Bowdoin Science Journal

neurobiology

How Epigenetics Dictates the Birth of New Neurons

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One of the most contentious debates in neuroscience has revolved around the question of whether the adult human brain can produce new neurons. Though there is evidence that rodents maintain a population of immature neurons throughout their lives, confirming this phenomenon in humans is troublesome, namely due to post-mortem tissue degradation and the lack of specific molecular markers. A new study by Disouky et al. (2026), published in Nature, carries out a deep dive into this process. Disouky et al. reveal that the “birth” of new neurons not only occurs in the adult human hippocampus but that its decline in Alzheimer’s disease is dictated by changes in the cell’s epigenetic landscape. In other words, while the sequence of the DNA remains the same, the chemical tags and structural packing of the genome changes, effectively deciding which genes are turned on or off.

To settle the debate, researchers analyzed over 355,000 individual cell nuclei from the hippocampi of young adults, healthy seniors, and people with Alzheimer’s. They discovered a clear assembly line in the brain where starter cells, known as neural stem cells, begin a transformation into neuroblasts. These cells then become Immature Neurons before finally graduating into mature granule neurons that are fully integrated into memory circuits. The team used a predictive calculation called RNA velocity to prove that these cells actually move through these stages, confirming that the adult human brain maintains a pool of neural stem cells. RNA velocity, by taking into account the concentration of various RNA populations, can project the dynamics within the cell (La Manno et al., 2018). In other words, a cell’s stage in development can be determined by what types of RNA it is producing.

The study’s most important discovery involves epigenetics, which dictates how the brain’s internal switches are managed. If DNA is like a massive library of books (genes), then epigenetics determines which books are actually open and readable. The researchers found that in Alzheimer’s disease, the problem isn’t just that cells are dying, but that the books for making new neurons are being slammed shut. This is known as a change in chromatin accessibility (Klemm et al., 2019). In Alzheimer’s patients, the number of immature neurons is slashed significantly compared to healthy individuals. Interestingly, in people with preclinical Alzheimer’s—those with early symptoms of Alzheimer’s—these DNA locks are beginning to appear. So, while the DNA itself remains the same, its expression differs.

A diagram depicting chromatin accessibility from various stages, to closed, permissive, and open domains.
Chromatic accessibility allows for differences in DNA expression without directly altering its genetic sequence. Figure from Klemm et al., 2019

When the authors looked at a third population group known as SuperAgers (SA)—people over 80 years old with the memory capacity of someone in their fifties—they found a distinct profile of neurogenesis, new neuron formation. The brains of SuperAgers contained a significantly greater number of immature neurons compared to those with Alzheimer’s. Even after excluding potential outliers, the researchers observed a 2.5-fold increase in immature neurons in the SuperAger group compared to other cohorts. This suggests there is a “resilience signature” of neurogenesis that may play a role in maintaining exceptional memory capacity despite advanced age. This signature is primarily characterized by maintained chromatin accessibility in regions that are typically “locked” or downregulated in the Alzheimer’s brain.

Ultimately, this research shifts the focus of Alzheimer’s study from simple cell death to the underlying gene regulatory networks that govern how cells function and grow. By identifying the specific “activator” and “repressor” switches (transcription factors) that are active in SuperAgers versus those that are shut down in Alzheimer’s, the study provides a roadmap for future medical interventions. For example, targeting the specific chromatin regions that govern synaptic plasticity could potentially prevent or mitigate the deterioration of neurogenesis seen in dementia. While the study notes limitations due to the high variability of human brain samples and limited sample sizes, the findings highlight the critical role of epigenetics as a more definitive indicator of cognitive health than traditional gene expression alone. This suggests that the future of treating cognitive decline may lie in opening up the brain’s internal library in order to restore its natural ability to regenerate and remember.

