Could therapeutic manipulation of critical periods of brain development benefit mental health?

Many critical periods of brain development occur during infancy and childhood. When these periods are switched on, the brain is plastic and neuronal circuits are shaped by environmental input — enabling the acquisition of sensory skills such as visual perception, motor skills and language, and higher cognitive processes. Brain plasticity during critical periods is also associated with a vulnerability to mental illness. The critical periods of brain development, the mechanisms controlling them, and therapeutic interventions that turn them on and off were described by Takao Hensch, Professor of Molecular and Cellular Biology, Harvard University, MA, in a fascinating plenary to a large attentive audience at IEPA 11.

Critical periods are windows of opportunity — but also windows of vulnerability

Brain circuits develop in response to environmental input during critical periods of the lifespan. If the brain circuit is not stimulated during a critical period, the brain function served by that circuit will be permanently compromised,1 explained Professor Hensch. For example, visual cortex connectivity and acuity are compromised if a child has amblyopia, but not if an adult loses sight in one eye.

Critical period anomalies are associated with schizophrenia and bipolar disorder

Cognitive functions remain plastic for some time. Critical periods are responsible for shaping sensory brain function first and then motor brain function and cognitive function. Cognitive functions remain plastic for some time. Many critical periods are being defined and they are probably as numerous as brain functions, said Professor Hensch.

Critical periods of brain development therefore represent:

  • windows of opportunity when the input enables the acquisition of skills
  • windows of vulnerability when the brain circuit is compromised and impairs sensory, motor and cognitive development — such critical periods are linked to the development of schizophrenia and bipolar disorder2,3

The triggers and brakes controlling the timing and duration of critical periods

New biological tools are revealing the triggers and brakes for critical periods, said Professor Hensch.

Schizophrenia is thought to be linked to oxidative stress in the PVI circuits that trigger critical periods

Surprisingly, critical periods are not controlled by the excitatory pyramidal neurons of the brain, which account for 80% of cerebral neurons, said Professor Hensch. Instead, they are controlled by the inhibitory gamma-aminobutyric acid (GABA)-secreting parvalbumin-containing interneurons (PVI), also known as basket cells. Secretion of GABA by these inhibitory interneurons switches on the critical periods.

Mental illnesses such as schizophrenia and bipolar disorer are associated with alterations in the PVI circuits, possibly due to oxidative stress.2,3

The onset of critical period brain plasticity is controlled by circadian clock genes4 and the PVIs mature at different times in different systems, added Professor Hensch. For example, the auditory critical period in mice occurs 15 days earlier than the optic critical period. He also noted that circadian rhythms are linked to a number of mental illnesses.

Critical periods can be switched on early or delayed, and extended or shortened

Critical periods are not fixed by chronological age, and critical period timing is itself plastic, continued Professor Hensch:

  • they can be switched on early (e.g. through pharmacological strengthening of GABA) or delayed (e.g. by dark rearing, which delays PVI development)5
  • their duration can be extended or shortened
  • their plasticity can be strengthened or dampened.

Professor Hensch then considered what might turn off the inhibitory circuits in adulthood. At least half a dozen brakes probably suppress plasticity, he said, including perineuronal nets (PNNs), which enwrap the PVI cells with increasing age. He suggested that although they turn off critical periods and their associated windows of opportunity, PNNs are beneficial because they protect PVIs by decreasing their vulnerability to oxidative stress.

Therapeutic manipulation of critical periods

A new critical period can be created by transplanting embryonic inhibitory neurons

Understanding the biological triggers and brakes responsible for the timing, duration and strength of critical periods enables their therapeutic manipulation:

  • to exploit their opportunity potential
  • to minimize their vulnerability potential
  • to re-awaken critical periods in adulthood to address neurodevelopmental disorders1 and brain injury

For example, transplanting embryonic inhibitory neurons into the adult mouse visual cortex reactivates critical period plasticity and creates a new critical period, restoring visual perception after childhood deprivation.6

References
  1. Hensch & Bilimoria. Cerebrum 2012. http://dana.org/Cerebrum/Default.aspx?id=39481. Accessed 16 October 2018.
  2. Steullet et al. Mol Psych 2017;22:936–43.
  3. Do et al. Schizo Bull 2015;41(4):835–6.
  4. Kobayashi et al. Neuron 2015;86(1):264–75.
  5. Hensch Nat Rev Neurosci 2005;6:877–88.
  6. Davis et al. Neuron 2015;86(4):1055–66.
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