Summary: Researchers have delved deeper into how specific interneurons in the brain affect memory as we age.
In a study focusing on the hippocampus, they found that reducing the number of somatostatin-positive interneurons led to cognitive deficits resembling aging. The mice with decreased interneurons showed signs of impaired memory, similar to naturally aged mice.
This breakthrough provides a new avenue to investigate potential treatments for age-related memory decline.
A decline in somatostatin-positive interneurons in the hippocampus was linked to significant memory challenges in mice.
Toxin-injected mice with reduced interneurons showed increased microglial activation, a sign of inflammation related to memory impairment, and had fewer dendritic spines vital for learning.
The effects observed in toxin-injected mice were parallel to those in naturally aged mice, suggesting the technique could model age-related cognitive deficits.
Source: University of Illinois
Normal aging is usually associated with a decline in memory, although it is unclear what factors play a role.
In a new study, researchers studied specific interneurons, which serve as communication centers that connect other neurons, in the regions of the brain that are important for learning and memory.
Increasing age places people at risk, whether it is because of a normal decrease in cognitive ability or due to postoperative cognitive disorders.
In the latter, the deficits can persist for many months after surgery especially when the patients are older than 60. Unfortunately, the underlying cellular mechanisms that cause these impairments are largely unknown.
Previous studies have shown that the region of the brain that is associated with learning and memory—the hippocampus—decreases in volume with age. Additionally, the levels of the molecule -aminobutyric acid, or GABA, and some of the interneurons that release it are also affected.
In the present study, the researchers focused on the hippocampal interneurons in a specific region, called the hilus of the dentate gyrus, that are characterized by their expression of somatostatin. This hormone has the ability to counteract the effects of growth hormones elsewhere in the body.
“In the past, other researchers have found that one of the differences between cognitively impaired and unimpaired rats was that the former had a lower number of somatostatin-positive interneurons in the hilus of the dentate gyrus,” said Uwe Rudolph (GNDP), a professor of comparative biosciences.
“We wanted to further investigate whether a loss of these neurons is really responsible for cognitive deficits, and whether it could thus serve as a model of aging in the hippocampus.”
The researchers decreased the numbers of somatostatin-positive interneurons in the hippocampus of mice by using a toxin. They injected this toxin into the dentate hilus, so that the toxin would only be expressed in the somatostatin-positive interneurons, killing approximately 50% of these cells. Starting 3 weeks later, they conducted behavioral studies to test the learning abilities and memory of the mice.
The mice underwent three types of tests: whether they could remember and differentiate novel objects from familiar ones, navigate mazes using their short-term memories, and use their spatial learning to find a hidden platform in a pool of water. In all three cases, the mice that had decreased levels of somatostatin-positive interneurons struggled compared to those that did not receive the toxin.
The researchers also looked for changes in cellular signals that occur due to lower levels of somatostatin-positive interneurons. To do so, they focused on the microglia, which are immune cells that are among the first to respond when something goes wrong in the brain.
“We looked at microglial activation, which is a hallmark of the inflammation that is associated with aging and memory impairment,” said Rajasekar Nagarajan, a postdoctoral researcher in the Rudolph lab. “We saw increased activation of microglia in the hippocampus of the mice that were injected with the toxin, even outside of the dentate gyrus.”
In addition to determining the status of microglia, the team measured a protein called brain-derived neurotrophic factor, which is active in the hippocampus and plays a role in long-term memory.
They found that there were lower BDNF levels in the hippocampal tissue of the toxin-injected mice. Furthermore, the researchers also found that these mice had fewer hippocampal dendritic spines, which are critical for learning and memory.
Unsurprisingly for the researchers, the results seen with the toxin-injected mice were essentially the same as with aged mice that were 18-19 months old and had not been injected with the toxin.
“18 months-old mice correspond to an age of approximately 60 years in humans. It roughly fits the time point at which we know that people more frequently develop neurocognitive deficits in response to surgery and anesthesia,” Rudolph said.
“Our results have shown that using this toxin to reduce the number of somatostatin-positive interneurons is sufficient to cause effects that resemble cognitive deficits in aging.”
The researchers are excited that they can use these techniques to investigate aging-related defects without waiting for the mice to grow old, which is an expensive and time-consuming undertaking.
“We will be using this method as a model to test which experimental compounds can be used to prevent or reverse both age-related and post-operative cognitive impairments,” Nagarajan said.
Genetic Ablation of Dentate Hilar Somatostatin-Positive GABAergic Interneurons is Sufficient to Induce Cognitive Impairment
Aging is often associated with a decline in cognitive function. A reduction in the number of somatostatin-positive (SOM+) interneurons in the dentate gyrus (DG) has been described in cognitively impaired but not in unimpaired aged rodents.
However, it remains unclear whether the reduction in SOM + interneurons in the DG hilus is causal for age-related cognitive dysfunction.
We hypothesized that hilar SOM+ interneurons play an essential role in maintaining cognitive function and that a reduction in the number of hilar SOM + interneurons might be sufficient to induce cognitive dysfunction.
Hilar SOM+ interneurons were ablated by expressing a diphtheria toxin transgene specifically in these interneurons, which resulted in a reduction in the number of SOM+ /GAD-67+ neurons and dendritic spine density in the DG. C-fos and Iba-1 immunostainings were increased in DG and CA3, but not CA1, and BDNF protein expression in the hippocampus was decreased.
Behavioral testing showed a reduced recognition index in the novel object recognition test, decreased alternations in the Y maze test, and longer latencies and path lengths in the learning and reversal learning phases of the Morris water maze.
Our results show that partial genetic ablation of SOM+ hilar interneurons is sufficient to increase activity in DG and CA3, as has been described to occur with aging and to induce an impairment of learning and memory functions.
Thus, partial ablation of hilar SOM + interneurons may be a significant contributing factor to age-related cognitive dysfunction. These mice may also be useful as a cellularly defined model of hippocampal aging.