Critical periods are developmental windows in which circuits
Critical periods are developmental windows in which circuits are more plastic and may be sculpted by the environment or experience (Hensch, 2005). A circuit or brain region might be considered mature when greater stability is achieved after a period of experience-dependent sculpting during an earlier critical period (Takesian and Hensch, 2013). The best-studied model of the developmental transition from plasticity to stability is the purchase ha peptide of primary visual cortex to monocular deprivation (Espinosa and Stryker, 2012). It remains an open question whether there is a critical period in associative cortices, particularly in frontal cortex circuits. There is some evidence that the frontal cortex may remain plastic to some degree throughout the lifespan in response to environmental conditions such as enrichment (Kolb et al., 2003), stress (McEwen and Morrison, 2013), or learning (Lai et al., 2012; Munoz-Cuevas et al., 2013; Johnson et al., 2016). To further the understanding of typical and pathological frontal cortex development, it is important to map the timecourse of plasticity in subcircuits connecting the frontal cortex. By identifying circuits that are reorganizing at different developmental stages, we may better understand when subcircuits are more vulnerable to adverse experiences or when developmental changes may unmask pre-existing pathology (Paus et al., 2008).
In the current study, we use two-photon microscopy to perform longitudinal imaging of limbic circuits proposed to be important for decision-making (Bechara et al., 1999; Kim and Ragozzino, 2005; Johnson and Wilbrecht, 2011; Sul et al., 2011; Gremel and Costa, 2013; Izquierdo et al., 2013; Luk and Wallis, 2013; Johnson et al., 2016). These subcircuits include long-range axonal projections to dorsomedial frontal cortex (dmPFC) from the basolateral amygdala (BLA) and the orbitofronal cortex (OFC). We also study the apical dendrites of local dmPFC layer 5 pyramidal cells. The dmPFC is an accessible frontal subregion including secondary motor cortex (M2) and frontal association area (FrA) (Franklin and Paxinos, 2008) and is implicated in associative learning (Sul et al., 2011; Lai et al., 2012). We observe these different subcircuits in the dmPFC during two developmental time windows, the late juvenile and early adult period. The juvenile period we selected (postnatal days 24–28) is when rodents transition to independence after weaning and can be considered analogous to late childhood in humans. The young adult period we selected (P64–68) is a time when we have previously shown that dmPFC dependent decision-making strategies differ from the juvenile period (Johnson and Wilbrecht, 2011). Here, we show that intermingled circuits within the dmPFC show unique patterns of change in density, plasticity, and stability before and after the adolescent transition.
Materials and methods
Discussion We labeled specific subcircuits in the limbic-frontal affective system and used chronic two-photon microscopy to follow the density and stability of axons and dendrites in the living brains of juvenile and adult mice. We measured the gain and loss of pre-synaptic boutons and post-synaptic spines, and measured the length of axonal and dendritic tips across time. We replicated the finding from human and rodent studies that dendritic spines show net pruning across this peri-adolescent period (Huttenlocher and Dabholkar, 1997; Zuo et al., 2005; Majewska et al., 2006; Petanjek et al., 2011). Critically, we show that pruning is not the universal developmental pattern for excitatory subcircuits in the frontal cortex. We found that long-range BLA→dmPFC axons increased their bouton density across this time period, while the density of boutons on OFC→dmPFC axons remained stable over the juvenile to adult transition. Furthermore, while both dmPFC spines and OFC boutons showed greater daily gains and losses in juvenile animals, BLA boutons were gained at a greater rate in adult mice, indicating late developmental enhancement of plasticity for the BLA→dmPFC circuit. Taken together, we show that neural processes present within the same cortical territory follow unique patterns of maturation.