Antidepressant restores youthful flexibility to aging inhibitory neurons in mice

August 20, 2018, Massachusetts Institute of Technology
Tracking the growth of neuron arbors under the microscope over two weeks, researchers typically saw growth beyond the arrow marker in six-month-old mice (green), but none beyond the marker in 18-month old mice (red). Credit: Nedivi Lab/Picower Institute

A new study provides fresh evidence that the decline in the capacity of brain cells to change, called "plasticity," rather than a decline in total cell number may underlie some of the sensory and cognitive declines associated with normal brain aging. Scientists at MIT's Picower Institute for Learning and memory show that inhibitory interneurons in the visual cortex of mice remain just as abundant during aging, but their arbors become simplified and they become much less structurally dynamic and flexible.

In their experiments published online in the Journal of Neuroscience they also show that they could restore a significant degree of lost plasticity to the cells by giving treating mice with the commonly used antidepressant medication fluoxetine, also known as Prozac.

"Despite common belief, loss of neurons due to cell death is quite limited during normal aging and unlikely to account for age-related functional impairments," wrote the scientists, including lead author Ronen Eavri and corresponding author Elly Nedivi, a professor of biology and and cognitive sciences. "Rather it seems that structural alterations in neuronal morphology and synaptic connections are features most consistently correlated with brain age, and may be considered as the potential physical basis for the ."

Nedivi and co-author Mark Bear, Picower Professor in the institute, are affiliated with MIT's Aging Brain Initiative, a multidisciplinary effort to understand how aging affects the brain and sometimes makes the brain vulnerable to disease and .

In the study the researchers focused on the aging of which is less well understood than that of excitatory neurons, but potentially more crucial to plasticity. Plasticity, in turn, is key to enabling learning and memory and in maintaining sensory acuity. In this study, while they focused on the , the plasticity they measured is believed to be important elsewhere in the brain, as well.

The team counted and chronically tracked the structure of inhibitory interneurons in dozens of mice aged to 3, 6, 9, 12 and 18 months (mice are mature by 3 months, live for about 2 years, and 18-month-old mice are already considered quite old). In previous work, Nedivi's lab has shown that inhibitory interneurons retain the ability to dynamically remodel into adulthood. But in the new paper, the team shows that new growth and plasticity reaches a limit and progressively declines starting at about 6 months.

But the study also shows that as mice age there is no significant change in the number or variety of inhibitory cells in the brain.

Retraction and inflexibility with age

Instead the changes the team observed were in the growth and performance of the interneurons. For example, under the two-photon microscope the team tracked the growth of dendrites, which are the tree-like structures on which a neuron receives input from other neurons. At 3 months of age mice showed a balance of growth and retraction, consistent with dynamic remodeling. But between 3 and 18 months they saw that dendrites progressively simplified, exhibiting fewer branches, suggesting that new growth was rare while retraction was common.

In addition, they saw a precipitous drop in an index of dynamism. At 3 months virtually all interneurons were above a crucial index value of 0.35, but by 6 months only half were, by 9 months barely any were and by 18 months none were.

Bear's lab tested a specific form of plasticity that underlies visual recognition memory in the visual cortex, where neurons respond more potently to stimuli they were exposed to previously. Their measurements showed that in 3-month-old mice "stimulus-selective response potentiation" (SRP) was indeed robust, but its decline went hand in hand with the decline in structural plasticity, so that it was was significantly lessened by 6 months and barely evident by 9 months.

Fountain of Fluoxetine

While the decline of dynamic remodeling and plasticity appeared to be natural consequences of aging, they were not immutable, the researchers showed. In prior work Nedivi's lab had shown that fluoxetine promotes interneuron branch remodeling in young mice, so they decided to see whether it could do so for older mice and restore plasticity as well.

To test this, they put the drug in the drinking water of mice at various ages for various amounts of time. Three-month-old mice treated for three months showed little change in dendrite growth compared to untreated controls, but 25 percent of cells in six-month-old mice treated for three months showed significant new growth (at the age of 9 months). But among 3-month-old mice treated for six months, 67 percent of cells showed new growth by the age of 9 months, showing that treatment starting early and lasting for six months had the strongest effect.

