Major depressive disorder (MDD) has been associated with reduced hippocampal volume, altered connectivity, and deficits in neuroplasticity, but the biological mechanisms underlying these changes are still not fully understood.
A new study published in Nature and led by Maura Boldrini Dupont, M.D., Ph.D., a psychiatrist at NewYork-Presbyterian and Columbia, demonstrates for the first time that neurogenesis stalls in the hippocampus of unmedicated adults with MDD, and also identifies broader molecular changes that may connect depression to biological pathways implicated in other brain and systemic disorders. The findings may lead to the development of new therapies.
“Historically, depression was thought to be a disease of neurotransmitter deficiency, especially serotonin,” says Dr. Dupont, who was the senior author of the study. “But we now think that depression stems from multiple issues that affect our neurons’ ability to adapt to stress and changing environments. What makes a person resilient or susceptible to the trauma that they experience? If we can understand that at the molecular level, we may be able to help people become more resilient.”
How Impaired Neurogenesis May Affect Memory and Mood
One cognitive process thought to be affected in MDD is pattern separation, the brain’s ability to distinguish between similar experiences and store them as distinct memories. “The hippocampus is important for our ability to distinguish between similar but different memories and separate the emotional connotation of past memories and current events,” Dr. Dupont says. When this ability is impaired, memories and their emotional value become associated with one another, which could contribute to the negative cognitive bias often observed in depression.
Previous studies in animal models showed that pattern separation is dependent on adult neurogenesis, and more recent research in patients with brain tumors — in whom neurogenesis was ablated by radiation therapy directed to the hippocampus — suggests the same is true in people.
“Turning neurogenesis back on by rewiring their hippocampus circuit may be a way to treat depression in some people,” Dr. Dupont says.
We’ve already identified some drugs that could potentially be repurposed to target these pathways.
— Dr. Maura Dupont
Brain Cell Analysis Reveals Widespread Molecular Changes
The study also suggests that molecular changes in MDD extend beyond neurogenesis and affect the broader hippocampal network.
The researchers identified dysregulation in genes that are involved in synaptic plasticity, neuronal communication, cellular metabolism, and intracellular transport. They also found evidence of inflammation and cellular stress within the hippocampus’s trisynaptic circuit, a key network that plays a role in memory formation and emotional processing.
To characterize these changes, they examined nearly 500,000 brain cells from postmortem hippocampal tissue collected from individuals with MDD and control subjects. The multiomics approach allowed them to look at gene expression, chromatin accessibility, and protein expression while mapping where affected cells were located within the hippocampal circuit. The analysis identified dysregulated genes linked both to inherited genetic risk and to epigenetic mechanisms that influence gene activity in response to environmental exposures and life experiences.
They also identified molecular signatures that overlap with pathways implicated in autoimmune, neurodevelopmental, and neurodegenerative disorders. Specifically, the findings included alterations in genes associated with autism, schizophrenia, Alzheimer’s disease, ALS, and autoimmune diseases, like systemic lupus erythematosus (SLE), psoriasis, or Crohn’s disease. “Some of these genes are shared with diseases that can also present with cognitive, emotional, or thought-process symptoms,” Dr. Dupont says. This suggests that MDD may share broader biological mechanisms with other brain disorders than previously recognized.
The team is evaluating whether some of the molecular pathways identified in the study could be targeted with existing drugs. In preliminary analyses, “we’ve already identified some that could potentially be repurposed to target these pathways,” she adds.
Researchers analyzed nearly 500,000 hippocampal cells from individuals with and without major depressive disorder, revealing widespread molecular changes across the hippocampal circuit. Colored circles denote distinct neuron types in a hippocampus analyzed by the researchers. Image courtesy of Dr. Maura Dupont.
Toward a Molecular Classification of Depression
Overall, the wide range of effects found by the researchers hint at the possibility that depression is not just a single disease. “Psychiatric illness today is classified based on clusters of symptoms, but that doesn't tell us anything about the actual molecular basis of this disease,” says Dr. Dupont. “It could be that similar molecular dysregulation occurs across different disorders, but depending on where it happens in the brain, the symptoms are very different.”
Studies like Dr. Dupont’s are beginning to define what depression looks like at the cellular level, which could lead to defining biologically distinct forms of depression and identifying new therapeutic targets.
She likens this contrast to oncology before the advent of molecular profiling. “We want to reclassify depression based on its molecular features, similar to what has been done in cancer,” Dupont says. “Classifying cancers based on their cellular characteristics, not their locations, has led to new and improved treatments. We hope the same will be true for depression and other psychiatric or brain diseases.”
