Rats were given bilateral lesions of the motor cortex on the day of birth (P1), tenth day of life (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Although all lesion groups were impaired at skilled reaching, the P10 group was less impaired than either of the other two lesion groups. Furthermore, on the other motor tests the P10 group did not differ from controls whereas both P1 and adult groups were impaired. Only the P1 lesion group was impaired at the acquisition of the Morris water task. Anatomical analyses revealed that the P1 and P10 rats had smaller brains than the other two groups as well as having a generalized decrease in cortical thickness. Dendritic analysis of layer III pyramidal cells in the parietal cortex revealed a decrease in apical arbor in the lesion groups and an increase in the basilar arbor of the P1 and adult lesion animals. The P1 and adult operated groups showed an increase in spine density in the basilar dendrites of layer V pyramidal cells. Finally, analysis of the pattern of corticospinal projections revealed that the P1 animals had a markedly wider field of corticospinal projection neurons than any of the other groups. The widespread anatomical changes in all lesion groups versus the relatively better behavioral recovery after P10 lesions suggests that day 10 represents an optimal period for adapting to brain damage and subsequent brain reorganization.
"The long-standing Kennard Principle states that lesions in infancy are associated with more complete recovery than in adults (Dennis, 2010). More recent work, however , has found that a subset of early insults may be especially devastating (Kolb et al., 2000) because, in addition to the injury, there is a longer-term derailment of developmental programs, due in part to the consequence of critical-period plasticity. Additional work is required to fully elucidate time windows and factors that balance the potential for increased recovery with the increased vulnerability of the immature brain (Anderson et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Much progress has been made in understanding how behavioral experience and neural activity can modify the structure and function of neural circuits during development and in the adult brain. Studies of physiological and molecular mechanisms underlying activity-dependent plasticity in animal models have suggested potential therapeutic approaches for a wide range of brain disorders in humans. Physiological and electrical stimulations as well as plasticity-modifying molecular agents may facilitate functional recovery by selectively enhancing existing neural circuits or promoting the formation of new functional circuits. Here, we review the advances in basic studies of neural plasticity mechanisms in developing and adult nervous systems and current clinical treatments that harness neural plasticity, and we offer perspectives on future development of plasticity-based therapy.
"Kolb and colleagues describe qualitatively different changes in distribution of synapses in young and old animals housed in complex environments and those provided with tactile stimulation, with these morphological responses paralleled by behavioural enhancement (Kolb and Gibb, 2001). Benefits were more robust for animals injured earlier (which were more severely impaired) than those injured later (which had better spontaneous recovery) (Kolb et al., 2000a). Timing of environmental manipulation post-injury is critical, with little impact acutely, but better recovery associated with exposure to an enriched environment after the acute recovery period (Giza et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Plasticity is an intrinsic property of the central nervous system, reflecting its capacity to respond in a dynamic manner to the environment and experience via modification of neural circuitry. In the context of healthy development, plasticity is considered beneficial, facilitating adaptive change in response to environmental stimuli and enrichment, with research documenting establishment of new neural connections and modification to the mapping between neural activity and behaviour. Less is known about the impact of this plasticity in the context of the young, injured brain. This review seeks to explore plasticity processes in the context of early brain insult, taking into account historical perspectives and building on recent advances in knowledge regarding ongoing development and recovery following early brain insult, with a major emphasis on neurobehavioural domains. We were particularly interested to explore the way in which plasticity processes respond to early brain insult, the implications for functional recovery and how this literature contributes to the debate between localization of brain function and neural network models. To this end we have provided an overview of normal brain development, followed by a description of the biological mechanisms associated with the most common childhood brain insults, in order to explore an evidence base for considering the competing theoretical perspectives of early plasticity and early vulnerability. We then detail these theories and the way in which they contribute to our understanding of the consequences of early brain insult. Finally, we examine evidence that considers key factors (e.g. insult severity, age at insult, environment) that may act, either independently or synergistically, to influence recovery processes and ultimate outcome. We conclude that neither plasticity nor vulnerability theories are able to explain the range of functional outcomes from early brain insult. Rather, they represent extremes along a 'recovery continuum'. Where a child's outcome falls along this continuum depends on injury factors (severity, nature, age) and environmental influences (family, sociodemographic factors, interventions).
"In particular, the therapeutic properties of A2AR antagonists may arise from their ability to produce a brain state with greater potential to respond to insult, a state similar to the early neonatal period. In studies comparing the effects of brain injury at PND 1, PND 10 and in adults, optimal recovery occurs from lesions produced at PND 10 (Kolb et al., 2000; Gonzalez et al., 2003). This timeline for optimal reorganization parallels the developmental pattern of IEG expression in the current study. "
[Show abstract][Hide abstract] ABSTRACT: Activity regulated cytoskeletal protein (Arc), c-fos and zif268 are immediate early genes (IEGs) important for adult brain plasticity. We examined developmental expression of these IEGs and the effect of neonatal noradrenergic lesion on their expression in developing and mature brain. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a specific noradrenergic neurotoxin, was administered to rats on postnatal day (PND) 3 and in situ hybridization was used to assay Arc, c-fos and zif268 mRNA on PND 13, 25 and 60. In contrast to decreases in Arc, c-fos and zif268 expression produced by noradrenergic lesions of mature brain, lesions on PND 3 yield a strikingly different effect. Neonatal lesions produce increases in c-fos and zif268 expression in specific frontal cortical layers on PND 13, while Arc shows no change. These lesions lead to increases in zif268 expression in frontal cortical layers on PND 25, with no changes in c-fos or Arc expression, and on PND 60 they produce a significant increase in c-fos expression in hippocampus with no significant changes in Arc or zif268 expression. 2-[2-(2-Methoxy-1,4-benzodioxanyl)]imidazoline hydrochloride (RX821002), an alpha-2 adrenergic receptor (A2AR) antagonist, administered to control PND 60 animals produces elevations of Arc, zif268 and c-fos mRNAs. This response was eliminated in animals lesioned with DSP-4 on PND 3. These data indicate that norepinephrine regulation of IEG expression differs in developing and mature brain and that loss of developmental norepinephrine leads to abnormally high postnatal IEG expression. Previous studies have shown an important role for norepinephrine in brain development. Our data support the idea that norepinephrine plays an important role during CNS development and that changes in noradrenergic signaling during development may have long lasting effects, potentially on learning and memory.
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