BPC Science Writing Competition 1st Place: “Turning Back Time: It’s Never Too Late to Learn Like a Child”

By Jocelyn Lippman-Bell

time-488112_640

If you could take a pill to restore your mind to the flexible state of childhood learning, would you do it?

This is not as far out of the realm of possibility as one might imagine. Children possess an enhanced capacity for learning compared to adults, in part due to the high level of neuronal plasticity, or adaptability, that enables neurons to be especially sensitive and reactive to incoming messages. These periods of high neuronal responsiveness, remodeling, and refinement are called critical periods, and allow environmental cues to mold the developing brain and optimize neural functioning. Critical periods exist for many different forms of learning, including acquiring language and motor skills, developing sharp vision (visual acuity), and learning how to interpret sounds. A mounting body of research aimed at controlling the opening and closing of critical periods is rapidly making the possibility of reestablishing neuronal flexibility in adulthood a reality.

Plastic circuits

The idea that critical periods can be manipulated emerged largely through research in the developing visual system. Starting with the seminal studies of Hubel and Wiesel, evidence began to build demonstrating that if one eye of an animal remains closed throughout its visual critical period, the deprived eye had forever lost the ability to develop perfect acuity, and connections to the non-deprived eye were persistently much stronger than those to the deprived eye [1-4]. However, raising an animal in complete darkness (i.e. no visual stimulation to either eye) essentially shifted the critical period so that when the lights came back on, regardless of how long the animal had been in the dark, they were able to recover function and normal neural connectivity for both eyes [5, 6]. Because of these observations, scientists realized that the critical period was not an absolute; it could be altered. Thus began the race to uncover the mechanisms governing critical period regulation.

Using clues from the light deprivation experiments, scientists theorized that the key element controlling the critical period time course was the precise balance of excitatory and inhibitory activity at developing local neural circuits. Therefore, researchers began looking to the major mode for neuronal inhibition in the brain, the neurotransmitter gamma-aminobutyric acid, or GABA. Inhibitory circuits come on line later in development than excitatory circuits, and dampen excitation. When Huang and colleagues at MIT examined mice with accelerated onset of inhibitory circuit development, they found not only that the mice developed visual acuity sooner than their unaffected siblings, but also that the critical period for vision closed prematurely in these mice [7]. Conversely, in mice that had genetic modifications that decreased GABA release and therefore inhibition, the critical period never closed throughout the lifespan of the mouse, likely because the neural circuits in these mice never reach the required peak inhibition [8].

Risk and benefits

It is now clear that critical periods can be experimentally altered, but what is the cost of such manipulation? One must consider that there is an evolutionary advantage underlying the loss of brain flexibility. In the first years of life, an overabundance of neuronal connections is formed, then refined in response to experience and environmental cues to optimize neural circuit function and our perception of our surroundings. What would it be like to be in the throes of a critical period? Imagine being three again. Young children absorb everything around them, everything they see, everything they hear. However, in absorbing everything, the child cannot focus as readily as an adult. They have trouble letting go of unimportant things. Recreating child-like brain flexibility to allow the brain to rewire could result in a loss of memories at best, or loss of sensory mapping or outright brain damage at worse. So for, say, a 50-year-old who wants to master windsurfing, this many not be a viable shortcut.

In contrast to the science fiction-esque idea of creating mind-expanding drugs for personal gain, the real promise of this research lies in its medical implications. Exploiting critical period reopening can open new avenues for cognitive recovery from stroke, enhanced acquisition of motor control of a prosthetic, and reversal of early childhood disorders such as amblyopia (or “lazy eye”, in which vision in one eye is weak despite the eye being perfectly healthy) [9]. Emerging work over the past year from Krishnan, He, and colleagues now also links shifted critical periods to autism and autistic-like disorders such as Rett Syndrome [10, 11], a debilitating neurological disease of early childhood that affects 1 in 10,000 girls worldwide.

Molecular targets

While reopening critical periods in humans offers theoretical usefulness, how can we actually accomplish this? Genetically decreasing overall inhibition in the brain tends not to be a viable treatment option. Without inhibition to keep it in check, excitation would overrun the brain, leading to massive seizures and likely death. Thus, therapeutic targeting requires a greater understanding of the specific molecules involved in critical period regulation, and of how to direct therapies only to the desired brain circuits. Though removing inhibition from the brain would be lethal, targeting specific GABA receptors has proven feasible. Luckily, not all GABA receptors regulate critical period closure. Only one subtype of GABA receptor, the GABAA receptor, seems to significantly modify plasticity, but not all the GABAA receptors are the same. GABAA receptors can be made up of different subunits, and the specific combinations of these subunits provide varying levels of influence on critical period closure [12].

