Targeted Activation of Hippocampal Place Cells Drives Behaviour

Post by Cody Walters

What’s the science?

The hippocampus contains neurons that are preferentially active at specific locations in space. The coordinated activity of these hippocampal ‘place cells’ is thought to form a cognitive map that stores spatial information and is used during memory-guided decision-making. While much research has been done correlating place cell activity with spatial memory, there has been comparatively little research examining the causal relationship between place cell activity and behavior. This week in Cell, Robinson et al. provided direct causal evidence that place cell activation can trigger a learned, location-specific behavior.

How did they do it?

The authors used a virtual reality spatial navigation task in which head-fixed mice navigated a linear track. The authors then used two-photon calcium imaging to measure layer CA1 pyramidal cell calcium fluorescence (a proxy for neuronal firing) and two-photon targeted optogenetics to selectively drive the activity of specific hippocampal neurons. In the virtual reality linear track, mice had to navigate to the reward zone (near the end of the track), remain stationary there for 3 seconds, then lick 3 times in order to receive a sugar-water reward. The virtual environment had an optogenetic stimulation point midway between the start zone and the reward zone. Hippocampal neurons were classified as being either start zone place cells, reward zone place cells, other place cells (corresponding to a position on the track other than the start zone or reward zone), or non-place cells (showing no spatial tuning).

What did they find?

The authors found that reward zone place cell stimulation resulted in an increase in licking behavior at the stimulation point. This result suggests that place cell activation can retrieve a learned behavior associated with the location in space encoded by those place cells. Furthermore, the authors found that the reward zone place cell activation resulted in a progressive deceleration near the stimulation point. On the other hand, start zone place cell activation resulted in reward zone overshoots and more time spent outside the reward zone.

Targeted optogenetic stimulation of place cell populations was found to either enhance or suppress calcium activity in non-targeted hippocampal neurons. The authors then demonstrated that the magnitude of suppression was greatest during the start zone place cell and reward zone place cell stimulation conditions (with no observed difference in the magnitude of suppression during non-place cell stimulation relative to the no stimulation condition). This result suggests that place cells might be involved in recruiting inhibitory interneurons to regulate network excitability. Lastly, the authors showed that optogenetic stimulation shifted place fields toward the stimulation point and caused a reduction in reward zone lick rate.

What’s the impact?

This study demonstrates that place cell stimulation can trigger location-specific behavior and cause place field remapping. This study extends our knowledge of the hippocampal cognitive map and its functional significance by providing direct evidence of a causal link between place cell activation and spatial behavior.

Robinson et al. Targeted Activation of Hippocampal Place Cells Drives Memory-Guided Spatial Behavior. Cell. (2020). Access the original scientific publication here.

The Relationship Between Fear and Fun

Post by Anastasia Sares

What's the science?

We usually think of fear as a purely negative emotion to be avoided at all costs, but people often put themselves in fearful situations intentionally, for fun. A child who initiates a game of chase with a caregiver and an adult watching a horror film are both examples of participating in this kind of behavior. However, this thrill is difficult to measure in a laboratory. This week in Psychological Science, Andersen and colleagues showed that fear and enjoyment coexist in a haunted-house experience and that there is a “sweet spot” of maximum enjoyment for each individual when the right level of fear is reached.

How did they do it?

Instead of trying to measure fear and pleasure in a laboratory experiment, the authors gathered their data directly at a haunted-house attraction. Participants were visitors to the attraction that agreed to take part in the study. Heart-rate monitors were attached to participants during the experience and they filled out questionnaires before and after. They also agreed to be videotaped, and independent raters later reviewed the videos to analyze them for signs of surprise, fear, and enjoyment. The heart rate data was split into different frequency bands using low-pass and band-pass filters. These reflected large-scale changes (for example a rise and fall in heart rate over the course of 10+ seconds) and small-scale changes (changes that happened over the course of fewer than 10 seconds). Both large- and small-scale fluctuations in heart rate were compared with the participants’ fear and enjoyment ratings on the questionnaires.

What did they find?

In the questionnaires, participants rated both their fear and enjoyment for three separate jump-scare events and their overall fear and enjoyment for the entire experience. The relationship between fear and enjoyment had an inverted-U shape, with enjoyment peaking when fear was not too little and not too much. The inverted-U shape found in this experiment is also common to other enjoyment- or engagement-related phenomena, like curiosity and music enjoyment. Large-scale fluctuations in heart rate were related to fear: the more fluctuation, the more fear. However, the small-scale fluctuations in heart rate had an inverted-U shape to the enjoyment ratings, indicating that these small-scale fluctuations were related to enjoyment.

