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).