Researchers at Columbia University have identified more dormant stem cells and fewer young, maturing neurons in the brains of adults with major depression. The study, published in Nature Medicine, also points to widespread disruptions in memory and emotion circuits — but it doesn’t yet prove whether the disruption is a cause or a consequence of depression.
A large-scale study of human brain tissue provides evidence that in people who have suffered fromDepression Major process of creating new nerve cells inHippocampus It doesn't stop completely—but it gets stuck in the way. The researchers found an accumulation of dormant neural stem cells, along with a decrease in the number of cells that progressed to the neuroblast stage, the young cells from which neurons are supposed to develop. Neurons Ripe.
The study was conducted inColumbia University and published in the journal Nature Medicine. The researchers analyzed 495,037 cell nuclei from hippocampal tissue from 11 people with Major depression and 19 control subjects without a psychiatric diagnosis, after quality screening. Using a combination of single-nucleus RNA sequencing, chromatin accessibility testing, spatial transcription, and protein analysis, they constructed a detailed map of cell types, gene activity, and their location within the hippocampus.
The findings do not suggest a new test for depression or immediate treatment. Because this is a study of tissues collected after death, it is impossible to determine whether the changes inneurogenesis Caused the depression, resulted from it, or reflect a combination of the illness, stress, and other factors.
Nerve cells are also formed in the adult brain.
Most neurons in the brain are formed before birth, but a small region in the hippocampus contains stem and progenitor cells that may continue to produce neurons into adulthood. This process is called adult hippocampal neurogenesis.
The existence and extent of the process in adult humans has been a subject of scientific controversy for years. The new study identified a sequence of cells that carry molecular markers characteristic of different stages of the process: fromNeural stem cells Dormant and activated, through stem cells and neuroblasts, to young and mature granule cells.
According to the researchers, the findings strengthen the evidence thatthe brain The adult human retains some ability to produce new nerve cells. However, in samples from people with major depression, the process appears to have difficulty progressing: more stem cells were found in a dormant state and fewer neuroblasts.
The connection between memory, emotion, and depression
The hippocampus plays a central role in the formation of episodic memories—memories of events and experiences—and in attaching emotional meaning to memories. One of its functions is “pattern separation”: the ability to distinguish between similar but different events and store them as separate memories.
For example, an encounter in which a friend seems tired and quiet is not necessarily a repeat of a previous experience of rejection. When pattern separation is impaired, a new event may become mixed with previous negative memories and be perceived through the same emotional meaning.
Animal experiments have previously shown that young neurons in the hippocampus participate in pattern discrimination and adaptation to new situations. They are particularly sensitive to new experiences and integrate relatively easily into circuits זיכרון Developing.
Professor Maura Dupont, who led the study, said that the conventional understanding of depression has expanded beyond the simple explanation of a deficiency in neurotransmitters, primarily serotonin. She said that depression may involve various problems that impair the ability of neurons to adapt to stress and changes in the environment.
Not only was neuron formation impaired
The disruptions were not limited to stem cells and young neurons. The researchers identified molecular changes in many parts of the trisynaptic circuit in the hippocampus, which is involved in forming memories and giving emotional meaning to experiences.
Changes in gene activity were found related to the formation of connections between neurons, the transfer of substances within the cell, energy production, synaptic plasticity and communication between cells. The researchers also identified signs of a disruption in the balance between excitatory and inhibitory activity, neuroinflammation and cellular stress.
The serotonin and glutamate communication systems also showed changes. The finding is important because it does not eliminate serotonin's involvement in depression, but rather places it within a broader and more complex biological picture.
Some of the genes whose activity was altered contained genetic variants that have been linked to major depression in previous studies. Other changes were found in epigenetic control—mechanisms that alter the strength of gene activity without changing the DNA sequence itself and that may be affected by stress, aging, and life experiences.
According to Dupont, the variety of changes found may indicate that depression is not a single biological disease, but rather a group of conditions that lead to similar symptoms through different pathways.
Important limitations
The study has some limitations that are important to consider. The tissues were examined at a single point in time after the donors' deaths, so it is not possible to use them to track the rate of neuron generation over time.
In addition, most people in the depression group died by suicide. Therefore, it is difficult to completely separate changes related to major depression from changes that may be related to suicide, the acute stress preceding death, or other medical circumstances.
The number of donors is much smaller than the number of cells tested. Almost half a million cell nuclei provide high molecular resolution, but are not equivalent to a sample of half a million people.
The researchers chose samples of people who were not receiving medication at the time of their death to reduce the possibility that the changes were caused by antidepressants. This advantage does not eliminate the limitations of a postmortem observational study.
Open to research on new treatments
The possibility of re-stimulating the maturation of neurons in the hippocampus may become a therapeutic direction in the future, but there is still a long way to go. First, it is necessary to identify which of the molecular pathways found actually cause the process to stop, and to test whether changing them improves brain function and depressive symptoms.
The study may also help to divide depression into biological subtypes. It is possible that in some patients, impaired neurogenesis is a key component, while in others, inflammatory, hormonal, genetic, or other neural mechanisms dominate.
The findings are not a reason to change existing treatment or discontinue medications. They provide a more detailed biological map of the disease and are candidates for future research—not a proven treatment.
Questions and Answers
Does the brain continue to produce neurons in adulthood?
The study found a sequence of cells carrying molecular markers of neuron formation in the adult hippocampus. It reinforces previous studies supporting the existence of neurogenesis in adult humans, although its extent and role are still being investigated.
Does stopping the creation of neurons cause depression?
It is not yet known. The study found a link between major depression and process disruption, but cannot determine which is cause and which is effect.
Has a new treatment for depression been found?
No. The researchers identified molecular pathways that may serve as targets for future drug development, but did not test treatment in humans.
Why were cell nuclei examined and not whole brain cells?
In brain tissue preserved after death, it is easier to isolate cell nuclei. The cell nucleus contains the genetic material and allows us to measure which genes are active and examine the state of chromatin in each individual cell.
Sources: The article in Nature Medicine, Columbia University Announcement.
More of the topic in Hayadan:
- The biology of depression
- save new brain cells
- How we link memories to each other and make associations
- Hippocampal-Focused Brain Stimulation Reduced Intrusive Memories in PTSD
For the scientific article: Opening the scientific article
