Housing in Environmental Complexity Following Wheel Running Augments Survival of Newly-Generated Hippocampal Neurons in a Rat Model of Binge Alcohol Exposure during the Third Trimester Equivalent

Background Binge-like alcohol exposure in neonatal rats during the brain growth spurt causes deficits in adult neurogenesis in the hippocampal dentate gyrus (DG). Previous data from our lab demonstrated that twelve days of voluntary wheel-running (WR) beginning on postnatal day (PD) 30 significantly increased the number of newly-generated cells evident in the DG on PD42 in both alcohol-exposed and control rats, but 30 days later a sustained beneficial effect of WR was evident only in control rats. This study tested the hypothesis that housing rats in environmental complexity (EC) following WR would promote survival of the newly-generated cells stimulated by WR, particularly in alcohol-exposed rats. Methods On PD4-9, pups were intubated with alcohol in a binge-like manner (5.25g/kg/day), sham-intubated, or reared normally. In Experiment 1, animals were either assigned to WR during PD30-42 or were socially housed (SH). On PD42, animals were injected with bromodeoxyuridine (BrdU; 200mg/kg) and perfused two hours later to confirm the WR-induced stimulation of proliferation. In Experiment 2, all animals received WR on PD30-42 and were injected with BrdU on the last full day of WR. On PD42, animals were randomly assigned either to EC (WR/EC) or SH (WR/SH) for 30 days and subsequently perfused and brains were processed for immunohistochemical staining to identify BrdU+, Ki67+ and BrdU+/NeuN+ labeled cells in DG. Results In Exp. 1, WR exposure significantly increased the number of proliferating cells in all three postnatal conditions. In Exp. 2, the alcohol-exposed rats given WR/SH had significantly fewer BrdU+ cells compared to control rats given WR/SH. However, WR/EC experience significantly increased the number of surviving BrdU+ cells in both the alcohol-exposed and sham-intubated groups compared to WR/SH rats of the same neonatal treatment. Approximately 80% of the surviving BrdU+ cells in the DG across the conditions were co-labeled with NeuN. Conclusions WR followed by EC could provide a behavioral model for developing interventions in humans to ameliorate hippocampal-dependent impairments associated with fetal alcohol spectrum disorders

Three classes of inhibitory amino acid terminals in the cochlear nucleus of the guinea pig

Electron microscopic postembedding immunocytochemistry was used to analyze and assess the synaptic distribution of glycine (GLY) and γ-amino butyric acid (GABA) immunoreactivities in the guinea pig cochlear nucleus (CN). Three classes of endings were identified containing immunolabeling for glycine, GABA, or both glycine and GABA (GLY/GABA). All classes were similar in that the terminals contained pleomorphic vesicles and formed symmetric synapses with their postsynaptic targets. A fourth class, which labeled with neither antibody, contained round vesicles and formed asymmetric synapses. Glycine endings predominated in the ventral CN, while GLY/GABA endings were prevalent in the dorsal CN. GABA endings were the least common and smallest in size. Glycine, GLY/GABA, and GABA endings differed in their proportions and patterns of distribution on the different classes of projection neurons in the CN, including spherical bushy, type I stellate/multipolar, and octopus cells in the ventral CN and fusiform cells in the dorsal CN. The vast majority of anatomically-defined, putative inhibitory endings contain GLY, GABA, or both, suggesting that most of the inhibition in the cochlear nucleus is mediated by these three cytochemically and, probably, functionally distinct classes of endings. The results of this study also suggest that a large proportion of the GABA available for inhibition in the CN coexists in terminals with glycine. © 1996 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50069/1/2_ftp.pd

Early Motor Balance and Coordination Training Increased Synaptophysin in Subcortical Regions of the Ischemic Rat Brain

