Sensitive periods: phases of heightened plasticity
Developing brain circuits are particularly susceptible to external
influences due to their high levels of neuroplasticity. The complex and
more recently evolved circuitries of the human brain are risky targets
of insults because of their complex gene–environment interactions and
their intricate integration into brain circuits established earlier in
development. Susceptibility to adverse impact is neither temporarily
constant nor topographically linear across brain areas but strongly
depends on specific windows of heightened plasticity that underlie the
staggered brain maturation. Such sensitive periods vary across different
brain regions and functions, yet share many important mechanisms and
components.
Sensitive periods in neurodevelopment are crucial for shaping the
brain´s structure and function. Disruptions during these periods due to
genetic, environmental, or epigenetic factors can be devastating and
increase the risk of developmental disorders. This is due to immature
organisms adapting to environmental insults during sensitive periods by
incorporating information permanently into their mature structure and
function. This is in contrast to mature organisms that compensate
insults by plastic responses in order to accommodate or buffer changes
in the environment (Andersen, 2003). Consequently, focusing on
neuroplastic, developmental processes that establish sensitive periods
thereby contributing to the emergence of complex traits offer a
different rationale than the classical genes-”for ”-paradigm.
Moreover, understanding the interplay between sensitive periods and the
progression of neurodevelopmental disorders like schizophrenia can help
identify temporal windows for intervention and prevention strategies
during which certain drugs (e.g., benzodiazepines or amphetamines) are
particularly effective.
Sensitive periods can be subdivided into an initiation/opening phase, a
plasticity phase, and a closing phase. Although, the boundaries between
these phases are floating, the opening and the closing phase are clearly
driven by differing phase-specific processes that ensure directionality.
The onset of a sensitive period is usually triggered by a combination of
environmental and genetic factors. Environmental factors refer to
stimuli that are quite specific to the nature of the neural circuit in
question, while genetic parameters include neurotrophic factors,
hormones, transcription factors, and neurotransmitters. During the
plastic phase, the ratio of excitatory to inhibitory synapses is
crucial. The excitatory/inhibitory ratio decreases due to the maturation
of GABAergic parvalbumin interneurons that innervate pyramidal cells.
The rise in inhibitory activity significantly contributes to the
sharpening and fine-tuning of cortical excitability as well as to the
synchronizing of neuronal networks and evocation of gamma oscillations.
Gamma oscillations facilitate complex cognitive functions, such as
working memory and attention that continue to improve well into
adulthood. While maturation proceeds, GABAergic signaling further
increases thereby suppressing spontaneous, stimulus-irrelevant activity
in favor of stimulus-driven inputs.
The plastic phase is strongly influenced by extrinsic cues that increase
the signal-to-noise ratio and contribute to the reliability and
efficiency of stimulus-evoked circuit activity (Hensch, 2005). Moreover,
synaptic pruning contributes to the refinement and specialization of
neural circuits for specific functions by reducing redundant synapses,
strengthening relevant connections, and increasing accuracy by
minimizing background noise. Pruning is mediated by genes of the
complement system and other microglia-related genes that promote
phagocytosis by microglia, genes of the major histocompatibility complex
(MHC), proteolytic enzymes that degrade extracellular matrix components
thereby facilitating the removal of synapses, and cytokines and
chemokines that are expressed on microglia.
Eventually, the closure phase of the sensitive period is characterized
by a stabilization of synapses. Synapses that have been reinforced by
activation are stabilized by means of cell adhesion molecules that align
pre- and postsynapses and consolidate synaptic connections. At the same
time, molecular inhibitors are upregulated. When a circuit becomes
efficient and reliable, stabilization occurs. This ensures consistent
and optimized neural responses (and adaptive behavioral responses) to
specific stimuli. The stabilization is achieved by preventing further
plasticity by means of reduction of excessive pruning and rewiring. This
last stage of the sensitive period is accomplished by the implementation
of physical barriers to pruning and outgrowth, such as the formation of
perineuronal nets on cell bodies and myelination of axons (Takesian &
Hensch, 2013).