The researchers also saw similar effects on SRP. Here, too, the effects ran parallel to the structural plasticity decline. Treating mice for just 3 months did not restore SRP, but treating mice for six months did so significantly.

"Here we show that fluoxetine can also ameliorate the age-related decline in structural and functional plasticity of visual cortex neurons," the researchers wrote. The study, they noted, adds to prior research in humans showing a potential cognitive benefit for the drug.

"Our finding that fluoxetine treatment in aging can attenuate the concurrent age-related declines in interneuron structural and visual cortex functional plasticity suggests it could provide an important therapeutic approach towards mitigation of sensory and cognitive deficits associated with aging, provided it is initiated before severe network deterioration," they continued.

Explore further: Disinhibition plus instruction improve brain plasticity

More information: Ronen Eavri et al, Interneuron simplification and loss of structural plasticity as markers of aging-related functional decline, The Journal of Neuroscience (2018). DOI: 10.1523/JNEUROSCI.0808-18.2018

Related Stories

Disinhibition plus instruction improve brain plasticity

April 12, 2011
(PhysOrg.com) -- The healthy brain has balance of excitatory and inhibitory signals that stimulate activity but also keep it under control. Some brain diseases, like autism and Down's syndrome, have too much inhibition, which ...

Scientists restore youthful plasticity to the brains of adult mice

August 8, 2017
Like much of the rest of the body, the brain loses flexibility with age, impacting the ability to learn, remember, and adapt. Now, scientists at University of Utah Health report they can rejuvenate the plasticity of the mouse ...

Adult brain neurons can remodel connections

November 24, 2008
Overturning a century of prevailing thought, scientists are finding that neurons in the adult brain can remodel their connections. In work reported in the Nov. 24 online edition of the Proceedings of the National Academy ...

Deep sleep critical for visual learning

October 4, 2017
Remember those "Magic Eye" posters from the 1990s? You let your eyes relax, and out of the tessellating structures, a 3-D image of a dolphin or a yin yang or a shark would emerge.

Memory molecule limits plasticity by calibrating calcium

May 23, 2018
The brain has an incredible capacity to support a lifetime of learning and memory. Each new experience fundamentally alters the connections between cells in the brain called synapses. To accommodate synaptic alterations, ...

More evidence shows natural plant compound may reduce mental effects of aging

July 10, 2017
Salk scientists have found further evidence that a natural compound in strawberries reduces cognitive deficits and inflammation associated with aging in mice. The work, which appeared in the Journals of Gerontology Series ...

Recommended for you

Precision neuroengineering enables reproduction of complex brain-like functions in vitro

November 14, 2018
One of the most important and surprising traits of the brain is its ability to dynamically reconfigure the connections to process and respond properly to stimuli. Researchers from Tohoku University (Sendai, Japan) and the ...

A 15-minute scan could help diagnose brain damage in newborns

November 14, 2018
A 15-minute scan could help diagnose brain damage in babies up to two years earlier than current methods.

New brain imaging research shows that when we expect something to hurt it does, even if the stimulus isn't so painful

November 14, 2018
Expect a shot to hurt and it probably will, even if the needle poke isn't really so painful. Brace for a second shot and you'll likely flinch again, even though—second time around—you should know better.

New clues to the origin and progression of multiple sclerosis

November 13, 2018
Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The ...

Mutations, CRISPR, and the biology behind movement disorders

November 12, 2018
Scientists at the RIKEN Center for Brain Science (CBS) in Japan have discovered how mutations related to a group of movement disorders produce their effects. Published in Proceedings of the National Academy of Sciences, the ...

In live brain function, researchers are finally seeing red

November 12, 2018
For years, green has been the most reliable hue for live brain imaging, but after using a new high-throughput screening method, researchers at the John B. Pierce Laboratory and the Yale School of Medicine, together with collaborators ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.