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Growing Up Without Breaking Down: Reviving Critical Period Neuroplasticity in the Visual System of the Aging Brain

Rakshita Balaji

With December underway, The Hall was decked as it hosted the last Science on Tap talk of the Fall 2021 semester. This talk featured Dr. Elizabeth Quinlan, professor in the UMD Department of Biology, Clark Leadership Chair in Neuroscience, and as of January 2021, Director of the Brain and Behavior Institute (BBI) at UMD. 

These lit-up mini trees were just a couple of the seasonal decorations at The Hall

Dr. Quinlan’s research interests lie in visual sensory perception, aging in the brain, and synaptic plasticity, the process by which neurons can alter their communication and connections to drive cognitive and sensory function. Neuroplasticity is more prevalent in childhood as a hallmark of the critical period in development. We experience this ourselves, Dr. Quinlan explained, when we consider how we learn languages; it is much harder to pick up a second language in adulthood than in childhood. For example, if you’re bilingual and grew up listening to your parents speak another language, you probably learned that language with little to no conscious effort. Contrast that with your experience in a foreign language class in high school, where you might have fallen short of fluency. Due to your growth, your brain as an adolescent lost the plasticity it had when you were a developing child, and this trend of plasticity loss persists into adulthood.

Plasticity eludes us throughout development – with exceptions

If plasticity in adulthood is scarce, how do our brains stay healthy and functional as we age? In short, age-related loss of plasticity is unavoidable. In exchange for a lifetime of rich experiences, memories, emotions, thoughts, ideas, and sensations, our brains lose some flexibility as they develop in structure.

However, interestingly enough, scientists have recently identified circumstances in which plasticity re-emerges in adulthood. Dr. Quinlan highlighted the following cases in her talk: 

  1. Language recovery in patients after suffering a stroke
  2. Somatotopic, or bodily touch sense, rewiring after injury (ex: phantom limb pain)

Plasticity, on the cellular level, depends on communication between neurons, which are cells of the brain that harness electrical and chemical signals to affect brain function. Neurons play a game of telephone, constantly communicating with one another in order to give instructions back and forth in the brain. When these neurons transmit a message, they do so through a synapse. Connectivity in a synapse only gets stronger the more that neurons send signals across it. As Dr. Quinlan pointed out in her talk, “learning strengthens synapses”. Just like in humans, the more that the neurons communicate, the more in sync they are with one another. 

Sketch of a synapse between two communicating neurons

The strength of the synapse between two cells can be measured by recording the electrical activity of the postsynaptic cell, the cell receiving the signal. If the communication between the two cells is strong, then we can use electrodes to measure a strong current in the “receiving” cell, indicating that the message was received loud and clear. 

You might be wondering, why wouldn’t plasticity only continue with age? If cells just need to communicate consistently to build stronger connections, wouldn’t a lifetime of communication yield strong synapses? You could imagine that once a circuit of these cells has strong synapses, it can be very hard to rewire them. Additionally, making new connections takes a lot of energy, which grows scarce with age. To save resources, the brain selectively chooses connections to keep and connections to neglect depending on what information or functions seem most necessary to store. 

Using this understanding, Dr. Quinlan’s work analyzed how changes in this cell to cell communication occurred in the adult brain. She wanted to find out just how much plasticity the adult brain was capable of after the aforementioned critical period in development. To investigate this, her lab created a model of aging using a sense that is known to deteriorate with age: vision. 

Amblyopia serves as a model to understand the aging visual system

Amblyopia, in Greek, means “dim vision”. When a person has amblyopia, there is a difference in the quality of visual input between their two eyes. This can present as strabismus (commonly known as appearing “cross-eyed”), anisometropia (differences in the power between both eyes), or deprivation (vision in one eye is altogether obscured by cataract that covers the lens of the eye). These conditions hinder visual perception for people who suffer from them. 

