Two new papers in the field of neuroscience

Two research papers were published highlighting the importance of studying different aspects of neuronal function at different points in time: when neurons are born and differentiate and during the ageing and degeneration processes associated with Alzheimer’s disease.

Neurons are one of the cells of the central nervous system and are considered the minimum functional unit. There are more than 100 billion neurons that are born, grow and communicate through dendrites and axons. Most of them are formed during embryonic development from stem cells, but in certain areas of the brain, such as the hippocampus, neurogenesis can occur, a mechanism that gives rise to the birth of new neurons in the adult brain.

Antonia Marin-Burgin -head of the Neuronal Circuits group- and the Institute’s theoretical physics laboratory, led by Luis Morelli, worked on this point. As a result of the interdisciplinary work, a PhD project of Diego Arribas, they recently published a paper in the journal eLife.

There, they report that adult-born neurons in the dentate gyrus, a region known as the “gateway” to the hippocampus, whose function is to receive information from the cortex, increase the coding fidelity of the dentate gyrus neuronal population. In other words, adult-born neurons aid the ability to distinguish stimuli that are similar, and thus to store or “encode” those stimuli differently in memory.

“In the work we studied the electrophysiological properties of both new and mature neurons and how they react to stimulation. This allowed us to build mathematical models of them, generate populations with these models and understand the contribution they make to information processing”, says Luis Morelli, head of the Information Processing in Cells and Tissues group.

The power of networking

The dentate gyrus is a region of the hippocampus that, because it is constantly producing new neurons, has neurons of different ages all the time. So, they noted that this heterogeneity in the age of the neural network is key because it ends up helping to better encode and differentiate stimuli. “If you study them individually, new neurons are not very good at encoding stimuli, but when they participate in a neural network they improve it, i.e. a neural network that has only mature neurons does a worse job than one that has both mature and immature neurons”, Marin-Burgin explains.

“This is important because one of the important functions of the dentate gyrus is to discriminate stimuli, and these neurons seem to be central to this. Moreover, this region plays a central role in memory formation, so the correct encoding of stimuli is key for this process to develop properly”, the researcher concludes.

At the other end of life

Once generated, neurons grow and live for a long time. Each neuron has a particular, complex structure with numerous extensions called dendrites and a long axon. The dendrites act as antennae to receive signals from other neurons, while the axon carries the electrical signals from the neuron to the next neuron in the circuit. It is this exchange of signals that allows them to communicate.

The process of neuronal ageing is characterised by a number of changes and challenges that affect their functioning, from less efficient communication, decreased plasticity (the ability of neurons to change and adapt based on learning) and increased vulnerability to neurodegenerative diseases. Ageing is the main risk factor for the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.

This is the context of the work carried out by Mariana Holubiec in the “Cellular neurobiology and genetics” group led by Tomás Falzone. Through one of the lines of her work, in which she proposes to use models of neuronal tissue or “human brain organoids” to study axonal transport defects and oxidative stress in Alzheimer’s disease.

A model study at scale

“What we did was to reprogramme skin samples from four family members, two of whom had a mutation in the APP gene that causes early familial Alzheimer’s, into stem cells. Based on the potential of the stem cells generated, we established a protocol for differentiation into human neural tissue. In this way, we were able to obtain brain organoids, a three-dimensional tissue structure that develops, if it has the mutation, characteristics similar to pathological formations found in human brains, which we use to evaluate the effect of different environmental conditions on neurodegenerative processes”, explains Falzone.

In this research, published in the journal Free Radical Biology & Medicine, they were able to evaluate the state of neuronal oxidation and discovered that organoids with the APP mutation have an increased oxidation state. This increase leads to changes in the shape of the mitochondria under external oxidative stress, as well as alterations in the membrane potential of this cellular component. “This shows that there is a mitochondrial vulnerability to oxidative conditions in organoids generated from cells with the APP mutation, which could indicate a greater sensitivity to the onset of a neurodegeneration process”, says the CONICET researcher.

In addition to this discovery, the generation of human neuronal tissue models that recapitulate basic aspects of Alzheimer’s disease are needed to determine whether or not the defective cellular processes that lead to the disease are independent of the accumulation of pathology and can be used to test reparative strategies.

This work was developed between the Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA, CONICET-MPSP) and the Instituto de Biología Celular y Neurociencias (IBCN, CONICET-UBA), involving the training of several post-docs and graduate and doctoral students at various stages, who worked on the development of basic science from human diseases with the intention of generating new experimental resources to expand institutional capabilities.