What's the impact?

The authors suggest that fear-seeking is a form of play. In other words, it helps us to simulate dangerous situations, learn how to manage our emotions, and react accordingly. This study also demonstrates the value of studies that are performed in a naturalistic environment. Control and consistency are important in experimentation, but sometimes we can gain valuable insights from studies conducted in more naturalistic environments that mimic real-life experiences.

Andersen et al. Playing with fear: A field study in recreational horror. Psychological Science (2020). Access the original scientific publication here.

Mis-Localization of LSD1 Underlies Tau-Mediated Neurodegeneration

Post by Shireen Parimoo

What's the science?

One of the hallmarks of Alzheimer’s disease is the presence of neurofibrillary tangles made up of misfolded tau proteins. The neurofibrillary tangles initially accumulate in regions of the medial temporal lobe, such as the hippocampus, before spreading to the rest of the brain, resulting in neuronal death. LSD1 is an enzyme that is typically found in the nucleus of cells and is important for neuronal survival. In the presence of tau pathology, however, LSD1 is mislocalized to the cell cytoplasm along with the neurofibrillary tangles. The Deletion of LSD1 from neurons also leads to neurodegeneration, suggesting that it might contribute to tau-related disorders like Alzheimer’s disease. This week in PNAS, Engstrom and colleagues used histological and RNA sequencing techniques to investigate the mechanistic role of LSD1 in tau-mediated neurodegeneration.

How did they do it?

The authors used wild-type and PS19-Tau transgenic mice that exhibited tau pathology in the brain, beginning in the temporal lobes at approximately 8 months old (Tau mice). First, they used immunofluorescence to compare the localization of LSD1 in hippocampal and cortical neurons of the Tau and wild-type mice. They then bred mice with an Lsd1 gene deletion (control mice) with the Tau mice (Tau-Lsd1 mice) to explore the interaction between tau and LSD1. Heterozygous deletion of the Lsd1 gene reduces the expression of the LSD1 enzyme. In addition to recording motor function and survival of the Tau-Lsd1 mice, the authors used immunohistochemistry to assess neurodegeneration and the localization of LSD1 in hippocampal cells. Next, they identified the molecular pathways that are altered in the presence of tau pathology using RNA sequencing, which allowed them to compare the gene expression profiles of the Lsd1, Tau, and Tau-Lsd1 mice. Finally, they injected LSD1 into hippocampal neurons of 8-month-old Tau mice and assessed the effects of LSD1 overexpression three months later.

What did they find?

LSD1 was localized to the nucleus of hippocampal and cortical neurons in wild-type mice. In contrast, LSD1 was found in both the nucleus and cytoplasm of Tau mice, and this shift to the cytoplasm was exacerbated in the Tau-Lsd1 mice. Both the Tau and Tau-Lsd1 mice exhibited signs of motor dysfunction around 6 months old after tau pathology was evident, but in contrast to the Tau mice, the Tau-Lsd1 mice were severely paralyzed by 12 months old. Similarly, Tau-Lsd1 mice had greater hippocampal neurodegeneration at 10 months old and lower rates of survival as compared to the Tau mice. Thus, the reduced expression and mislocalization of LSD1 occurs in the presence of pathological tau and accelerates the onset of death.

The gene expression profiles of Tau-Lsd1 mice were markedly different compared to control mice. Tau-induced gene expression changes were more severe when LSD1 was reduced. Overexpressing LSD1 in the hippocampus of Tau mice further led to gene expression changes in the opposite direction to the Tau-Lsd1 mice, as well as lower cell death. However, LSD1 overexpression did not rescue motor function and the mice still developed paralysis. Overall, these findings suggest that the interaction between Tau and LSD1 results in neurodegeneration and paralysis by altering the expression of cellular proteins, which can be partially rescued by overexpressing LSD1.

What's the impact?

This is the first study to demonstrate the mechanism by which tau accumulation in neurons interacts with the LSD1 enzyme, providing deeper insight into how neurodegeneration occurs in tauopathies. The finding that some of the adverse effects of pathological tau can be mitigated by overexpressing LSD1 is particularly exciting. This discovery paves the way for future research to further explore whether motor function can also be rescued by altering LSD1 expression in other regions of the brain and raises the possibility that tauopathies such as Alzheimer’s disease can be targeted therapeutically through the LSD1 pathway.

Engstrom et al. The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration. PNAS (2020).Access the original scientific publication here.