Having two eyes is beneficial because, Dr. Quinlan says, “It’s good to have a spare”. In addition, she explained the importance of having two eyes for depth perception. In the process of binocular integration, visual inputs from the two eyes, which slightly differ on their own (known as binocular disparity), converge to create a three-dimensional rendering of our surroundings. Specifically, the primary visual cortex of the brain receives the mixed sensory signals from the retinas along the visual pathway and accordingly pieces together our perceived three-dimensional image. When the inputs between the two eyes are vastly different or asymmetrically deprived altogether, visual images of the environment are improperly rendered in the visual cortex. Going back to the cellular telephone: In the case of amblyopia, messages from the “sending” cell are warped to begin with, causing a flawed message to be transduced by the “receiving” cells along the visual pathway and up to the cortex. 

Schematic of binocular disparity (Cheng, 2021).

Even though amblyopia can be physically corrected by surgery, the sharp contrast in visual perception between the two eyes can persist. This is primarily due to the aforementioned synapses that developed prior to surgery; plasticity is required for the connections between the cells to change and adapt to the visual input following surgical correction. This need for plasticity to restore visual function makes amblyopia a viable test case to examine how the brain can change in adulthood. Specifically, Dr. Quinlan’s lab induced deprivation amblyopia in mice to find out how the brain would adapt to visual input after alleviating deprivation, which reflected surgical correction of amblyopia in humans.

Mice failed visual perception test in adulthood after correction of deprivation amblyopia 

The commonality that Dr. Quinlan’s lab cited in the two aforementioned cases for plasticity was the removal or disturbance of activity in some area(s) of the brain. This made amblyopia a desirable model for assessing plasticity, since the lack of input from one eye throughout development removed activity in the region of the visual cortex that would have received signals from the corresponding retina.

To initially test deprivation, adult mice were left in the dark for three days. After three days, they were brought back into light with one eye covered. After ten days, they noticed that there was a shift in ocular dominance, or the balance of visual input between the left and right eyes. Since one eye was covered, it would make sense that there would be less signals communicated from that eye up to the visual cortex as compared to the eye that was open. This verified that there was indeed plasticity, a change in connections, induced by this deprivation of visual input to one eye. 

Next, Dr. Quinlan and her colleagues wanted to test the mouse’s ability to tell differences between visual stimuli presented to it through a behavioral task called a Two-Alternative Forced Choice task. Mice were presented two choices of visual stimuli while they were submerged in a pool of water. By the way, Dr. Quinlan noted, mice do not prefer to swim. If the mouse chose the screen that presented them with grating bars, it would gain access to a hidden platform under the water that could help it get out. In this manner, the mouse is forced to make a choice between two alternatives.

Diagram of the Two Alternative-Forced Choice Task (Prusky, 2003)

This task becomes difficult when the contrast between the gratings decreases over trials. As the gratings get blurrier and blurrier, it becomes more tough to discriminate between a solid screen and the gratings. To figure out how well the mouse could perceive subtle differences between the two stimuli, Dr. Quinlan’s lab measured the highest frequency at which the mouse could make seven out of ten correct discrimination choices between the gratings and the solid screen. 

One group of animals were raised monocular, with only one eye open, from birth to adulthood. In adulthood, the animal had the amblyopic eye opened and was trained on this task to see whether improvement in perception would follow. For 90 days after having both eyes open, Dr. Quinlan’s lab noticed no spontaneous improvement in perception. While it seems disappointing, this finding was understandable. Sweeping plasticity is a rarity in adulthood, which is why disruptions in visual perception can persist after a surgery, especially past the critical period in development. If that is the case, how exactly can the brain adjust to cure lasting symptoms?

Plasticity could be unlocked in the light after dark

Dr. Quinlan’s lab had another idea to induce plasticity in the mice. They wondered what would happen if they put the mice in the dark before opening the amblyopic eye. To measure the impact of the dark exposure, which essentially deprived visual input to both eyes, adult animals with induced amblyopic closure of one eye were placed in the dark for ten days before having the amblyopic eye opened. Did this make a difference? After re-exposing the mice to light and opening the amblyopic eye, visual perception was tested again. It turned out that within two days of training on the visual discrimination task following reintroduction of visual input to both eyes, Dr. Quinlan and her lab saw improvement in the mice’s performance on the task.

