Margaret T. T. Wong-Riley

He is an excellent clinician and researcher with extensive

The landmark studies of Wiesel and Hubel in the 1960's initiated a surge of investigations into the critical period of visual cortical development, when abnormal visual experience can alter cortical structures and functions. Most studies focused on the visual cortex, with relatively little attention to subcortical structures. The goal of the present review is to elucidate neurochemical and synaptic mechanisms common to the critical periods of the visual cortex and the brain stem respiratory system in thenormalrat. In both regions, the critical period is a time of (i) heightened inhibition; (ii)reducedexpression of brain-derived neurotrophic factor (BDNF); and (iii)synaptic imbalance, with heightened inhibition and suppressed excitation. The last two mechanisms are contrary to the conventional premise. Synaptic imbalance renders developing neurons more vulnerable to external stressors. However, the critical period isnecessaryto enable each system to strengthen its circuitry, adapt to its environment, and transition from immaturity to maturity, when a state of relative synaptic balance is attained. Failure to achieve such a balance leads to neurological disorders.

Key points: With daily electrophysiological recordings and neurochemical analysis, we uncovered a transient period of synaptic imbalance between enhanced inhibition and suppressed excitation in rat visual cortical neurons from the end of the fourth toward the end of the fifth postnatal weeks. The expression of brain‐derived neurotrophic factor (BDNF), which normally enhances excitation and suppresses inhibition, was down‐regulated during that time, suggesting that this may contribute to the inhibition/excitation imbalance. An agonist of the BDNF receptor tropomyosin‐related kinase B (TrkB) partially reversed the imbalance, whereas a TrkB antagonist accentuated the imbalance during the transient period. Monocular lid suture during the transient period is more detrimental to the function and neurochemical properties of visual cortical neurons than before or after this period. We regard the period of synaptic imbalance as the peak critical period of vulnerability, and its existence is necessary for neurons to transition from immaturity to a more mature state of functioning. The mammalian visual cortex is immature at birth and undergoes postnatal structural and functional adjustments. The exact timing of the vulnerable period in rodents remains unclear. The critical period is characterized by inhibitory GABAergic maturation reportedly dependent on brain‐derived neurotrophic factor (BDNF). However, most of the studies were performed on experimental/transgenic animals, questioning the relationship in normal animals. The present study aimed to conduct in‐depth analyses of the synaptic and neurochemical development of visual cortical neurons in normal and monocularly‐deprived rats and to determine specific changes, if any, during the critical period. We found that (i) against a gradual increase in excitation and inhibition with age, a transient period of synaptic and neurochemical imbalance existed with suppressed excitation and enhanced inhibition at postnatal days 28 to 33/34; (ii) during this window, the expression of BDNF and tropomyosin‐related kinase B (TrkB) receptors decreased, along with glutamatergic GluN1 and GluA1 receptors and the metabolic marker cytochrome oxidase, whereas that of GABA_ARα1 receptors continued to rise; (iii) monocular deprivation reduced both excitatory and inhibitory synaptic activity and neurochemicals mainly during this period; and (iv) in vivo TrkB agonist partially reversed the synaptic imbalance in normal and monocularly‐deprived neurons during this time, whereas a TrkB antagonist accentuated the imbalance. Thus, our findings highlight a transitory period of synaptic imbalance with a negative relationship between BDNF and inhibitory GABA. This brief critical period may be necessary in transitioning from an immature to a more mature state of visual cortical functioning.

We have identified a critical period of respiratory development in rats at postnatal days P12-13, when inhibitory influence dominates and when the response to hypoxia is at its weakest. This critical period has significant implications for Sudden Infant Death Syndrome (SIDS), the cause of which remains elusive. One of the known risk factors for SIDS is prematurity. A common intervention used in premature infants is hyperoxic therapy, which, if prolonged, can alter the ventilatory response to hypoxia and induce sustained inhibition of lung alveolar growth and pulmonary remodeling. The goal of this study was to test our hypothesis that neonatal hyperoxia from postnatal day (P) 0 to P10 in rat pups perturbs the critical period by altering the normal progression of neurochemical development in brain stem respiratory-related nuclei. An in-depth, semiquantitative immunohistochemical study was undertaken at P10 (immediately after hyperoxia and before the critical period), P12 (during the critical period), P14 (immediately after the critical period), and P17 (a week after the cessation of hyperoxia). In agreement with our previous findings, levels of cytochrome oxidase, brain-derived neurotrophic factor (BDNF), TrkB (BDNF receptor), and several serotonergic proteins (5-HT_1A and _2A receptors, 5-HT synthesizing enzyme tryptophan hydroxylase [TPH], and serotonin transporter [SERT]) all fell in several brain stem respiratory-related nuclei during the critical period (P12) in control animals. However, in hyperoxic animals, these neurochemicals exhibited a significant fall at P14 instead. Thus, neonatal hyperoxia delayed but did not eliminate the critical period of postnatal development in multiple brain stem respiratory-related nuclei, with little effect on the nonrespiratory cuneate nucleus.

Light-tissue interactions are an important aspect of low-level laser therapy (LLLT). The biological effect, the depth to which light reaches, and other issues result from these interactions. Light dosimetry is also important because it is how we can compare different treatments and optimize the parameters. This chapter intends to present an overview of the main topics related to light- tissue interactions and light dosimetry.

The critical period of respiratory development in rats is a narrow window toward the end of the second postnatal week (P12–13), when abrupt neurochemical, electrophysiological, and ventilatory changes occur, when inhibition dominates over excitation, and when the animals’ response to hypoxia is the weakest. The goal of this study was to further test our hypothesis that a major mechanism underlying the synaptic imbalance during the critical period is a reduced expression of brain‐derived neurotrophic factor (BDNF) and its TrkB receptors. Our aims were to determine (1) that the inhibitory dominance observed in hypoglossal motoneurons during the critical period was also demonstrable in a key respiratory chemosensor, NTS_VL; (2) if in vivo application of a TrkB agonist, 7,8‐DHF, would prevent, but a TrkB antagonist, ANA‐12, would accentuate the synaptic imbalance; and (3) if hypoxia would also heighten the imbalance. Our results indicate that (1) the synaptic imbalance was evident in the NTS_VL during the critical period; (2) intraperitoneal injections of 7,8‐DHF prevented the synaptic imbalance during the critical period, whereas ANA‐12 in vivo accentuated such an imbalance; and (3) acute hypoxia induced the weakest response in both the amplitude and frequency of sEPSCs during the critical period, but it increased the frequency of sIPSCs during the critical period. Thus, our findings are consistent with and strengthen our hypothesis that BDNF and TrkB play a significant role in inducing a synaptic imbalance during the critical period of respiratory development in the rat.