'Star cells' make long-term fear memories fade before they form

Manipulating important non-neuronal brain cells called astrocytes using light prevented fear memories from being retained long-term, according to new research. The findings add to growing evidence about astrocytes’ role in memory and open the door to potential treatments for conditions like PTSD, which is characterized by abnormal fear memory.

Astrocytes, the long-tailed, star-shaped cells that make up the majority of cells in the central nervous system, are known to perform metabolic, structural, and neuroprotective tasks in the brain. But scientists have started discovering that these cells play an important role in memory, too.

In a recent study, researchers from Tohoku University in Japan found that part of the process of memory formation is dependent on astrocytes and that using light to manipulate the cells can prevent memories, especially traumatic ones, from being retained long-term.

“We believe that this could change the way we understand memory formation,” said Ko Matsui, a professor at the Super-network Brain Physiology laboratory at the University and the study’s corresponding author. “The effect of astrocytes on memory likely also depends on various contexts, including mental, social, or environmental factors.”

The researchers surgically implanted optical fibers into the brains of mice directly above the anterior basolateral amygdala (aBLA). This region plays a crucial role in expressing behavior and memories that are evoked by fear. They then used optogenetics, where genes for light-sensitive proteins are introduced into specific brain cells to monitor and control their activity precisely using light, to photoactivate the astrocytes in that region.

The mice were genetically altered to express either channelrhodopsin-2 (ChR2) or archaerhodopsin (ArchT) in astrocytes specifically. Originating in algae, channelrhodopsins are a family of proteins that function as light-gated ion channels. They’re widely used to modulate the activity of neurons and other excitable cells. When channelrhodopsins are expressed in the cells of other organisms, they enable the use of light to control things like electrical excitability and intracellular acidity. A ChR2 light-gated channel is highly permeable to protons, meaning that when it’s opened, the astrocyte becomes acidified. Conversely, archaerhodopsin proteins, a family of photoreceptors found in bacterial species, pump protons out of cells, alkalinizing them.

The mice were given electric shocks to prompt the formation and storage of fear-related memories. A mouse presented with an aversive electrical foot shock will typically jump, an escape response, and then freeze, a defensive response that’s used as an indication of fear perception. The fear produced by electrical foot shocks is often strongly imprinted as a fear memory.

Mice whose astrocytic ChR2 had been photoactivated immediately after a foot shock displayed a significantly reduced freezing response 24 hours later, suggesting that the photoactivation had prevented the fear memory from being ‘saved.’ Interestingly, six minutes after the treatment, the mice displayed the same degree of freezing as untreated mice, suggesting that their short-term memory was intact. However, the researchers noted that there was a window in which ChR2 photoactivation remained effective. In one group of mice, photoactivation was performed 33 minutes after the shock and produced no effect on the freezing response.

“This result suggests that the interference of long-term memory formation is only effective when the astrocytic ChR2 photoactivation is carried out within a narrow time window following the foot shock,” said the researchers.

A different response was noticed in mice whose astrocytes were alkalinized. Astrocytic ArchT photoactivation failed to produce a significant difference in the freezing response the day after a mild shock was used but produced a significant reduction in freezing when it was used with a strong foot shock. From this, the researchers surmised that ArchT photoactivation was likely to only be effective against “emotional responses elicited by excessive fear.” When the researchers tested the animals’ memory three weeks later, they found that freezing levels remained constant, suggesting that ArchT photoactivation inhibited the long-term decay of fear memories.

“These insights could open up potential avenues for therapeutic interventions that target astrocytes in conditions characterized by abnormal fear memory, such as post-traumatic stress disorder,” the researchers said. “Furthermore, it would be intriguing to explore whether similar effects are seen in other types of memory beyond fear memory.”

The study was published in the journal GLIA.

Source: Tohoku University