce different cognitive spatial maps.
Through the interlaced experiment of limonene and pinene, we studied whether different odors can cause different spatial maps
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The two odors produced different cellular representations of locations, showing remapping (Figure 3A)
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In the limonene and pinene experiments, except for the first odor cue (1 meter), only 11% of the cells were excited in the same position
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According to these findings, after the first odor clue, the correlation between the experimental average vectors of group activity dropped from 80% for the same odor to 15% for different odors, and was still very small above 1 m (Figure 3B)
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The remapping between the limonene and pinene trials was observed in the presence of odor cues as early as the first day of training (Figure 3C)
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These data indicate that in the same task, different odors at the same location will produce different cognitive spatial maps
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Figure 3 Olfactory markers induce location cells to relocate and generate different cognitive spatial maps (Source: Fischler-Ruiz et al.
, Neuron, 2021) 4.
The gradual and continuous appearance of location cell maps and the improvement of navigation behavior.
The author further analyzes The interaction between path integration and odor cues was investigated, and the appearance of location cells during training and related improvements in navigation behavior were investigated
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On the first day of training under the odor cue, the mice started licking and reduced their running speed at about 2 meters, and briefly inhibited the licking and increased the running speed at the beginning of the 3m odor cue (Figure 4 A, B)
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The expected licking behavior is quantified by calculating the licking ratio, which is defined as the average licking rate within 0.
3 m of the reward divided by the average licking rate within the last 3 m of the virtual trajectory
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After the first day of odor training, the licking rate of mice increased with each day of odor training.
It can be seen that the licking rate increased from 2.
74±0.
18 to 7.
14±0.
20 (Figure 4D)
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These observations indicate that mice use path integration to optimize their navigation behavior
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The evolution of location cell markers reflects the gradual improvement of navigational behavior
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In the subsequent training, the number and density of location cells gradually increased (Figure 4F, G)
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Correspondingly, the position estimation error after decoding is reduced by more than 2 times (Figure 4H)
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In a few days, as more cells respond in the area of ​​1~3 m, the peaks of cell density at 1 m and 3 m appear gradually.

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In the iterative process of spatial map expansion, more and more distant sensory cues are identified as landmarks
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This iterative process may be the basic mechanism to extend the cognitive space map to unknown areas
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Figure 4 The gradual and continuous appearance of the location cell map and the improvement of navigation behavior (Source: Fischler-Ruiz et al.
, Neuron, 2021) 5.
The population level activity and state space trajectory in CA1 reflect the gradual progress of the cognitive space map Evolution During the first day of training on the existence of odors, the author observed that the correlation of the population vector appeared a peak immediately after x = 1 m, which means that the population vector at the second odor cue was realigned to the first odor cue The state of the place
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In the odor training process, the correlation after x = 1 m is significantly weakened
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After odor training, the group response at the second odor cue is not correlated with the response at the first odor cue (Figure 5A)
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This result is consistent with spatial strategies, rather than strategies based on sensory discrimination
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In addition, the authors observed that during the 4-day odor cue training process, from day 1 to day 4, the number of neurons that responded to the two odor positions decreased by more than 2 times (Figure 5 BD, Figure 1 J)
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These data indicate that these two odor cues are gradually and sequentially identified as spatial landmarks, marking different locations
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 Principal component analysis (PCA) was used to study the state-space trajectory of neural population activities in mice during learning tasks
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After 4 days of odor training, the two-dimensional neural trajectory has a closed-loop shape, and the distance on the trajectory is roughly proportional to the corresponding distance on the neural trajectory (Figure 5E)
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Therefore, the trajectory of this low-dimensional neural activity projection has topological and measurement similarities with the task
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 On the first day of odor exposure, the trajectory exceeding the odor cues circulates at 3 m and returns along a path similar to the trajectory at 1 m of the odor cues (Figure 5F)
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Through training, the reverse loop was reduced, and it disappeared by the fourth day (Figure 5G, H)
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Therefore, the decorrelation of the group response caused by the 1-m and 3-m odor cues is accompanied by the separation of neural trajectories and space
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Figure 5 The population level activity and state space trajectory in CA1 reflect the gradual evolution of the cognitive space map (Source: Fischler-Ruiz et al.
, Neuron, 2021) 6.