 

References

Disouky, A., Sanborn, M. A., Sabitha, K. R., Mostafa, M. M., Ayala, I. A., Bennett, D. A., Lu, Y., Zhou, Y., Keene, C. D., Weintraub, S., Gefen, T., Mesulam, M., Geula, C., Maienschein-Cline, M., Rehman, J., & Lazarov, O. (2026). Human hippocampal neurogenesis in adulthood, ageing and Alzheimer’s disease. Nature, 652(8112), 1264–1273. https://doi.org/10.1038/s41586-026-10169-4

Klemm, S. L., Shipony, Z., & Greenleaf, W. J. (2019). Chromatin accessibility and the regulatory epigenome. Nature Reviews Genetics, 20(4), 207–220. https://doi.org/10.1038/s41576-018-0089-8

La Manno, G., Soldatov, R., Zeisel, A., Braun, E., Hochgerner, H., Petukhov, V., Lidschreiber, K., Kastriti, M. E., Lönnerberg, P., Furlan, A., Fan, J., Borm, L. E., Liu, Z., Van Bruggen, D., Guo, J., He, X., Barker, R., Sundström, E., Castelo-Branco, G., . . . Kharchenko, P. V. (2018). RNA velocity of single cells. Nature, 560(7719), 494–498. https://doi.org/10.1038/s41586-018-0414-6

Pupil Mimicry Strengthens Infant-Parent Bonding

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Sometimes, it is a wonder how something so small can connect human beings on a deeper level, but that is what pupil mimicry does. Pupil mimicry describes the changes in pupil size that occur in both participants during eye contact, which can help with social bonding. It also reflects the different cognitive and emotional processes that occur during eye contact and socialization, such as showing social interest (Aktar et al., 2020). When pupil size synchronously dilates, meaning the pupil expands when eye contact is made, there is a promotion of trust and bonding between the two responders. The opposite is true for synchronous pupil constriction, which diminishes a positive social bond between the two responders.  

Pupil mimicry is an old, robust phenomenon (Prochazkova et al., 2018) that is modulated by oxytocin. This evolutionarily conserved neuropeptide acts as a hormone and neurotransmitter and facilitates social bonding (Aktar et al., 2020). Pupil mimicry has been observed in monkeys and chimpanzees, where it also increases trust and social familiarity (Kret et al., 2014). This effect occurs in infants as well, which suggests that pupil mimicry may help facilitate bonding between infants and their parents. But how can scientists measure that? 

It has been shown that young infants can differentiate between their own-race faces and other-race faces. Therefore, scientists hypothesized that infants would have quicker pupillary responses to pupils belonging to the same race as their parents when compared to other races. Researchers Aktar, Raijmakers, and Kret conducted a study with three aims to test this hypothesis: 

  1.  Do infants’ pupils react to dynamic videos of eyes with pupil sizes that change realistically? 
  2. Do parents and infants have the same speed in matching pupil size? 
  3. Do both the parents’ and infants’ pupils have differing rates of pupil mimicry between own-race faces and other-race faces

For the first aim, infants and parents watched black-and-white dynamic videos of same-race models (Dutch male and female) that had constricting, static, or dilating pupils while their pupillary reactions were tracked (Figure 1; Aktar et al., 2020). For the second and third aims, infants and parents watched black-and-white dynamic videos with two races: Dutch for the same-race category and Japanese for the other-race category (Aktar et al., 2020). The researchers compared the parents’ pupil mimicry speed to the infants’. 

Figure 1: Experimental set-up of infants and parents as they observe the stimuli (Aktar et al., 2020).

The researchers confirmed that both infants and parents were able to perform pupil mimicry. They also found that parents had quicker pupil response to dilated or constricted pupils than infants, possibly due to adults being more cognitively advanced than infants. Finally, they concluded that there was no significant difference in pupil mimicry response between own race and other races, but there were slight pupil mimicry delays. The researchers have several explanations for the slight delays. For instance, the infants’ pupils tend to stay dilated when they see a dilated pupil, regardless of race, since infants are still developing their pupil mimicry control. For adults, pupil mimicry tends to take about 2.5 milliseconds longer when given other-race stimuli. This may be from greater cognitive effort used to process other-race faces than own-race faces (Aktar et al., 2020). 

The key finding of the research is race does not affect the participants’ rate of pupil mimicry during emotionally neutral interactions (Aktar et al., 2020). So, though pupil mimicry helps strengthen parent-infant relationships, infants also have the skills to establish trust and awareness with strangers regardless of race. However, when infants are not in a neutral setting, meaning an environment where they feel unsafe and discontent, they are more likely to seek out their parents and less likely to make eye contact (Aktar et al., 2020). That is why, if the infants felt fussy or frightened, the researchers sat the parents right next to them to provide a feeling of safety (Figure 1). Eye contact conveys a great deal of information. Maybe the next time you make eye contact with someone, stare at them to see how their pupil responds to you!

