Posts Tagged ‘neurogenesis’

By Ashley P. Taylor

During adulthood, the mouse brain manufactures new neurons in several locations, including the hippocampus and the subventricular zone of the forebrain. The hypothalamus, previously identified as an area with an important role in aging, also generates new neurons from neural stem cells. In a study published July 26 in Nature, Dongsheng Cai and his team at the Albert Einstein College of Medicine in New York connect the dots between these two observations, reporting that hypothalamic neural stem cells have widespread effects on the rate of aging in mice.

In what David Sinclair, who studies aging at Harvard Medical School and who was not involved in the work, calls a “Herculean effort,” the researchers “discovered that stem cells in the hypothalamus of the mouse play a role in overall health and life span,” he tells The Scientist.

Cai and his team found that killing hypothalamic neural stem cells accelerates aging, and transplantation of additional neural stem cells into the same brain region slows it down. Further, the stem cells’ anti-aging effects could be reproduced simply by administering the cells’ secreted vesicles, called exosomes, containing microRNAs (miRNAs).

“If this is true for humans, one could imagine a day when we are treated with these small RNAs injected into our bodies or even implanted with new hypothalamic stem cells to keep us younger for longer,” Sinclair adds.

Researchers who study aging have long been searching for a central location that controls the process system-wide. In a 2013 paper, Cai and his team reported aging-associated inflammation in the hypothalamus of the mouse, which they could experimentally manipulate to speed up or slow down various types of aging-related decline, from muscle endurance to cognitive skills.

This study, Cai says, suggested the hypothalamus might be that central locus in control of aging. The researchers wanted to understand more about how this region of the brain drives aging and what role hypothalamic neural stem cells might play in that process, so they undertook a series of experiments.

Age-defying stem cells

The researchers first confirmed that cells bearing protein markers of neural stem cells (Sox2 and Bmi1) were present in the hypothalamus of early-to-middle-aged mice (11 to 16 months old) and that the number of those cells decreased in older mice.

Next, they destroyed neuronal stem cells in the hypothalamus by injecting the third ventricle, adjacent to the hypothalamic region where the stem cells are found, with a lentivirus that converted an administered compound into a toxin in cells expressing the stem-cell marker Sox2. Three or four months later, the researchers compared a variety of aging-related measures, including muscle endurance, coordination, social behaviors, novel object recognition, and cognitive performance, between mice injected with the virus and various control groups of mice that received a brain injection of some sort but in which the toxin could not be produced and the hypothalamic stem cells were consequently not ablated.

The mice in the experimental group lost 70 percent of their hypothalamic stem cells and, based on results of the physiological tests, had accelerated aging. Mice with ablated hypothalamic stem cells also died earlier than control mice.

Next, the researchers implanted middle-aged mice with neural stem cells derived from newborn mice to see if the additional stem cells would slow aging. But the implanted stem cells almost all died, which the researchers believe was a result of the inflammatory environment of the aging hypothalamus. Newborn neuronal stem cells genetically engineered to withstand that environment, on the other hand, did survive, and mice implanted with those cells lived longer and performed better on aging-related measures than control mice.

“What’s cool about this study is that they specifically delete a population of cells in the hypothalamus of the brain . . . and they show pretty striking alterations in whole-body aging,” says Anna Molofsky, a psychiatrist at the University of California, San Francisco, who studies glial cells and whose graduate work focused on neuronal stem cells and aging. “That’s really showing that there’s a mechanism within the brain that’s regulating whole-body organismal aging,” she adds. Molofsky, who was not involved in the work, says that these results support the idea of the hypothalamus as a central regulator of aging.

Anti-aging mechanism

Although neural stem cells are known for their ability to produce new neurons, that doesn’t seem to be their primary method for protecting against aging. The anti-aging effects of these hypothalamic stem cells were visible at around four months—not long enough, the authors write, for significant adult neurogenesis to have taken place.

The authors looked instead for some other factor that might be responsible for the stem cells’ effects. In the hypothalamic neural stem cells, the researchers detected exosomes—secreted vesicles that can contain RNA and proteins—containing a variety of miRNAs, short RNA molecules that inhibit the expression of targeted genes. These exosomes were not present in non-stem cells of the hypothalamus.

To test the effects of the exosomes alone on aging, the researchers purified the vesicles from cultured hypothalamic neural stem cells and transplanted them into middle-aged mice, finding that the exosome-treated mice aged more slowly than vehicle-treated controls. They also found that the exosomes could ameliorate the aging symptoms of mice whose hypothalamic neurons had been ablated.

Cai says microRNAs could be a potential mechanism by which hypothalamic neural stem cells have such wide-ranging effects on aging, yet he believes that neurogenesis may also be involved.

Regardless of the mechanism, Molofsky says, “the medical applications could be pretty profound.” The phenotypes, such as muscle mass and skin thickness, affected by these stem cells are the same ones that cause age-related disease, she notes. “The fact that you can reverse that with a brain-specific modulation, potentially, in a cell type that one could pharmacologically target, I think potentially that could be very profound, assuming that the mouse work translates to humans.”

