Hippocampal Cells Track Moments in Time

Post by Peter Imoesi

What's the science?

The ability of humans to recall the ‘what, where, and when’ for a series of past events is referred to as episodic memory. The ability to link these distinct events or experiences together has been associated with a set of cells known as hippocampal time cells in rodents. These cells have been found to play a crucial role in the sequential organization of memory. This week in the Journal of Neuroscience, Reddy and colleagues implanted microelectrodes into the hippocampus of epileptic patients to measure the activity of hippocampal time cells and their association with episodic memory.    

How did they do it?

All participants had been diagnosed with epilepsy that was non-responsive to drug treatment. Microelectrodes were implanted into the hippocampal region of the patients. Computed tomography (CT) co-registered with a magnetic resonance imaging (MRI) was used to confirm the exact location of the microelectrodes. Participants performed two sets of a sequence learning experiment in front of a computer. In the first experiment, patients were presented with a predefined set of images in sequential order. Each image was presented for 1.5 seconds, with a 0.5-second inter-stimulus interval (delay) before the next. Subjects were probed on their learning of the image, and a “trial” of interest was considered to be two consecutive probe events. The second experiment was identical except for a 10-second gap periodically inserted between some images, during which participants saw a blank screen.

What did they find?

The authors were able to record from 429 hippocampal neurons in the first experiment and 96 hippocampal neurons in the second experiment. In the first experiment, the authors established time cells within the hippocampus were controlled by temporal context. Specifically, they found that the activity of 111 cells was related to time, and the activity of another 50 cells was related to the identity of the images. The activity of a few other neurons was found to be influenced by a combination of time, image identity, and other factors. In the second experiment with the gap periods, the authors found a total of 26 hippocampal neurons were controlled by time. In addition, a few cells were responsive during the 10 second gap period. This suggests there are some hippocampal neurons that specifically respond to a changing temporal context.

What's the impact?

This study demonstrated the role of time cells within the hippocampal region of the brain. These time cells have the capacity to store sensory information in sequential learning in the presence or absence of a stimulus. The characterization of time cell function in humans will play a pivotal role in understanding the mechanisms underlying episodic memory.

Reddy et al. Human hippocampal neurons track moments in a sequence of events. Journal of Neuroscience (2021). Access the original scientific publication here.  

We Arrive at Negative Conclusions More Easily Under Threat

Post by D. Chloe Chung

What's the science?

We accumulate information over time to make important decisions, sometimes even in highly stressful situations. As there is often endless information available to us, we need to decide when to stop gathering information in order to make judgments. However, under stressful, threatening conditions, we are prone to make decisions even with a small amount of information (e.g. hearing a faint sound in a dark alleyway, perceiving it as a threat, and concluding that the environment is dangerous). This week in the Journal of Neuroscience, Globig and colleagues investigated how we process information in threatening situations.

How did they do it?

A total of 83 participants were divided into a threat manipulation group and a control group. The threat manipulation group was informed that they would later have to deliver a speech on an undisclosed topic in front of judges. Then, they were asked to solve difficult math problems in a limited time. These anticipated threats were designed to increase the anxiety and stress levels in participants. On the contrary, the control group was told that they would later have to write a short essay on a random topic that would not be judged and were given easier math problems to solve. After the manipulation, both groups played the “Factory Game”: Participants had to determine whether they were in a telephone or television factory based on the number of telephones or televisions shown on a moving conveyor belt that they were observing. During this test, for each participant, one type of factory was randomly assigned as the “desirable” factory and the other one as the “undesirable” factory. Participants were told that they would earn points when they visit the desirable factory but lose points when they visit the undesirable factory. They were also told that they would earn points when making a correct judgment about the factory type but would lose points upon a wrong judgement. The two payments were independent of each other.

What did they find?

After first checking that the level of anxiety was successfully increased in the “threat manipulation group” participants, the authors observed that the threat manipulation group tended to determine that they were in the undesirable factory (for example, the television factory) after observing a smaller proportion of undesirable items (televisions) compared to the control group. This means that with perceived threats, participants were more likely to draw conclusions based on less evidence, but only when drawing conclusions about the undesirable condition specifically. When it came to the desirable factory, the presence of perceived threats did not change the amount of evidence required to draw conclusions about the desirability of the situation. To understand how threat affects evidence accumulation specifically the authors used a computational modelling approach, finding a higher relative rate for negative evidence in the threat manipulation group. They found that threat biases the way in which participants weigh valenced (positive or negative) information.

