Summary: Researchers have developed an enhanced imaging technique that can detect small fluctuations in the rate at which neurons are generated in the brain.
PET imaging of new neurons in the brain promises to advance our understanding and treatment of depression.
The adult brain was long regarded as being unable to grow new neurons—you were stuck with what you had. We know now that this view is wrong and that the human brain continues to produce new neurons throughout our lives.
At least two distinct populations of neural stem cells continue to divide and produce new neurons throughout life in a process known as neurogenesis. One group births immature neurons that migrate to the olfactory bulb at the front of the brain, where they contribute to the sense of smell. The other generates neurons that enter the dentate gyrus of the hippocampus, a deep-brain structure critical for learning and memory.
Scientists have previously found a link between reduction in the neural volume of the hippocampus and depression. They have also discovered that antidepressants known as selective serotonin reuptake inhibitors, which include fluoxetine (Prozac), stimulate the growth of new cells in this region of the brain. Both these pieces of evidence suggest that adult neurogenesis in the hippocampus may play an important role in depression.
Yosky Kataoka, Yasahisa Tamura and their colleagues at RIKEN have developed an enhanced molecular imaging technique that is so sensitive it can detect small fluctuations in the rate at which neurons are birthed in the brain. They anticipate that this technique could lead to new ways to diagnose depression and monitor the effects of antidepressants.
Tracing neural growth
Monitoring neurogenesis noninvasively is very challenging. While magnetic resonance imaging (MRI) can be used to observe neurogenesis in rats, MRI tracers have to be injected directly into the brain fluid, making the procedure risky and difficult to perform.
Another imaging technique that has been used to visualize and measure the rate of adult neurogenesis in the rodent hippocampus is positron emission tomography (PET). PET involves injecting small amounts of a radioactive tracer, which binds to a specific target molecule in tissues and organs, and then detecting the gamma rays it emits using a scanner. This enables researchers to monitor the distribution of the target molecule in an organ.
Scientists have used a PET tracer called 3′-deoxy-3′-[18F]fluoro-L-thymidine [18F]FLT that gets trapped in
newborn brain cells to try to measure adult neurogenesis. Until now, though, they have been unsuccessful in these attempts because there was little difference in signal strength between regions with and without cell growth.
Yasuhisa Tamura of the RIKEN Center for Life Science Technologies and his colleagues suspected that the problem with [18F]FLT was arising because membrane proteins called drug transporters actively pump the tracer out of the brain. So to counteract this and boost the technique’s sensitivity, they tried injecting rats with a drug prior to injecting the animals with the radioactive tracer. The team chose probenecid, a drug typically used to treat gout, because it inhibits drug transporters at the blood–brain barrier.
The color of depression
For periods of up to a month, the researchers gave the stress hormone corticosterone, which suppresses neurogenesis and induces depression-like behaviors, to one group of rats. To another, they gave both corticosterone and the antidepressant drug fluoxetine.
When they scanned the animals’ brains, they discovered that the radioactivity was strong enough to allow them to distinguish between reductions in neurogenesis caused by corticosterone and recovery induced by treatment with the antidepressant. Treating the animals with probenecid increased the uptake of the radioactive tracer by the brain, thus making the radioactive signal given off by newborn cells stronger.
To confirm their results, Tamura and his colleagues dissected the rats’ brains and tagged newborn cells in slices of hippocampal tissue with fluorescent antibodies. They determined the number of tagged cells by examining the samples under a microscope. In line with the brain-scanning results, this analysis revealed that rats treated with corticosterone for one month had about 45 per cent fewer newborn neurons in the dentate gyrus than untreated control animals. In contrast, rats given both corticosterone and fluoxetine showed no such difference.
These results demonstrated that the enhanced PET imaging technique can visualize adult neurogenesis in the brains of live animals and that it is sensitive enough to detect dynamic alterations in the rate of the process caused by treatment with antidepressants.
Of mice and men
Although antidepressants stimulate adult neurogenesis in rodents, it is not known whether this is how they alleviate the symptoms of depression in humans.
Tamura says the enhanced imaging method developed by his team could help to resolve these questions and may eventually help clinicians not only to diagnose depression but also to evaluate the effectiveness of antidepressant treatments.
“This is a very interesting finding because it has been a long-time dream to find a noninvasive test that can give objective evidence of depression and simultaneously show whether drugs are working in a given patient,” says Kataoka, who led the team. “We have shown that it is possible, at least in experimental animals, to use PET to show the presence of depression and the effectiveness of drugs.”
The team is keen to apply their imaging technique to humans. “Since it is known that these same brain regions are involved in depression in the human brain, we would like to try this technique in the clinic and see whether it turns out to be effective in humans as well,” explains Kataoka. Fortunately, this should not be too challenging to do. “Both probenecid and the PET tracer are already applicable to humans, so we can directly translate the work to humans. We are now testing it in non-human primates,” says Tamura.
Image Source: NeuroscienceNews.com image is credited to Tamura et al.
Original Research: Abstract for “Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging” by Yasuhisa Tamura, Kayo Takahashi, Kumi Takata, Asami Eguchi, Masanori Yamato, Satoshi Kume, Masayuki Nakano, Yasuyoshi Watanabe and Yosky Kataoka in Journal of Neuroscience. Published online August 3 2016 doi:10.1523/JNEUROSCI.0220-16.2016
Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging
Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3′-deoxy-3′-[18F]fluoro-l-thymidine ([18F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [18F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [18F]FLT combined with probenecid, an inhibitor of drug transporters at the blood–brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [18F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment.
SIGNIFICANCE STATEMENT Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging has been studied to allow visualization of neurogenic activity; however, PET imaging has not been widely used due to the lower accumulation of the PET tracer in the neurogenic regions. Here, we succeeded in establishing highly quantitative PET imaging for neurogenic activity in adult brain with an inhibitor for drug transporter. This enhanced PET imaging allowed evaluation of the decline of neurogenic activity in the hippocampus of rats with depression and the recovery of neurogenic activity by antidepressant treatment.
“Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging” by Yasuhisa Tamura, Kayo Takahashi, Kumi Takata, Asami Eguchi, Masanori Yamato, Satoshi Kume, Masayuki Nakano, Yasuyoshi Watanabe and Yosky Kataoka in Journal of Neuroscience. Published online August 3 2016 doi:10.1523/JNEUROSCI.0220-16.2016