Neuroplasticity is the capacity of the central nervous system (CNS) to undergo structural and functional changes in response to environmental sensory experiences or even to adapt following injury (Ismail et al., 2017). Several genetic, molecular, and cellular mechanisms can modulate the synapses of neuronal circuits and cause functional improvement, loss, and/or behavioral changes (Johnston, 2009). The plasticity of the nervous tissue after stimuli or injury is more evident during the early postnatal period, i.e., a time window known as the critical period (CP) for neuroplasticity (Pascual-Leone et al., 2005). This short postnatal time window is characterized by heightened nervous system receptivity for adapting to stimuli provides a stable and long-term experiential foundation (Wiesel and Hubel, 1965).

Small rodents such as rats and mice have a lissencephalic brain with well-established primary sensory areas and have been used to investigate the CP for neuroplasticity (Stafford, 1984; Schlaggar et al., 1993; de Villers-Sidani et al., 2007). However, there is still no consensus on the time window start and end of all sensory areas. For instance, the CP for neuroplasticity of somatosensory (S1) may start at birth, i.e., P0 (Rice and Van Der Loos, 1977; Schlaggar et al., 1993), followed by visual (V1) and auditory (A1) areas (Stafford, 1984; Levine et al., 2017; Park et al., 2019).

Therefore, the CP for neuroplasticity can vary in accordance with the primary sensory areas related to different brain maps. In addition, environmental stimuli can influence the organization of S1, V1, and A1 in their respective sensorial maps. The effects of different stimuli and intrinsic mechanisms on the CNS have been investigated by several neuroscience researchers to establish the duration of the CP for neuroplasticity related to different primary sensory areas (Stafford, 1984; Goodman and Shatz, 1993; Schlaggar et al., 1993; Antonini et al., 1999; de Villers-Sidani et al., 2007, 2008; Fischer et al., 2007; Faguet et al., 2009; Zhou et al., 2011; Seelke et al., 2012; Levine et al., 2017; Park et al., 2019; van der Bourg et al., 2019). Considering the complexity of the CP for neuroplasticity and the respective time windows for each primary sensory area, preclinical studies can help to develop treatments for brain injuries such as the use of cochlear implants in cases of auditory deprivation (Kral, 2013). Therefore, this systematic review aimed to investigate and compare the time window of the CP for neuroplasticity in S1, V1, and A1 areas.

This systematic review aimed to assess the time windows of the CP for neuroplasticity in small rodents. The findings of selected studies indicated different time windows for each primary sensory area (S1, V1, and A1). The time window of the CP for neuroplasticity in the S1 area starts early, followed by A1 and V1 areas. S1 and A1 were found with the longest and shortest time windows, respectively. Moreover, the S1 completely and partially overlaps the A1 and V1 time windows of the CP, respectively (Figure 5).

Considering that the outcome of a systematic review depends on the methodological quality of the studies (Hooijmans et al., 2014), 10 domains were used to avoid a high risk of bias, and any essential domain was considered with a high risk of bias (Figures 3, 4). Both “blinding of caregivers and researchers” and “outcome assessor blinding” were considered “unclear” in most studies since some conditions or outcome assessments were not accurately detailed. However, these domains were not considered essential for assessing the methodological quality.

Although small rodents are widely used to investigate neuroplasticity, only 12 studies met the eligibility criteria (Figure 1). These animals are easy to handle, and their mechanisms of molecular glues or cellular events involved in the CP for neuroplasticity are very similar to those observed in large mammals (Reagan-Shaw et al., 2008). Thus, anatomical, physiological, and biochemical mechanisms investigated in experimental models with rats and mice have provided applicable findings regarding the time window of the CP for neuroplasticity (Reagan-Shaw et al., 2008).

The time window of the CP for neuroplasticity usually starts at neurogenesis followed by neuronal migration during the first postnatal week (Berry and Rogers, 1965). The time window in S1 starts earlier than in the V1 and A1 areas (Figure 5). The fundamental mechanisms of the brain formation of mice and rats are under continued debate. Thus, the early cortical patterning centers such as fibroblast growth factors (FGFs) have been suggested to define the border of each cortical area by controlling the expression of regulatory genes (Schubert et al., 2015). These genes encode cell adhesion molecules such as cadherins and axon guidance molecules such as ephrins, which characterize neocortex arealization (O'Leary and Wilkinson, 1999; Pallas, 2001). The shift of the gamma-aminobutyric acid (GABA) from excitatory to inhibitory activity is also an important subject (Represa and Ben-Ari, 2005). Furthermore, the end of the time window of the CP for neuroplasticity is modulated by GABAergic interneurons that restrict the pruning of excess connections: Hebbian Theory (Martens et al., 2015). In addition, environmental stimuli play an important role to connect the thalamocortical afferents to the correct cortical primary sensory area (Hanganu-Opatz, 2010). Interestingly, the peak of the time window of the CP for neuroplasticity may occur halfway of topographic map formation (Seelke et al., 2012) and at different moments from the first postnatal day in the S1, V1, and A1 areas (Figure 5).