Removing odor cues or reward locations will change the location of the cells In the absence of odor cues, does the rich location cell representation and improved navigation behavior that appear in odor training persist? On the 5th day, after 4 days of odor training, the mice underwent a course of treatment, in which the pinene test and the odorless test were randomly crossed (Figure 6A)
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By comparison, the number of cells on the 5th day is larger than that on the 0th day (Figure 6 B, C), and the licking behavior is more accurate than that on the 0th day (Figure 6D)
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In the 5th day test with odor prompt, the number of cells in the position beyond 2 meters was 2.
4 times that in the test without odor (Figure 6 E, F)
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In addition, the accuracy of licking is expected to be lower in the 5th day test without odor prompts (Figure 6G)
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 Next, the author explored the dependence of location cell activities on rewards
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On the 6th day, the mice performed an experiment without a water reward (Figure 6H)
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Under these conditions, the mice ran at a similar speed, but did not lick and did not stop at 4 meters (Figure 6 I, J)
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The proportion of positional cells decreased from 35% to 0.
7% (Figure 6K)
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Therefore, in this task, the robust location cell representation depends on the existence of rewards
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When rewards are withheld, the absence of location cells may reflect the loss of spatial information provided by reward clues or the lack of motivation for the task
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Figure 6 Removal of odor cues or reward locations will change the characterization of the location cells (Source: Fischler-Ruiz et al.
, Neuron, 2021) 7.
Path integration and convergence model of odor cues during cell formation.
Odor cues can be used to navigate the land The observations of the markers inspired a model to explain how the fusion of path integration and odor cues generates a cognitive spatial map in the hippocampus
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The model includes a group of position cells driven by the input of a set of path integrators, and feedback from the position cells back to the path integrator (Figure 7A)
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As path integration becomes less reliable, the inter-trial variance increases with the distance travelled (Figure 7B)
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Figure 7: Path integration and convergence model of odor cues during cell formation (Source: Fischler-Ruiz et al.
, Neuron, 2021) Model location cells are formed by simulating the platform potential effects observed during the formation of CA1 location cells
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Here a noise level is selected for the path integrator so that reliable location units are only formed at distances less than 2m (Figure 7C)
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Then repeat the process at the position of the 3-meter odor cue to form an iterative process, making it possible to represent the complete location unit on the entire 4-meter trajectory (Figure 7D)
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The system described by the author is composed of two networks: location cells and path integrators, which store the trajectory of the relationship between them in their synapses when the unit cells are located
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The position cell is driven to the maximum extent by the path integrator, which matches the input that occurs when the position field is formed
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The system is calibrated through an external event that determines when these relationships agree
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This event is a milestone
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This model is also consistent with experimental observations
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First, in the experimental data after the model and odor training, the equivalent sensory input at different locations activated cell subgroups at different locations
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Second, the model predicts that the cell density and reliability of the location decrease with the distance from the odor cue, and the density and reliability of each cue's location will have a local peak (Figure 7 E, F)
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In addition, the model predicts that in the presence of odor cues, the reliability of location units on the entire trajectory will increase with training (Figure 7 F, G)
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The predictions of these two models are consistent with the experimental data (Figure 2D, E)
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The conclusion and discussion of the article, enlightenment and outlook The iterative mechanism of spatial map expansion proposed by this model is consistent with the experimental results on the evolution of location unit representation during the training process
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In other words, odor can be used as a location marker to stimulate the interaction model of path integration and odor cues in sequence, thereby forming a long-distance cognitive spatial map
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 The author uses the Inscopix microscope to image the activity of CA1 cells combined with theoretical modeling, providing strong evidence for the process of odor cues as position marker signals, which will form a cognitive spatial map of the hippocampus after iterative expansion
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The integration of internal pathways and external sensory signs generates a cognitive spatial map in the hippocampus
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In a virtual navigation task, the author used the Inscopix calcium imaging microscope to record the activity of CA1 cells to study how mice behave, recognize and use local olfactory cues to estimate their position
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The authors observed that the presence of odor cues in multiple locations in the virtual environment greatly enriched the characterization of location cells and significantly improved navigation
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Presenting the same odor in different locations will produce different location cell representations
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The odor cues at the proximal position enhanced the cell density at the local location and also resulted in the formation of location cells beyond the cues
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This led to the identification of the second, more distant scent cue as a unique landmark, indicating an iterative mechanism for extending the spatial representation to the unknown
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Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
09.
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