How Does the Hippocampus Preserve Memory for Time?

Post by Baldomero B. Ramirez Cantu

The takeaway

The re-expression of hippocampal area CA1 and entorhinal cortex activity supports memory for time, particularly for long timescales. The activity in these two regions is predictive of temporal memory integrity.

What's the science?

Episodic memory refers to the ability to recall specific events, experiences, or episodes from one's past, involving the recollection of these events in a specific temporal context. It allows individuals to remember the content of past experiences and also when those events occurred (e.g., last week, last month, or last night). While the concept of episodic memory is well-defined, identifying the underlying neurobiological mechanisms responsible for appropriately recalling the temporal context of memories is still an area of active research. This week in Nature Communications, Zou et al. published a study that delves into the role of regions in the medial temporal lobe (MTL) in the recall of temporal memory context. Their findings shed light on how specific brain areas contribute to this crucial aspect of episodic memory.

How did they do it?

In this study, Zou and colleagues conducted a human functional magnetic resonance imaging (fMRI) experiment to explore the neurobiological basis of temporal memory precision. The experiment involved presenting participants with a vast number of natural scene images multiple times over 30-40 scan sessions spanning an 8-10 month period. Following the scanning sessions, the participants engaged in a temporal memory task, where they were asked to estimate the original encounter time for a subset of the previously presented images, using a scale ranging from days to months in the past.

These analyses were used to investigate whether the accuracy of temporal memory retrieval could be predicted based on the re-expression of neural activity patterns observed during the initial encounter with the images. The researchers hypothesized that the reinstatement of neural activity patterns, indicative of context reinstatement, might play a role in preserving temporally precise memories.

To achieve high-resolution imaging, the researchers employed ultra-high field strength (7 Tesla) and a spatial resolution of 1.8mm. This allowed them to specifically interrogate subregions of the hippocampus, including CA1, and surrounding MTL structures, such as the entorhinal cortex (ERC). These brain regions are known to be critical for memory processing.

What did they find?

Participants showed a high level of accuracy in recalling the temporal context of each image, highlighting the impressive nature of their temporal memory performance.

The authors found that greater activity pattern similarity in specific MTL regions (CA1 and ERC) across repeated exposures is associated with higher temporal memory precision. These findings support the idea of context reinstatement as a mechanism underlying the accurate recall of when events occurred in memory. Additionally, the results indicate that these effects are specific to temporal memory and not driven by general recognition confidence or overall memory strength.

The authors show that the similarity between the first and second exposures of an image is crucial for precise temporal memories. This finding supports the idea that context reinstatement during the second exposure (E2) plays a unique role in remembering when an event occurred. Furthermore, the study highlights the distinct neural processes involved in temporal and recognition memory, emphasizing the importance of initial exposure and second exposure (E1-E2) similarity for the precision of temporal memory.

What's the impact?

This study deepens our understanding of how the brain processes and retains temporally precise memories, with potential implications for memory-related research, clinical interventions, and advancements in neuroscience and cognitive science.

Access the original scientific publication here.

How Do Sleep Oscillations Promote Long-Term Memory Storage?

Post by Trisha Vaidyanathan

The takeaway

In 1924, a study found that participants remembered a list of nonsense syllables better if they slept – rather than stayed awake – after learning. Since then, many studies have demonstrated how sleep promotes memory. A prevailing theory is that long-term memory is formed during sleep where short-term memories in the hippocampus are transferred to the cortex for long-term storage. This memory storage process is thought to rely on the precise timing of three distinct neural oscillations in the brain. 

What is long-term memory storage?

Memory consolidation, also known as long-term memory storage, is the process by which newly formed “short-term” memories are transformed into long-term, stable memories. Short-term memories are largely encoded in the hippocampus, where the neural representation of a memory is prone to fading. However, these hippocampal representations can be transferred to the cortex for long-term storage during memory consolidation, where there is unlimited capacity for new memories throughout our lifetime.

Memory consolidation starts with “hippocampal replay”

A new memory is composed of several features, including sound, vision, taste, and even emotion. The hippocampus integrates all these features into one unique neural representation or a precise pattern of neuronal activity. As such, new memories are initially completely dependent on the hippocampus. During sleep, the hippocampal neuronal representation of a memory continually “replays” and the sequence of neuronal activity repeats over and over again. Hippocampal replay events mostly occur during a specific stage of sleep called non-rapid eye movement (NREM) sleep and represent the starting point by which these memories are transferred to the cortex for long-term storage.

Three key oscillations coordinate to promote long-term memory storage

How exactly is information transferred from the hippocampus to the cortex during sleep? The prevailing theory is that this transfer occurs because of the precise timing of 3 different types of neuronal oscillations. A neuronal oscillation is generated when a population of neurons continually alternates between synchronous activity and synchronous silence. The precise timing of these oscillations drives communication between brain areas because of spike timing dependent plasticity, or the phenomenon in which two co-active neurons will strengthen their connection. 

The first key oscillation is the sharp wave ripple, a high-frequency oscillation (150-250Hz) generated in the hippocampus during NREM sleep. The sharp wave ripple is critical for memory consolidation since hippocampal replay occurs during the burst of activity that is generated in the active phase of a sharp wave ripple. 

The second key oscillation is the sleep spindle. Sleep spindles are slower oscillations (12-15Hz) that originate in the thalamus during NREM sleep and spread to the cortex and hippocampus. In the hippocampus, sharp wave ripples tend to nest into the troughs – or the active phases – of sleep spindles. This spindle-ripple coupling forms the first bridge by which neuronal activity is transferred outside of the hippocampus.

The last key oscillation is the slow oscillation, a low-frequency oscillation (<1Hz), generated within the cortex in NREM sleep. The active phase of the slow oscillation also called the UP state, can drive the thalamus to generate sleep spindles (which, as mentioned above, are associated with hippocampal sharp wave ripples). This slow-oscillation-spindle-ripple coupling is thought to be the foundation of memory consolidation from the hippocampus to cortex.

In sum, a prevailing model of memory consolidation is that the cortex opens a window for memory consolidation during sleep when a cortical slow oscillation drives the thalamus to generate a sleep spindle, which in turn synchronizes a hippocampal sharp wave ripple containing a replay event. The resulting synchronous activity – the replay event nested in the sharp wave ripple, nested in the sleep spindle, nested in the slow oscillation – across the cortex, thalamus, and hippocampus is believed to drive memory consolidation through neuronal spike timing dependent plasticity. 

How does this affect our memories?

The theory that long-term memory storage relies on the transfer of memory from the hippocampus to the cortex suggests that our memories could be susceptible to alteration during this process. In fact, there is evidence that suggests the cortex can integrate new memories into pre-existing stored information. This may underlie our ability to extract general principles from a series of individual memories. Additionally, other factors like emotional state may bias how memories are stored. However, further research is needed to better understand these transformations of memory and how they occur.

References +

Goode, T. D., Tanaka, K. Z., Sahay, A. & McHugh, T. J. An integrated index: engrams, place cells, and hippocampal memory. Neuron 107, 805–820 (2020). https://doi.org/10.1016/j.neuron.2020.07.011

Guskjolen, A., Cembrowski, M. S. Engram neurons: Encoding, consolidation, retrieval, and forgetting of memory. Mol. Psychiatry (2023) https://doi.org/10.1038/s41380-023-02137-5

Jenkins, J. G., Dallenbach, K. M. Obliviscence During Sleep and Waking. The American Journal of Psychology, 35, 605–612 (1924). https://doi.org/10.2307/1414040

Joo, H.R., Frank, L.M. The hippocampal sharp wave–ripple in memory retrieval for immediate use and consolidation. Nat Rev Neurosci 19, 744–757 (2018). https://doi.org/10.1038/s41583-018-0077-1

Klinzing, J.G., Niethard, N. & Born, J. Mechanisms of systems memory consolidation during sleep. Nat Neurosci 22, 1598–1610 (2019). https://doi.org/10.1038/s41593-019-0467-3

Skaggs, W. E., McNaughton, B. L. Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science 271, 1870–1873 (1996). https://doi.org/10.1126/science.271.5257.1870

A Key Micronutrient Identified in Breast Milk Promotes Synaptic Growth

Post by Lani Cupo

The takeaway

Myo-inositol (MYO) is a micronutrient identified in human milk from around the world which helps establish synaptic connections between neurons early in life.

What's the science?

Diet can have a big impact on brain development early in life and preservation later in life, however, it is unclear what micronutrients are important in contributing to connectivity between neurons. This week in PNAS, Paquette and colleagues analyzed samples of human breast milk from around the world to identify a micronutrient MYO that is present during periods when neuronal connections are formed. They then validate the ability of MYO to promote synapse formation in cultured neurons and mouse models.

How did they do it?

First, the authors collected samples of breast milk from women from Mexico City (N = 10), Shanghai (N = 10), and Cincinnati (N = 10) at 5 time points throughout the first year postpartum. Focusing on inositol, a sugar that is elevated in human milk compared to cow’s milk, the authors quantified the amount of MYO, a form of inositol not bound in other molecules, across time. Second, using human induced pluripotent stem cells the authors cultivated human glutamatergic neurons to examine the impact of MYO on synaptic sites.

Next, the authors cultivated hippocampus neurons from rats in vitro (in a Petri dish) and exposed them to differing dosages of MYO to examine the impact on the synapses between neurons. Then, the authors conducted an analysis in mice by supplementing them with MYO from birth to 35 days old and examining synaptic sites in the visual cortex. Finally, they examined the impact of MYO in mature tissue - aging neurons from the mouse hippocampus - before exposing them to the sugar.

What did they find?

First, the authors found that MYO levels are highest in the first weeks of lactation, a time period associated with dramatic increases in synaptic density in babies. Second, introducing MYO to cultured neurons increased post-synaptic staining intensity, an indicator of increased sites for synaptic connections.

Next, the authors found that MYO increased synapse formation in a dose-dependent manner with higher dosages leading to an increased impact. These results provided further evidence of MYO’s role in promoting synapse formation for both excitatory and inhibitory neurons. Then, the authors found enlarged synaptic sites in the visual cortex of mice exposed to supplements of MYO after giving birth. This further emphasizes the role of MYO across species and brain regions. Finally, the authors found evidence of increased synapses in mature tissue as well, suggesting a potential preservative effect of MYO in adults.

What's the impact?

The authors highlight the importance of the micronutrient MYO in synapse formation and neuronal connectivity, both in development and mature tissue. Their results provide avenues to improve pediatric nutrition products, and may, in time, promote synapse protection in aging.

Access the original scientific publication here