This systematic review indicated that the time window of the CP for neuroplasticity in S1 starts at P0 (Figure 5) due to the influence of intrinsic and extrinsic factors. For instance, sensory deprivation at the early postnatal development of whiskers changes the functional and morphological organization of the barrel field (Schlaggar et al., 1993) and leads to adult-like anatomical and functional S1 map (Seelke et al., 2012). All findings related to the time window of the CP for neuroplasticity in S1 were found from P0 to P21. The endocannabinoid CB1 receptor and brain-derived neurotrophic factor (BDNF) may regulate the development of interneurons in a specific S1 subregion such as the barrel field, forelimb, hind limb, and trunk (Li et al., 2009; Seelke et al., 2012; van der Bourg et al., 2019).

The time window of the CP for neuroplasticity can simultaneously occur in different cortical areas. The CP for neuroplasticity in A1 only starts when the time window in S1 is already halfway (Figure 5), followed by the refinement of cerebral cortical responses and simultaneous significant changes in the cochlea (Kalish et al., 2020). Since the duration of the CP for neuroplasticity in A1 may not extend beyond the first month of postnatal life (Park et al., 2019), early auditory stimulus seems important for the development of binaural hearing (Polley et al., 2013). It is very complex to determine the time window of the CP for neuroplasticity in A1 since different sound levels stimulate only some specific subregions (de Villers-Sidani et al., 2008), and the inhibitory neuronal activity is involved in the bilateral hearing development and the maturation of auditory refinement responses that end within P11–P14 (Kalish et al., 2020). Similar to S1, the extension of the CP for neuroplasticity in A1 may occur due to environmental stimuli that modulate intrinsic mechanisms such as continuous BDNF downregulation and tropism change of GABA receptor subunits (Zhou et al., 2011; refer to Figure 5).

The time window of the CP for neuroplasticity ends in A1 when it virtually starts in V1 represented by the eyes of the small rodent opening at P14. Stafford (1984) reported that monocular deprivation causes severe effects from the second up to the fourth postnatal week. However, the reorganization of contralateral and ipsilateral eye pathways is less affected at P40 (Antonini et al., 1999). Similar to S1 and A1, the time window of the CP for neuroplasticity in V1 is very complex to understand since the regulatory molecules involved in the determination of binocular zone are very different from those related to the monocular zone (Fischer et al., 2007; Faguet et al., 2009; Levine et al., 2017). At the same time, the environmental visual stimulus also activates the expression of some immediate early genes (IEGs) related to neuroplasticity modulation (Mower et al., 2002; Taha et al., 2002).

The data available in the studies of this systematic review indicate that the time window of the CP for neuroplasticity (Table 1) remains unclear (Ribot et al., 2021) since this complex event involves several different knowledge subjects (Wang et al., 2010; Erzurumlu and Gaspar, 2012; Levelt and Hübener, 2012; Takesian et al., 2018). In addition, it involves different molecular, cellular, and morphological mechanisms in S1, A1, and V1 that are influenced by environmental stimuli. This background supports novel approaches for further clinical trials on the treatment of reversible sensory deprivations by using prostheses, implants, and robotic exoskeletons.

Although both the start and end of the time window of the CP for neuroplasticity in S1, V1, and A1 are still not precisely determined, this review roughly estimated the time window in the primary sensory areas of small rodents in the function of several intrinsic and extrinsic factors. In addition, S1 showed the longest time window of the CP for neuroplasticity followed by V1 and then A1. Due to its complexity and variability, the determination of both the start and end of the CP for neuroplasticity and the mechanisms involved is still unclear. Moreover, advanced clinical trials on therapies for neuronal dysfunctions are encouraged to better understand its clinical relevance for humans.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

CB contributed to the study concept and design, obtained funding, and performed supervision. LP, GC, and MC contributed to data acquisition. LP and GC contributed to the drafting of the manuscript. ID and CB contributed to critical revision for important intellectual content. All authors had full access to all data and took responsibility for the integrity of the information, text, and the accuracy of the analysis. All authors contributed to the article and approved the submitted version.

This review was financially supported by the National Council for Scientific and Technological Development (CNPq, grants 310054/2018-4, 447835/2014-9, 483404/2013-6, 444967/2020-6, and 444982/2020-5) and the Coordination for the Improvement of Higher Education Personnel (CAPES, grant PROCAD 21/2018).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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