What’s the impact?

This work confirms that the way we collect and process evidence can be greatly impacted by threats present in our situation, suggesting that we draw conclusions about our undesirable situation quickly, and with little evidence. Findings from this study suggest that, for those who are more sensitive to threats due to anxiety or other mood disorders, this process of accumulating negative information faster could be harmful as it may lead to an overly negative assessment of their situation.

Globig et al. Under threat weaker evidence is required to reach undesirable conclusions. Journal of Neuroscience (2021).Access the original scientific publication here.

Environmental Enrichment Can Counteract the Effects of Aging on DNA Methylation

Post by Shireen Parimoo

What's the science?

Environmental enrichment (EE) in early life and development is related to improved cognition and has been shown to reduce behavioural deficits in diseased and aging mice. The beneficial cognitive effects of EE occur due to increased neuroplasticity and neurogenesis in the hippocampus, which is important for learning and memory. Age-related cognitive decline is linked to changes in DNA methylation, an epigenetic mechanism by which methyl groups are added to DNA molecules. As a result, DNA methylation can regulate gene expression and consequently, influence aspects of neuronal development and functioning. Currently, it is not known whether EE promotes hippocampal neuroplasticity and neurogenesis through epigenetic mechanisms. This week in Nature Communications, Zocher and colleagues used DNA methylation sequencing and gene enrichment analyses to examine the impact of EE on hippocampal dentate gyrus (DG) neurons.

How did they do it?

Six-week-old female mice were raised in an enriched environment (EE) or a standard environment for three months. The authors used reduced representation bisulfite sequencing to identify regions of the genome that showed changes in DNA methylation (i.e., differentially modified genes) in the DG. They also performed gene set enrichment analysis to determine which types of neuronal pathways those differentially modified genes were involved in. To examine the effect of EE on aging, the authors compared DNA methylation and gene enrichment profiles of young and old mice raised in both a standard environment and an EE. They also compared older and younger EE mice to assess whether EE could counteract the effect of aging on DNA methylation. Additionally, they investigated whether adult exposure to EE had a similar impact on DNA methylation as lifelong EE exposure. To do this, 14- and 3-month-old mice were housed in EE and their DNA methylation and gene enrichment profiles were compared after three months. Lastly, the authors analyzed human genomic datasets to identify genes that are dysregulated in pathological aging (e.g., Alzheimer’s disease, cognitive decline). They compared these genes to the differentially modified genes in EE mice in order to understand the link between EE-induced methylation and cognition.

What did they find?

There were no global differences in DNA methylation between mice raised in EE and standard environments, but there was evidence of differential modification of genes in EE mice. That is, methylation on some locations on the genome, such as enhancer regions, resulted in gene enrichment (increased gene expression) whereas other locations were depleted (decreased gene expression). The enriched genes were involved in neuronal structure, neurotransmitter signaling, neurogenesis, and synaptic plasticity. Interestingly, enriched genes in older mice raised in a standard environment (compared to younger mice) were involved in overlapping processes with enriched genes in EE mice, indicating that EE and aging have similar effects on DNA methylation in the DG.

Enriched genes were associated with neuroplasticity, cell signaling, and hippocampal neurogenesis. In fact, there were 60% more newborn DG neurons in older EE mice than in the standard environment mice, further demonstrating that EE is associated with increased neurogenesis. Moreover, many of the genes that were enriched by EE in older mice were depleted in older mice raised in a standard environment, indicating that age-related methylation was counteracted by EE-induced methylation. This was the case in mice who were exposed to EE early on, as well as in older age. Finally, many of the genes that were differentially modified by EE in mice were also dysregulated in human adults with neuropathology (e.g., Alzheimer’s disease). Together, these findings indicate that EE alters the DNA methylation of genes that are putatively associated with cognitive functioning through their downstream effects on neural signaling, neuroplasticity, and neurogenesis.

What's the impact?

This study is the first to show that EE can alter and reverse the effects of aging on DNA methylation in mouse hippocampal DG neurons, particularly in genes involved in neuroplasticity and neurogenesis that are crucial for learning and memory. This work paves the way for future research to explore the specific mechanisms by which EE alters DNA methylation and subsequently influences cognitive functioning.

Zocher et al. Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus. Nature Communications (2021). Access the original scientific publication here.