References

Aktar, E., Raijmakers, M. E. J., & Kret, M. E. (2020). Pupil mimicry in infants and parents. Cognition and Emotion, 34(6), 1160–1170. https://doi.org/10.1080/02699931.2020.1732875

Kret, M. E., Tomonaga, M., & Matsuzawa, T. (2014). Chimpanzees and humans mimic pupil-size of conspecifics. PloS one, 9(8), e104886. https://doi.org/10.1371/journal.pone.0104886

Prochazkova, E., Prochazkova, L., Giffin, M. R., Scholte, H. S., De Dreu, C. K. W., & Kret, M. E. (2018, July 16). Pupil mimicry promotes trust through the theory-of-mind network – PNAS. Proceedings of the National Academy of Sciences. https://www.pnas.org/doi/10.1073/pnas.1803916115

Toxin Therapy

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While the growth of mold on fruits and vegetables forgotten in the fridge is not an atypical occurrence, lethal spores slowly sprouting in improperly preserved or fermented foods lead to more than a smelly fridge. The Clostridium botulinum bacterium produces deadly botulinum toxins (BoNT) that destroy proteins critical for the release of acetylcholine, the neurotransmitter primarily responsible for muscular function, into the neuromuscular synapse. The simple bacterium may be microscopic, but its ability to inhibit signals in the muscular network are potent and can induce irreversible paralysis. 

Clostridium botulinum produces lethal toxins that disrupt muscular contraction.
Photo credits: Dr. Phil Luton/Science Photo Library/Corbis

Exocytosis, the release of neurotransmitters into the synapse via vesicle-membrane fusion, primarily requires the complete assembly of three proteins: SNAP-25, syntaxin, and synaptobrevin. The bridging of these proteins between the vesicle and the plasma membrane are crucial for neurotransmitter release. Once the vesicles bind to the plasma membrane, neurotransmitters are released into the synapse and the action potential signals from the presynaptic neurons are sent to the postsynaptic muscle fibers. When these signals are blocked, however, muscle contractions are inhibited — initiating paralysis. 


Several types of botulinum toxins target critical proteins for exocytosis and inhibit the release of acetylcholine.

The structure of BoNT allows it to penetrate neurons and cleave the proteins that transfer the signals for movement. The toxins have 2 subunits, a light and heavy chain, which work together to penetrate the neuron and wreak havoc. The heavy chain dictates which neurons are affected by the toxins by strongly binding to the external membrane. They facilitate the entry of the light chain into the cytoplasm of synaptic terminals, which then disrupts exocytosis by snipping the critical proteins for vesicle-membrane fusion. The structure of the light chain determines which proteins are cleaved. The toxins ultimately causes a paralytic effect by inhibiting membrane fusion of vesicles and acetylcholine release at neuromuscular junctions.

The extreme potency and lethality of botulinum toxins makes them potentially fatal bioweapons. Small amounts of BoNT can be deadly, where “a single gram of crystalline toxin, evenly dispersed and inhaled, can kill more than one million people.” The lethal dose for humans orally is estimated to be 30 ng and by inhalation 0.80 to 0.90 µg. An estimate of only 39.2 g of pure BoNT could eradicate humankind. While the inhibition of neurotransmitter release is irreversible, the paralytic effects are felt in full force by four to seven days after exposure. The long latency of effects can delay alarm and medical treatment. While some paralytic effects may be mediated by the growth of new nerve terminals and synaptic connections, these recovery processes can take up to months.

The lethality of these toxins have been harnessed for a range of purposes, from cosmetic procedures to treatments for movement disorders. BoNT is colloquially well-known as Botox, the drug commonly used to smooth facial wrinkles and enhance a youthful appearance. Beyond the surface, Botox has also been FDA-approved to treat chronic migraines, excessive sweating, and several other medical conditions. Other applications are under investigation, but the botulinum toxins have been found to reduce tremors, tics, muscle spasms, and other movement disorders that derive from debilitating neurological diseases.

The potential uses of these toxins may enhance the quality of life for many people. While the use of deadly botulinum toxins for medical treatments may seem unorthodox, these compounds have proven to be incredibly versatile in their application.