Most\u00a0of\u00a0our\u00a0brain’s\u00a0100 billion\u00a0neurons are created\u00a0before\u00a0we’re\u00a0born, but the trickle of neurons created in the adult brain\u00a0hippocampus\u00a0could\u00a0be\u00a0instrumental\u00a0in preventing depression,\u00a0suggest\u00a0findings from\u00a0a new study by\u00a0researchers at Columbia University\u00a0Vagelos College of Physicians and Surgeons.\u00a0<\/p>\n
The study\u00a0shows\u00a0for the first time that\u00a0neurogenesis stalls in the brains\u00a0of\u00a0adults\u00a0with major depressive disorder\u00a0and\u00a0identifies\u00a0the molecular\u00a0programs\u00a0that control neurogenesis, which may help researchers develop new therapies.\u00a0<\/p>\n
“Historically, depression was thought to be a disease of neurotransmitter\u00a0deficiency, especially\u00a0serotonin,\u00a0but\u00a0we now think that\u00a0depression stems from multiple\u00a0issues\u00a0that affect our neurons’\u00a0ability to adapt to\u00a0stress and changing environments,” says Maura Dupont,\u00a0professor of psychiatry<\/a>, who led the research.\u00a0<\/p>\n “Without the ability to create new neurons, people with depression may not\u00a0have the\u00a0resilience\u00a0to effectively adapt to the environment.”\u00a0<\/p>\n Role of new neurons in the brain’s hippocampus\u00a0<\/p>\n The new study focused on the brain’s hippocampus-a region known for its\u00a0central role\u00a0in\u00a0episodic memory and emotional responses to the environment\u00a0and\u00a0one of the few places in the\u00a0adult\u00a0brain that creates new neurons.\u00a0The\u00a0region\u00a0isn’t the only part of the brain involved in depression, but with its role in\u00a0emotions\u00a0and memory,\u00a0it’s\u00a0thought to play a role in pushing patients to interpret events in a negative light.\u00a0<\/p>\n “The hippocampus is important for our ability to distinguish between similar but different\u00a0memories and separate the emotional connotation of past memories and current events,” Dupont says.\u00a0When this ability, called\u00a0pattern separation,\u00a0is impaired, memories, together with their emotional value,\u00a0become less distinct and more likely to blend together.\u00a0<\/p>\n You may be out with a friend for lunch, but she’s tired and doesn’t talk much. With intact pattern separation, you remember this as a unique event. With impaired pattern separation, it becomes mixed with previous memories of feeling rejected, leading you to think, “They’re upset with me. And I see this a lot in my patients, where they can only retrieve negative information from their memories.”\u00a0<\/p>\n Maura Dupont, professor of psychiatry, Columbia University Irving Medical Center<\/p>\n Studies in mice have\u00a0established\u00a0that pattern separation is dependent on\u00a0adult\u00a0neurogenesis, and a recent study\u00a0in\u00a0patients with brain tumors-in whom neurogenesis\u00a0was\u00a0ablated by\u00a0radiation\u00a0therapy directed to the\u00a0hippocampus-suggests the same is true in people.\u00a0<\/p>\n “It’s important to\u00a0emphasize that we do not yet know the complete mechanism, particularly in humans, but the newborn neurons seem\u00a0to\u00a0enhance pattern separation because they are\u00a0especially responsive to new experiences and can be incorporated into new memory circuits more easily,\u00a0allowing new memories\u00a0to be stored\u00a0separately from the old ones,” Dupont says.\u00a0“Turning\u00a0neurogenesis back on may be a\u00a0way to treat depression in some people\u00a0by rewiring their hippocampus circuit.”\u00a0<\/p>\n Depression associated with widespread changes in the brain\u00a0<\/p>\n Neurogenesis does not work alone in the brain, but as part of a\u00a0hippocampus\u00a0circuit\u00a0where episodic memories and their emotional valence are stored. The study shows that the whole circuit suffers from molecular\u00a0changes.\u00a0<\/p>\n Those changes include alterations in genes that are involved in creating new connections\u00a0and\u00a0cross-talk\u00a0between neurons, providing energy,\u00a0and transporting cargo within cells.\u00a0The hippocampus’s primary means of\u00a0establishing\u00a0new emotional memories-the\u00a0trisynaptic\u00a0circuit-\u00a0also\u00a0showed\u00a0signs of inflammation<\/a> and cellular stress in the depressed patients.\u00a0<\/p>\n The researchers were able to\u00a0detect these\u00a0changes after examining an extraordinary number of brain cells-nearly half\u00a0a million-collected from\u00a0depressed\u00a0patients and\u00a0control subjects soon after each donor’s death.\u00a0<\/p>\n With an array of recently developed\u00a0cutting-edge\u00a0techniques, the researchers recorded\u00a0the activity of every gene in\u00a0each\u00a0cell\u00a0and\u00a0if the cells’\u00a0proteins\u00a0were\u00a0altered.\u00a0The massive amount of data\u00a0provided\u00a0an unprecedented view of each cell’s activities\u00a0and\u00a0the exact anatomical location in the hippocampus circuit where the affected cells are positioned.\u00a0<\/p>\n Their\u00a0data also\u00a0identified\u00a0some\u00a0genes with altered\u00a0activity\u00a0that have been shown to have\u00a0genetic\u00a0variants associated with major depression, while other dysregulated genes were affected by\u00a0epigenetic changes\u00a0reflecting environmental factors at play. “These are like\u00a0dimmer switches that control how active genes are, and\u00a0they are affected by life\u00a0experiences such as stress, learning, aging,\u00a0chemicals, etc.,” Dupont says.\u00a0<\/p>\n “Overall, the\u00a0wide range of\u00a0effects\u00a0we\u00a0found\u00a0could reflect different pathogenetic mechanisms, perhaps indicating that depression is not just one disease,”\u00a0she adds.\u00a0<\/p>\n Right now, researchers have only a rudimentary understanding of the biological causes of depression, Dupont says. But studies like hers will define what depression\u00a0looks like\u00a0at the cellular level, which could lead to the development of new treatments.\u00a0<\/p>\n “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\u00a0and other psychiatric or brain diseases.”\u00a0<\/p>\n Source:<\/p>\n Columbia University Irving Medical Center<\/a><\/p>\n Journal reference:<\/p>\n