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from more cortical neurons (called hyperconnectivity), even when examined before ear opening. This suggests that the lack of sound inputs even before ear opening had caused circuit changes (Figure 3A).
Conversely, raising mice with background sounds before ear opening showed that the presence of sounds even before ear opening reduces connections to the subplate neurons (Meng et al., 2021). These bidirectional changes indicate that even though sound transmission and neural process- ing is immature at early ages, the auditory environment can already shape auditory cortical circuits. These experiments suggest that a lack of sound input leads to a compensatory increase in connections to subplate neurons and thereby can potentially alter subsequent developmental processes. Importantly, these experiments show that manipulating the sound experience before the onset of the “classic” critical period, which starts at the ear opening period, can alter the development of ACtx circuits (Meng et al., 2021).
The effects of the sound experience at the next stage of development, such as after ear opening, have been well studied, especially on circuits in layer 4 and beyond. This period starts when MGB fibers contact layer 4 neurons; sensory-evoked neural activity during this later stage of development when the eyes and ears function is piv- otal for shaping and fine-tuning brain circuits. Hence, it has been called the “critical period” but might be better labeled as the “L4 critical period.” Sound expo- sures during this time, for example, raising rodents in the presence of noise or tones from just before ear open- ing (in mice around postanal day 11 [P11]), resulted in altered frequency selectivity of ACtx neurons and abol- ished (Zhang et al., 2002) or altered (Zhang et al., 2001) tonotopic maps in the ACtx. All these sound exposures were effective during a period lasting less than a week following ear opening and therefore show that there is a limited period when L4 circuits seem to be malleable.
These results force us to rethink the early developmental period during which MGB axons are present in the sub- plate (Kostovic and Rakic, 1990) and when the cochlea is able to transduce sounds. This period is likely highly dynamic in that it involves circuit refinement and emer- gence of topographic maps (Figures 2C and 3B). Thus, this period represents a “proto-organizational period” in which an outline of cortical organization develops.
Accordingly, we can divide the early developmental pro- cess into three distinct phases (Figure 3B).
(1) Prehearing Period: No sensory evoked activity is present. Only spontaneous activity is present.
(2) Proto-Organizational Period: Sound-evoked activity is present and can drive plasticity in the subplate. Because of closed ear canals, sound thresholds are high. Peripheral spontaneous activity is also present but decreasing. Layer 4 is not directly acti- vated by MGB.
(3) Normal-Hearing Period: Sound-evoked activity is present. The MGB directly activates layer 4 and sound manipulations can cause layer 4 plastic- ity. The beginning of this period marks the classic critical period. Because of open ear canals, sound thresholds are low.
Clinical Implications of Early Sensory Effects on Cortical Circuits
Congenital hearing loss is a relatively common condition found in 1 in about 1,000 newborns and is of diverse origin (Chen and Oghalai, 2016). Long-term deafness results in large-scale and fine-scale changes in the ACtx and beyond. For example, adult congenitally deaf cats have a decreased cortical thickness in different audi- tory cortical regions (Berger et al., 2017), suggesting the atrophy of neurons and/or connections. Similarly, wide- spread changes in large-scale brain structure are also seen in humans with hearing loss (Manno et al., 2021). How- ever, we now know that deafness already results in brain changes at the younger ages (likely even before birth); thus the adult phenotype might be due to cascading and compounding changes throughout the development of cortical circuits.
The early susceptibility of subplate neurons to sound is important in the case of babies in the NICU where they are exposed to an abnormal sound environment. Care must be taken to adjust the ambient sensory environ- ment as to not overactivate or deprive cortical circuits. Moreover, these considerations are important in other contexts because in many prelingually deaf humans, cochlear implants (CIs) are fitted within the first years to restore hearing. The programming of these devices must consider that auditory cortical processing might already have been altered at time of implantation and is changing during the initial period of use.
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