by Ingrid Fadelli , Medical Xpress

Embryonically active neurons labeled in brain-wide regions, highlighting particularly dense and broad activation in piriform cortex (also known as primary olfactory cortex). Credit: Wang et al.

The activity of neurons in the mammalian brain is known to contribute to the development of the brain at the early stages of development. While past neuroscientific studies have gathered evidence supporting this notion, the extent to which early neuronal activity regulates the maturation of neural circuits has not yet been fully determined.

Researchers at Stanford University and Duke University School of Medicine carried out a study exploring the contribution of neurons in the mouse brain to the formation of connections between cortical regions during development. Their findings, published in Neuron, highlight the key role of neurons in the mouse piriform cortex, a brain region that supports the processing and coding of olfactory information, in the development of recurrent neural circuits.

"We were interested in the general question of how neural activity shapes brain wiring during development," Liqun Luo, supervising author of the paper, told Medical Xpress. "This question has previously been studied in the context of how peripheral sensory information, such as vision and touch, shapes the brain circuits that process such peripheral input. However, little was known about how activity within the brain itself shapes neurodevelopment in early life."

Determining what neurons are most active within the developing mammalian brain, particularly before an animal is born, has so far proved to be highly challenging. Luo and his colleagues recently developed a new technique that can be used to reliably assess the activity levels of neurons in the pre-natal and early mouse brain, which they called targeted recombination in active populations (TRAP).

"Using this new technique, we first surveyed which neurons are particularly active in the embryonic brain, before mice receive external sensory input," said Luo. "We found that the embryonic olfactory cortex is particularly active and decided to figure out what functions these active neurons might serve in brain wiring."

We first asked if our embryonically active neurons have distinct connectivity within the brain, as this can often give clues to their function. To do this, we tested whether the embryonically active neurons are preferentially connected with each other compared to control neurons nearby, and we found that they are.

"These initial experiments were carried out in brain slice in vitro that enabled us to do electrophysiological recordings with ease," explained Kevin M. Franks, co-senior author of the paper.

"We then tested in young mice in vivo what kinds of odors these embryonically active olfactory cortex neurons are tuned to. We suspected that they might be particularly tuned to odors in the neonatal environment, such as smells of mom and milk that are important to neonatal mice."

Initially, the team hypothesized that piriform cortex neurons that were active in mouse embryos would be most reactive to odors in the environment of newly born pups, such as that of mother's milk. Yet their findings disproved this hypothesis, as these olfactory cortex neurons were found to be tuned to a broad range of sensory stimuli.

Models of how embryonically active neurons affect development of network connectivity. Our findings suggest that model 3 is correct, given embryonically active neurons are broadly connected within the network and can affect development of network connectivity. Credit: Wang et al.

"This combination of broad connectivity and broad sensory tuning led us to hypothesize that perhaps the function of these embryonically born neurons is that of a network hub, important to facilitate the maturation of connectivity between olfactory cortical neurons themselves, so-called recurrent connectivity, which is very strong in the adult olfactory cortex," said Franks.

"To cut a long story short, our experiments (including analysis of in vivo firing patterns, both in response to and in the absence of odor, and the consequence of artificial activation and inhibition) strongly supported this hypothesis."

The findings gathered by the researchers suggest that the early activity of neurons in the mouse piriform cortex play a key role in the maturation of intracortical connectivity, a new finding given most previous studies have focused on the maturation of circuits involved in the initial processing of sensory information.

Instead of simply refining sensory inputs, the activity of neurons could thus shape the architecture of the cortex itself, which in turn influences the brain's representation of sensory inputs.

"Our study broadens the role of neural activity in brain wiring," said David C. Wang, first author of the paper.

"It also provides in vivo evidence for 'hub neurons'—particularly active neurons with broad connectivity that had previously been only reported ex vivo—and their function in circuit maturation. This recurrent connectivity that our hub neurons influence is implicated in various phenomena. This includes processing of sensory information (i.e., associating similar sensory inputs or distinguishing different ones) as well as runaway excitation in seizures."

The recent work by Luo, Franks, Wang and their collaborators offers evidence that a relatively small group of neurons could influence the brain's early development. Notably, the team's findings were collected using cutting-edge experimental methods, including TRAP, in vivo neuronal activity recording and non-invasive optogenetic techniques.

The recent study was a collaborative effort that combined the expertise of distinct research labs at Stanford and Duke. Wang, an MD/Ph.D. student who was part of Luo's lab at the time, performed the in vivo experiments in Franks' laboratory at Duke University over an 8-month period.

"Our study showcases the power of scientific collaboration," said Wang. "Without the combination of expertise of the Luo and Franks labs, and many stimulating conversations between the two labs, this would not have been possible."

The recent work by Wang, Franks, Luo and their collaborators could soon pave the way for new experiments aimed at further examining the contribution of neurons in the mouse piriform cortex to the maturation of brain circuits. Meanwhile, the researchers are conducting further studies exploring the function of embryonically active neurons in other brain regions.

"We are now also looking at the effects of postnatal experience on the wiring and function of the olfactory cortex especially in the context of odor learning and memory," added Franks.

More information: David C. Wang et al, Embryonically active piriform cortex neurons promote intracortical recurrent connectivity during development, Neuron (2024). DOI: 10.1016/j.neuron.2024.06.007

Journal information: Neuron 

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