Research on the organization of our memory has long been a topic of fascination among neuroscientists given that this could lead to treatments for reversing cognitive impairments. Here, we review some recent findings on how memory is organized which show the importance of a coordinated “wave” of neuronal activity in spatial navigation, and the temporal nature underlying how linked memories are encoded.
To this end, the results described herein highlight the crucial and variable role of the hippocampus – the brain’s memory centre – in the formation and consolidation of our memories, and by extension our sense of identity.
Conducting the brain’s neuronal “orchestra”: spatial maps in our mind’s eye
For a mouse, how is a map of space updated and produced when it is navigating its environment? In a recent study, scientists report for the first time that the CA1 central hippocampal area in the mouse brain is responsible for this map – and that this occurs via neural wave input from brain regions nearby. To demonstrate this, the hippocampal area CA3 located near to CA1 was manipulated such that its input was turned off. Indeed, when the input was stopped, there was a significant jumbling of the updated maps.
In this study, mice were genetically engineered to express a toxin in CA3 that stopped the function of synaptic junctions connecting CA3 to other areas of the brain. This does not change neuronal activity but removes communication between synapses, and allowed the scientists to investigate what happens to the space map in CA1 when CA3 input was eliminated.
Next, the electric current from individual neurons and the total electric current from a larger group of neurons (termed local field potentials) were recorded while mice ran on a track. The scientists would then be able to measure each theta cycle, or the time over which the neural spatial map in the hippocampus was updated as determined by the activity of the mice.
Although the transgenic mice had no difficulty in performing a navigation task, and single neuron signals could accurately represent spatial information, the key finding was that there were clear errors in the organization of these neuronal signals at the global population level. A simple analogy to illustrate this would be that eliminating the input from CA3 to CA1 did not alter the neural “music” but instead removed the “conductor”.
This study is the first to shed light on the circuitry connecting ensembles of place cells (a type of hippocampal neuron involved in spatial navigation) and how they update themselves. More specifically, removing CA3 input would hinder the ability to predict spatial location. This highlights the critical importance of neurons activating in sequence to ensure that we can organize memories across time.
We see here that the neural “orchestra” needs the “conductor” in the form of CA3 input, and that individual neurons in the hippocampus are not enough to generate a functioning map of space. This emphasizes the interdependence of strategies that determine the coding of neurons. Notably, there was a marked reduction in neural oscillations that were typical of communication from CA3 to CA1. Given that such disruptions have been previously linked to neurodegenerative diseases such as Alzheimer’s, future work into brain rhythm organization could hence improve understanding of how the brain’s circuitry is organized in such diseases.
Losing connections between related memories as we age – can this be reversed?
In another study, a group of scientists used a tiny microscope (dubbed the Miniscope) to view the brain through a miniature window and investigate how memories in the brain are linked over time. Although such connections are progressively weakened with age, these scientists were able to create a way allowing for separate memories to be reconnected in the middle-aged mouse brain. Importantly, this has vast potential for development into a treatment for patients with age-linked dementia.
The head-mounted Miniscope used in this study allowed scientists to visualize neurons firing in the brain as the mice were allowed to move freely. Three unique boxes were used for this study, and the first part of the study involved young mice. Here, each mouse was placed in all three for 10 minutes per session. Placement in the first and second boxes was separated by a week while that in the second and third boxes was separated only by five hours. Additionally, the mouse was given a shock in the third box.
After two days, each mouse was returned to all three boxes. Unsurprisingly, the mice froze with fear upon recognizing the characteristics of the third box. However, what was intriguing was that the mouse also froze when placed in the second box despite the fact that there had been no shock administered in this box earlier. This suggested that the memory of the shock was transferred from the third box to the experience in the second box that took place five hours before.
A similar experiment was subsequently carried out with middle-aged mice using two boxes, five hours apart, and whereby a shock was given in the second box. It was found that these older mice froze only in the second box where they were shocked, and not in the first box. In this regard, the Miniscope found that the two memories were not linked and instead had separately encoded neural circuits. More strikingly, this indicated that aging weakened the ability of neurons to be excited and encode a memory.
Perhaps the most exciting finding in this study was that these lost connections could in fact be rescued. In the following set of experiments, the scientists first excited neurons in a region of the hippocampus prior to placing the mice in the first box. The mice were then introduced to the first and second box, where a foot shock was administered after two days. Upon reintroduction to the first box, the mice froze as they linked the shock in the second box to the first, implying that enhanced neuronal excitability rescued the age-related deterioration in memory linking.
It is especially pertinent to note that memories do not occur in isolation in real life, given that past experiences affect how new memories are formed and influence our decision-making processes in the future. Hopefully, research in this field would one day help people with age-related cognitive decline in terms of improving their abilities to connect and retain memories.
References
Cai, D. J., Aharoni, D., Shuman, T., Shobe, J., Biane, J., Song, W., … Silva, A. J. (2016). A shared neural ensemble links distinct contextual memories encoded close in time. Nature, 534(7605), 115–118. doi:10.1038/nature17955
Feng, T., Silva, D., & Foster, D. J. (2015). Dissociation between the experience-dependent development of Hippocampal Theta sequences and single-trial phase Precession. Journal of Neuroscience, 35(12), 4890–4902. doi:10.1523/jneurosci.2614-14.2015
Middleton, S. J., & McHugh, T. J. (2016). Silencing CA3 disrupts temporal coding in the CA1 ensemble. Nature Neuroscience. doi:10.1038/nn.4311
Moser, E. I., Roudi, Y., Witter, M. P., Kentros, C., Bonhoeffer, T., & Moser, M.-B. (2014). Grid cells and cortical representation. Nature Reviews Neuroscience, 15(7), 466–481. doi:10.1038/nrn3766
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