Chapter 1 - Balancing Plasticity/Stability Across Brain Development
Introduction
Neural circuits are shaped by experience—the potency of which changes dynamically across the lifespan. A focus on the cellular and molecular bases of these changes has begun to unravel mechanisms, which control the onset and closure of such “critical periods” for plasticity. This work in animal models offers new insight for tapping into the brain’s potential to rewire both in the clinic and classroom. Two important concepts have emerged (Fig. 1A):
- (1)
Excitatory–inhibitory (E–I) circuit balance is a trigger. The classical enduring loss of visual acuity (amblyopia) due to altered visual input early in life fails to occur when inhibitory function is compromised (Hensch, 2005). Specific GABA circuit maturation underlies the onset timing of plasticity and is shifted across brain regions consistent with the cascading nature of critical periods. Notably, premature gain of function by pharmacological agents can trigger premature onset, while genetic disruptions lead to a delay. These manipulations are so powerful that they can determine whether an animal is before, at the peak, or past a plastic window. Thus, critical period timing per se is plastic.
- (2)
Molecular “brakes” limit adult plasticity. While it is possible that plasticity factors are simply more abundant early in life, an emerging view is that the brain is intrinsically plastic, and one of the outcomes of normal development is then to stabilize the neural networks that are initially sculpted by experience. This is demonstrated most clearly by the late expression of brake-like factors beyond the critical period, which act to limit excessive circuit rewiring (Bavelier et al., 2010). These factors include structural brakes which physically prevent neurite pruning and outgrowth, and functional brakes acting on neuromodulatory systems. Their removal unmasks potent plasticity in adulthood, which can be used to correct neurodevelopmental disorders.
It is increasingly clear that the cortex does not adhere to a simplified model of shifting between plastic and nonplastic states. Instead, transitions in and out of critical periods might reflect shifts in plasticity sites or mechanisms (Wang et al., 2012) due to evolving molecular factors or changes in cortical activity patterns (Toyoizumi et al., 2013). Here, we review recent findings primarily in the visual cortex and discuss how these principles may apply more broadly.
Section snippets
Critical Periods: Pruning Circuits by Early Experience
Critical periods have been observed in various systems across species (Hensch, 2004). Primary sensory areas in particular—the brain’s first filters to the outside world—exhibit especially striking examples of experience-dependent plasticity during defined windows of early life. Such periods are needed to establish an optimal neural representation of the surrounding environment to guide future action. Given the extraordinary biological resources that must be devoted to rewiring neural circuitry,
Critical Period Plasticity of Excitatory and Inhibitory Circuits
The precise response to developmental experience reflects dynamic excitatory and inhibitory circuits displaying transient changes following sensory manipulation (Feldman, 2009, Hooks and Chen, 2007, Levelt and Hübener, 2012). Studying these dynamics has provided new insight into both the induction and expression of critical period plasticity (Fig. 1B).
Inhibitory Control of Plasticity
Directly manipulating inhibitory transmission leads to shifts in the timing of the critical period for ocular dominance plasticity (Hensch, 2005). Critical period onset is accelerated by activating GABAA inhibitory receptors prematurely with benzodiazepines (Fagiolini and Hensch, 2000, Fagiolini et al., 2003, Hensch et al., 1998, Iwai et al., 2003), or by promoting inhibitory circuit maturation (Di Cristo et al., 2007, Hanover et al., 1999, Huang et al., 1999, Sugiyama et al., 2008). Instead,
How do PV Circuits Control Plasticity?
Although it is clear that PV cells are a central hub controlling critical period timing, the way in which these cells regulate plasticity remains elusive. Recent studies have proposed that a transient suppression of PV cells may gate cortical plasticity. For example, excitatory drive onto PV cells is reduced by ~ 70% as rapidly as 1 day after monocular deprivation during the critical period (Aton et al., 2013, Kuhlman et al., 2013, Yazaki-Sugiyama et al., 2009). Mimicking a transient 24 h
Mental Disorders
The realization that critical period timing is itself plastic offers insight into neurodevelopmental disorders. Targeting these molecular triggers and brakes may offer therapeutic strategies to reinstate plasticity when it is inappropriately timed or fails to close properly. In the postmortem schizophrenic brain, deficient myelination, reduced perisomatic GABA synapses, and excessive spine pruning are commonly observed (Insel, 2010). Moreover, PNNs are compromised in the amygdala and prefrontal
Future Directions
Neural circuits are molded early in life to best represent the sensory input arriving at that time, and then eventually become hard-wired. The use of a molecular/genetic approach has revealed that specific GABA circuits orchestrate the functional and structural rewiring of neural networks during “critical periods” of cortical plasticity, which become limited in adulthood by the further expression of “brake-like” factors. Ongoing work focuses on (1) confirming to what extent these mechanisms
Acknowledgments
Supported by the Canadian Institute for Advanced Research (A. E. T., T. K. H.) and the Nancy Lurie Marks Family Foundation (A. E. T.).
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