Another promising line of research comes out of the studies of Rett Syndrome, an autistic-like neurodevelopmental disorder. Altered expression of a single gene, MeCP2, causes Rett Syndrome [13], and the mouse model replicates the human disorder fairly well, providing a straightforward approach for examining functional changes relevant to the disorder. Recent research in a Rett Syndrome mouse model discovered that the main inhibitory neurons involved in critical period plasticity maturated earlier than normal in the visual cortex of animals with MeCP2 gene mutations [10]. Further, the visual critical period opened and closed earlier than normal in these mice, and could be restored by dampening inhibition [10], reminiscent of the foundational studies of critical period manipulation. Taken together, these data strongly implicate MeCP2 expression, and probably regulation, as a major molecular influence on the visual critical period.

Though the GABAA and MeCP2 pathways are only two of many possible candidates currently emerging as regulators of critical period, a major hurdle remains. Controlling the time course of critical periods depends on more than just altering the molecular pathways. Once the inhibitory circuitry matures, the inhibitory cells (parvalbumin (PV) cells) regulating critical period plasticity become enwrapped in a mesh of extracellular matrix proteins and adhesion molecules that basically form nets around the PV cells [14, 15]. These nets may physically constrict further plasticity of the inhibitory cells, holding the critical period window closed tightly in place. While molecular targets such as GABAA receptors and MeCP2 may represent promising targets for chemically restoring critical period plasticity, research into reversing the structural constraint has proven less fruitful.

Old brain, new tricks

The realization that critical periods could be manipulated and thus reopened brings to the table a new discussion of the mature and immature brain. A child’s brain differs so radically from that of the adult, for example, in receptor expression, in the balance of excitation and inhibition, and in the neuronal capacity for plasticity, that it can never be taken for granted that therapies successful for neuronal conditions in adults would be either safe or effective in children. However, understanding how the brain transitions from immaturity to maturity may blur these lines, holding the key to the possibility of turning back neural time and reopening our minds to cognitive malleability.

REFERENCES

  1. Wiesel, T.N. and D.H. Hubel, Single-cell responses in striate cortex of kittens deprived of vision in one eye. . J Neurophysiol, 1963. 26: p. 1003-17.
  2. Timney, B., The effects of early and late monocular deprivation on binocular depth perception in cats. Brain Res, 1983. 283(2-3): p. 235-43.
  3. Guire, E.S., M.E. Lickey and B. Gordon, Critical period for the monocular deprivation effect in rats: assessment with sweep visually evoked potentials. J Neurophysiol, 1999. 81(1): p. 121-8.
  4. Gordon, J.A. and M.P. Stryker, Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J Neurosci, 1996. 16(10): p. 3274-86.
  5. Timney, B., D.E. Mitchell and F. Giffin, The development of vision in cats after extended periods of dark-rearing. Exp Brain Res, 1978. 31(4): p. 547-60.
  6. Fagiolini, M., T. Pizzorusso, N. Berardi, L. Domenici and L. Maffei, Functional postnatal development of the rat primary visual cortex and the role of visual experience: dark rearing and monocular deprivation. Vision Res, 1994. 34(6): p. 709-20.
  7. Huang, Z.J., A. Kirkwood, T. Pizzorusso, V. Porciatti, B. Morales, M.F. Bear, L. Maffei and S. Tonegawa, BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell, 1999. 98(6): p. 739-55.
  8. Fagiolini, M., & Hensch, Inhibitory threshold for critical-period activation in primary visual cortex. Nature, 2000. 404(6774): p. 183-186.
  9. Hensch, T.K. and P.M. Bilimoria, Re-opening Windows: Manipulating Critical Periods for Brain Development. Cerebrum, 2012. 2012: p. 11.
  10. Krishnan, K., B.S. Wang, J. Lu, L. Wang, A. Maffei, J. Cang and Z.J. Huang, MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc Natl Acad Sci U S A, 2015. 112(34): p. E4782-91.
  11. He, L.J., N. Liu, T.L. Cheng, X.J. Chen, Y.D. Li, Y.S. Shu, Z.L. Qiu and X.H. Zhang, Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity. Nat Commun, 2014. 5: p. 5036.
  12. Hensch, T.K., Critical period plasticity in local cortical circuits. Nat Rev Neurosci, 2005. 6(11): p. 877-888.
  13. Amir, R.E., I.B. Van den Veyver, M. Wan, C.Q. Tran, U. Francke and H.Y. Zoghbi, Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet, 1999. 23(2): p. 185-8.
  14. Beurdeley, M., J. Spatazza, H.H. Lee, S. Sugiyama, C. Bernard, A.A. Di Nardo, T.K. Hensch and A. Prochiantz, Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci, 2012. 32(27): p. 9429-37.
  15. Mix, A., K. Hoppenrath and K. Funke, Reduction in cortical parvalbumin expression due to intermittent theta-burst stimulation correlates with maturation of the perineuronal nets in young rats. Dev Neurobiol, 2015. 75(1): p. 1-11.
Advertisements

Tags: , ,

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: