A newly discovered developmental process reveals that the brain’s primary memory centers start out as overly tangled, random connections that are pruned to form highly structured and efficient networks as the animal grows. These physical and functional changes optimize the brain’s ability to store and retrieve memories throughout life. A study detailing this change was recently published in a journal. nature communications.
The hippocampus is a seahorse-shaped region deep in the brain that is responsible for memory formation and spatial navigation. Within this region is a special circuit called the CA3 network. This area functions as an autoassociative memory system. In other words, it helps the brain recall complete memories from tiny pieces of information. For example, the network allows a person to recall an entire childhood kitchen with just the smell of a single spice.
To accomplish this feat, nerve cells in this region communicate through electrical and chemical connections called synapses. The brain’s elasticity allows these connections to grow stronger or weaker over time as the animal learns new things. Researchers understand how this network works in the adult brain, but how it physically takes shape after birth remains unclear.
Researchers at the Austrian Institute of Science and Technology wanted to understand how this important memory network develops. Two competing philosophical and biological models framed their approach. The first model is tabula rasa, or blank slate theory. This concept suggests that the brain starts with very few connections and slowly builds up connections as the animal experiences the world.
The opposite model is the tabula plena, or complete slate theory. In this scenario, the brain starts out with excess connections and is gradually pruned away, leaving only the most necessary pathways. Neuroscientist Victor Vargas Barroso led a study to determine which models accurately describe hippocampal development. Vargas Barroso worked with Peter Jonas, a professor of life sciences at the institute, to create a schematic diagram of the mouse brain.
To trace the wiring of this brain region, the research team examined the brains of mice at three different developmental stages. They observed mice shortly after birth, adolescence, and adulthood. The research team used an advanced recording technique called multicellular patch-clamp recording. This method allowed them to simultaneously monitor the tiny electrical signals of up to eight individual neurons.
By stimulating one cell and listening to the responses of others, the researchers were able to precisely map which neurons were communicating with each other. To physically confirm these connections, we filled the cells with a special dye. This allowed the researchers to reconstruct three-dimensional models of nerve cells using high-resolution microscopy. In total, they tested more than 7,000 potential connections between nerve cells.
Through this mapping process, the researchers observed significant changes in the way the cells connected. In the youngest mice, the neurons appeared to be tightly packed and randomly formed. As the mice became adults, the total number of connections decreased. Networks have moved from highly localized, dense networks to sparse, widespread, and highly structured networks.
“This discovery was very surprising,” Jonas said in a press release. “Intuitively, you might expect the network to grow over time and become denser. Here we see the opposite. It follows a so-called pruning model: complete at first, then streamlined and optimized.”
The physical shape of the neurons also changed in unexpected ways. Neurons have two main types of branches: axons, which send signals, and dendrites, which receive signals. The researchers found that the axons that transmit the signals actually become shorter and less complex as the animals age.
In contrast, the dendrites receiving the signal continued to grow and developed more receptor sites. This means that the trimming process was very unilateral and primarily affected the neurons’ outgoing communication cables. In adult mice, the remaining axonal connections are no longer evenly spread out but become concentrated in certain specialized patches.
Beyond the physical wiring, the research team discovered major changes in the way cells send electrical messages. In the immature brain, the single connection between cells was incredibly strong. One signal from one neuron is often enough for the receiving cell to fire its own electrical pulse. Researchers call this the near-explosion effect.
In adult mice, these individual connections were much weaker. A single received signal was no longer sufficient to trigger a response in the receiving cell. Instead, adult neurons required simultaneous signals from multiple different neighboring cells to reach their firing threshold.
This change means that the mature brain relies on integrating multiple pieces of information at once, rather than responding strongly to a single input. The brain moves from a system that relies on timing to one that detects spatial matches. To see how these physical changes affect memory, the researchers built a computer simulation of a network with 100,000 neurons.
Computer simulations tested how different types of connections affect the network’s ability to recall stored patterns. The results show that moving from a dense, responsive network to a sparse, weaker, and wider network actually maximizes a system’s memory storage capacity. It turns out that specialized networks with weak connections are much more efficient in obtaining information.
Jonas thinks that starting with a massive tangle of connections might allow neurons to connect quickly early in development. This brain region doesn’t just store visual, olfactory, or sound information alone. It connects all these sensory inputs to create a coherent memory.
“This is a complex task for neurons,” Jonas explained in the release. “Initial active connections followed by selective pruning may enable precisely this integration.” Without this dense starting point, neurons would be too far apart to find each other, making communication nearly impossible.
Although these results provide new understanding of brain maturation, this study has several limitations. The researchers performed the mapping on thin slices of brain tissue. Because they only looked at specific slices, they were unable to observe long-range connections spread throughout the brain. The exact biological mechanisms that cause physical trimming of axons also remain unidentified.
Future research will need to explore what triggers this selective pruning process. Scientists suspect that specialized immune cells in the brain act as biological scissors that cut off excess bonds. Certain types of inhibitory neurons that develop during adolescence may also play a role in this body remodeling.
The researchers also hope to use live imaging techniques to watch individual synapses appear and disappear over time in living animals. This live imaging could reveal whether the structural patterns seen in the adult brain are preprogrammed by genetics or carved by the animals’ daily experiences. At present, it is unclear how the brain decides which connections to maintain and which to break.
This discovery could also shed light on human development. Humans develop episodic memory relatively late, about two years after birth. This developmental milestone closely matches the timeline of adolescent mice in this study.
This chronology may help explain infantile amnesia, which prevents adults from remembering events from their childhood. Memories may be formed in initially dense networks, but become inaccessible when the brain prunes its connections. Further research on the human brain will be needed to see if our own memories follow this exact same developmental path.
The study, “Developmental emergence of sparse and structured synaptic connections in hippocampal CA3 memory circuits,” was authored by Victor Vargas-Barroso, Jake F. Watson, Andrea Navas-Olive, Alois Schlögl, and Peter Jonas.