What kind of magic is going on in the dark to improve vision? Perhaps, Dr. Quinlan said, the dark exposure “evens the score” between the two eyes; somehow depriving both eyes of input cues the brain into activating plasticity. What was interesting, though, were the changes that were seen in the light exposure following the dark.

Neurons float in what is known as an extracellular matrix (ECM), made up of macromolecules that support cells and their communication. You could imagine this matrix like the microscopic wires that connect synapses as they communicate. If you were an operator with billions of lines of cell communications to maintain, it would be hard for you to change those structures on a whim; after all, we wouldn’t want our neurons to get their wires crossed. Over time, a perineuronal net can form in the ECM, which maintains stable synapses.

Dr. Quinlan and her colleagues observed that these nets did not actually break apart in the dark. Instead, they found that the perineuronal net and the more structurally-rigid elements of the extracellular matrix degraded in the light. They predict that in the dark, the perineuronal nets become more susceptible for degradation to occur after the animal gets re-exposed to light. It seems that even in neuroscience, we rely on a balance between the dark and the light…

☆ For more information about perineuronal net breakdown by enzymes and effects of visual deprivation on the process, check out this article about Dr. Quinlan’s research here: 

Visual Deprivation Lowers Threshold for Enzymatic Pathway that Rejuvenates Synaptic Plasticity in the Brain | College of Computer, Mathematical, and Natural Sciences.  

Future implications 

Of course, it seems a bit ridiculous to ask humans to sit in the dark for days at a time just to “hack” the plasticity in their brains. And yet, the Quinlan Lab was curious. Two of Dr. Quinlan’s colleagues consented to spending five days straight in the dark, and they reported having vivid visual hallucinations during that time, even without being able to see anything. This could tell us something important about how the brain maintains cognitive visual activity without actual visual input. Additionally, Dr. Quinlan clarified that neither the mice nor the humans were controlled for their sleep patterns, so the possible influence of sleep during continuous dark exposure on mechanisms of plasticity has yet to be distinguished. 

The process by which visual perception is recovered through rewiring in the brain can help us restore or sharpen function along the sensory pathway, from visual sensation in the retina to cognitive and decision-making functions based on perception in the cortex. When it comes to aging, we may also be able to slow deterioration of cognitive and sensory functions by reviving plasticity and changing the way our neurons communicate at the synaptic level. Neuroplasticity speaks to our human capacity for adaptation and resilience, making it a powerful tool to uncover how we can heal and grow. 

Cited Sources: 

Cheng, E. (2021). Binocular integration as nonlinear mixing: How binocular neurons in primary visual cortex preserve eye-specific information for downstream visual processing. Society for Neuroscience 2021.

Murase, S., Winkowski, D., Liu, J., Kanold, P. O., & Quinlan, E. M. (2019). Homeostatic regulation of perisynaptic matrix metalloproteinase 9 (MMP9) activity in the amblyopic visual cortex. ELife, 8, e52503.

Prusky, G. T., & Douglas, R. M. (2003). Developmental plasticity of mouse visual acuity. European Journal of Neuroscience, 17(1), 167–173.

Check out the links in the article to learn more!

Rakshita Balaji is a junior Neuroscience major who plans to attend graduate school to study Neuroscience. She does research in the Caras Lab, where she studies auditory perception and perceptual learning, which deals with neuroplasticity. She recommends the following books for anyone interested in neuroscience and neuroplasticity: The Ghost in My Brain by Clark Elliott and The Tell-Tale Brain by V.S. Ramachandran. She also recommends listening to Red (Taylor’s Version) by Taylor Swift, to whom she owes inspiration for the title of this recap. Rakshita wishes you a restful winter break and a happy holiday season/new year! 

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