Y. Zhang et al., “Hypothalamic stem cells control ageing speed partly through exosomal miRNAs,” Nature, doi:10.1038/nature23282, 2017.


A new study shows the death of newborn brain cells may be linked to a genetic risk factor for five major psychiatric diseases, and at the same time shows a compound currently being developed for use in humans may have therapeutic value for these diseases by preventing the cells from dying.

In 2013, the largest genetic study of psychiatric illness to date implicated mutations in the gene called CACNA1C as a risk factor in five major forms of neuropsychiatric disease — schizophrenia, major depression, bipolar disorder, autism, and attention deficit hyperactivity disorder (ADHD). All the conditions also share the common clinical feature of high anxiety. By recognizing an overlap between several lines of research, scientists at the University of Iowa and Weill Cornell Medicine of Cornell University have now discovered a new and unexpected role for CACNA1C that may explain its association with these neuropsychiatric diseases and provide a new therapeutic target.

The new study, recently published in eNeuro, shows that loss of the CACNA1C gene from the forebrain of mice results in decreased survival of newborn neurons in the hippocampus, one of only two regions in the adult brain where new neurons are continually produced – a process known as neurogenesis. Death of these hippocampal neurons has been linked to a number of psychiatric conditions, including schizophrenia, depression, and anxiety.

“We have identified a new function for one of the most important genes in psychiatric illness,” says Andrew Pieper, MD, PhD, co-senior author of the study, professor of psychiatry at the UI Carver College of Medicine and a member of the Pappajohn Biomedical Institute at the UI. “It mediates survival of newborn neurons in the hippocampus, part of the brain that is important in learning and memory, mood and anxiety.”

Moreover, the scientists were able to restore normal neurogenesis in mice lacking the CACNA1C gene using a neuroprotective compound called P7C3-A20, which Pieper’s group discovered and which is currently under development as a potential therapy for neurodegenerative diseases. The finding suggests that the P7C3 compounds may also be of interest as potential therapies for these neuropsychiatric conditions, which affect millions of people worldwide and which often are difficult to treat.

Pieper’s co-lead author, Anjali Rajadhyaksha, associate professor of neuroscience in Pediatrics and the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine and director of the Weill Cornell Autism Research Program, studies the role of the Cav1.2 calcium channel encoded by the CACNA1C gene in reward pathways affected in various neuropsychiatric disorders.

“Genetic risk factors that can disrupt the development and function of brain circuits are believed to contribute to multiple neuropsychiatric disorders. Adult newborn neurons may serve a role in fine-tuning rewarding and environmental experiences, including social cognition, which are disrupted in disorders such as schizophrenia and autism spectrum disorders,” Rajadhyaksha says. “The findings of this study provide a direct link between the CACNA1C risk gene and a key cellular deficit, providing a clue into the potential neurobiological basis of CACNA1C-linked disease symptoms.”

Several years ago, Rajadhyaksha and Pieper created genetically altered mice that are missing the CACNA1C gene in the forebrain. The team discovered that the animals have very high anxiety.

“That was an exciting finding, because all of the neuropsychiatric diseases in which this gene is implicated are associated with symptoms of anxiety,” says Pieper who also holds appointments in the UI Departments of Neurology, Radiation Oncology, Molecular Physiology and Biophysics, the Holden Comprehensive Cancer Center, and the Iowa City VA Health Care System.

By studying neurogenesis in the mice, the research team has now shown that loss of the CACNA1C gene from the forebrain decreases the survival of newborn neurons in the hippocampus – only about half as many hippocampal neurons survive in mice without the gene compared to normal mice. Loss of CACNA1C also reduces production of BDNF, an important brain growth factor that supports neurogenesis.

The findings suggest that loss of the CACNA1C gene disrupts neurogenesis in the hippocampus by lowering the production of BDNF.

Pieper had previously shown that the “P7C3-class” of neuroprotective compounds bolsters neurogenesis in the hippocampus by protecting newborn neurons from cell death. When the team gave the P7C3-A20 compound to mice lacking the CACNA1C gene, neurogenesis was restored back to normal levels. Notably, the cells were protected despite the fact that BDNF levels remained abnormally low, demonstrating that P7C3-A20 bypasses the BDNF deficit and independently rescues hippocampal neurogenesis.

Pieper indicated the next step would be to determine if the P7C3-A20 compound could also ameliorate the anxiety symptoms in the mice. If that proves to be true, it would strengthen the idea that drugs based on this compound might be helpful in treating patients with major forms of psychiatric disease.

“CACNA1C is probably the most important genetic finding in psychiatry. It probably influences a number of psychiatric disorders, most convincingly, bipolar disorder and schizophrenia,” says Jimmy Potash, MD, professor and DEO of psychiatry at the UI who was not involved in the study. “Understanding how these genetic effects are manifested in the brain is among the most exciting challenges in psychiatric neuroscience right now.”