Ana JakovljevicNeuro Imaginarium

Neuroscience

Can We Change Brain Plasticity by Eating Differently?

A note on nutrition, perineuronal nets, oligodendrocytes, microglia, and the extracellular matrix mechanisms that help regulate plasticity.

Can we change brain plasticity by eating differently, and are there substances that can affect modulators of plasticity such as the brain extracellular matrix?

Apparently, in the study conducted by Sara Kohnke et al. in 2021, mice changed brain composition at the cellular scale when regulating food intake in the mediobasal hypothalamus and median eminence, crucial brain areas for processing energy balance. When they were fed after all-night fasting, progenitors of oligodendrocytes, the cells that insulate neuron axons, were proliferating and differentiating.

But the interesting change happened at the very regulators of plasticity: perineuronal nets, formations of extracellular matrix that wrap around certain neurons, especially parvalbumin-expressing interneurons. The main hypothesis is that the condensation state of PNNs dictates the density and stability of synaptic projections onto neurons, and it is shown that their removal can act as reopening a plasticity window for certain brain changes (Pizzorusso, 2002).

In PNN remodeling during feeding after a fasting period, precursors of oligodendrocytes had an important role. In genetically obese mice, differentiation of oligodendrocytes and the expression of PNNs was weakened. When Kohnke et al. enzymatically degraded PNNs, the animals responded by eating more and gaining more weight. What we can see from this research is that PNNs from the mediobasal hypothalamus are necessary to keep body weight balance, and that nutrition control is tightly connected with differentiation of oligodendrocytes.

This research showed us that by affecting PNNs, we disrupt the system that orchestrates behavior towards food. The next question is, what do the rest of the cells in the nervous system do, how do neurons respond to food intake or fasting, is excitation increased, and are microglia and astrocytes behaving differently?

Partial answers to my questions I found in the review work of Nan Zhang et al. from 2024. Astrocytes are big players in the synthesis and maintenance of PNNs, especially in their maturation, since PNNs in the prenatal and early postnatal period have different composition and condensation states (Lensjo et al., 2017). Astrocytes secrete enzymes that degrade PNNs, and although there is no evidence so far that they modulate PNN expression in different nutritional conditions, like oligodendrocytes, they certainly have the mechanism to do so.

The next are microglia, the cleaners of the CNS, phagocytosing all waste products in the brain, including degraded compartments of PNNs. It is known that microglia can affect PNNs in two ways: by secreting enzymes that degrade them, or by directly phagocytosing molecules that are in the composition of PNNs.

Amy Reichelt et al., in 2021, shed light on the role of microglia and PNNs in food intake regulation in adolescence and adulthood, hypothesizing that younger brains may be resistant to diet-induced neuroinflammation. They found out that if mice eat a sugar- and fat-rich diet, like most of the food that we nowadays consume, the microglia in the mice prefrontal cortex and hippocampus were in their activated morphological shape, and PNNs decreased their expression only in the hippocampus of adolescent mice. These findings imply that microglia in their inflammation state ate PNNs in the hippocampus, leaving neurons in a more sensitive and dysregulated state and possibly affecting stabilization of synapses.

The most advanced approaches toward controlled and targeted degradation of PNNs are being performed in Nicole Allen's project from 2024. Their approach is to use nanoparticles that bind to molecules that compose PNNs and give a signal to microglia to degrade those targeted PNNs, in order to unlock plasticity in that brain area. That is being achieved by using the biotin-labeled enzyme TurboID, with the goal of precise control to promote brain health and repair.

Another interesting approach came from Chunmei Wang, who started a project in 2025 to investigate the role of PNNs in controlling obesity and metabolism. Observing abundant PNNs in the amygdala, they showed that chronic disruption of PNNs led to hyperphagia and weight gain in mice, and conversely, chronic increase of PNNs resulted in lower body weight. Building from these findings, they started investigating estrogen receptors, regulators of energy and glucose balance in both females and males.

Since so far we cannot directly orchestrate the expression of PNNs in order to regulate plasticity, we can appreciate that nutrition plays an enormous role in our plasticity mechanisms. While we are waiting for targeted enzymes to unlock our brain potential, one thing that we can all do every day is keep sugar and fat intake controlled. In that way, we are giving our brain a chance to naturally reach that high-plasticity, learning state, the one that we need in order to break bad habits and imagine new, healthier alternatives.

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