The aim of this study was to evaluate the effect of early motor balance and coordination training on functional recovery and brain plasticity in an ischemic rat stroke model, compared with simple locomotor exercise. Adult male Sprague-Dawley rats with cortical infarcts were trained under one of four conditions: nontrained control, treadmill training, motor training on the Rota-rod, or both Rota-rod and treadmill training. All types of training were performed from post-operation day 1 to 14. Neurological and behavioral performance was evaluated by Menzies' scale, the prehensile test, and the limb placement test, at post-operation day 1, 7, and 14. Both Rota-rod and treadmill training increased the expression of synaptophysin in subcortical regions of the ischemic hemisphere including the hippocampus, dentate gyrus, and thalamus, but did not affect levels of brain-derived neurotrophic factor or tyrosin kinase receptor B. The Rota-rod training also improved Menzies' scale and limb placement test scores, whereas the simple treadmill training did neither. The control group showed significant change only in Menzies' scale score. This study suggests that early motor balance and coordination training may induce plastic changes in subcortical regions of the ischemic hemisphere after stroke accompanied with the recovery of sensorimotor performance

How Memory Conforms to Brain Development

Nature exhibits countless examples of adaptive networks, whose topology evolves constantly coupled with the activity due to its function. The brain is an illustrative example of a system in which a dynamic complex network develops by the generation and pruning of synaptic contacts between neurons while memories are acquired and consolidated. Here, we consider a recently proposed brain developing model to study how mechanisms responsible for the evolution of brain structure affect and are affected by memory storage processes. Following recent experimental observations, we assume that the basic rules for adding and removing synapses depend on local synaptic currents at the respective neurons in addition to global mechanisms depending on the mean connectivity. In this way a feedback loop between “form” and “function” spontaneously emerges that influences the ability of the system to optimally store and retrieve sensory information in patterns of brain activity or memories. In particular, we report here that, as a consequence of such a feedback-loop, oscillations in the activity of the system among the memorized patterns can occur, depending on parameters, reminding mind dynamical processes. Such oscillations have their origin in the destabilization of memory attractors due to the pruning dynamics, which induces a kind of structural disorder or noise in the system at a long-term scale. This constantly modifies the synaptic disorder induced by the interference among the many patterns of activity memorized in the system. Such new intriguing oscillatory behavior is to be associated only to long-term synaptic mechanisms during the network evolution dynamics, and it does not depend on short-term synaptic processes, as assumed in other studies, that are not present in our model.Financial support from the Spanish Ministry of Science and Technology, and the Agencia Española de Investigación (AEI) under grant FIS2017-84256-P (FEDER funds) and from the Obra Social La Caixa (ID 100010434, with code LCF/BQ/ES15/10360004). This study has been also partially financed by the Consejería de Conocimiento, Investigación y Universidad, Junta de Andalucía and European Regional Development Fund (ERDF), with reference SOMM17/6105/UGR

Concurrence of form and function in developing networks and its role in synaptic pruning

A fundamental question in neuroscience is how structure and function of neural systems are related. We study this interplay by combining a familiar auto-associative neural network with an evolving mechanism for the birth and death of synapses. A feedback loop then arises leading to two qualitatively different types of behaviour. In one, the network structure becomes heterogeneous and dissasortative, and the system displays good memory performance; furthermore, the structure is optimised for the particular memory patterns stored during the process. In the other, the structure remains homogeneous and incapable of pattern retrieval. These findings provide an inspiring picture of brain structure and dynamics that is compatible with experimental results on early brain development, and may help to explain synaptic pruning. Other evolving networks—such as those of protein interactions—might share the basic ingredients for this feedback loop and other questions, and indeed many of their structural features are as predicted by our model.We are grateful for financial support from the Spanish MINECO (project of Excellence: FIS2017-84256-P) and from “Obra Social La Caixa”

Experience-Dependent Plasticity and Modulation of Growth Regulatory Molecules at Central Synapses

Structural remodeling or repair of neural circuits depends on the balance between intrinsic neuronal properties and regulatory cues present in the surrounding microenvironment. These processes are also influenced by experience, but it is still unclear how external stimuli modulate growth-regulatory mechanisms in the central nervous system. We asked whether environmental stimulation promotes neuronal plasticity by modifying the expression of growth-inhibitory molecules, specifically those of the extracellular matrix. We examined the effects of an enriched environment on neuritic remodeling and modulation of perineuronal nets in the deep cerebellar nuclei of adult mice. Perineuronal nets are meshworks of extracellular matrix that enwrap the neuronal perikaryon and restrict plasticity in the adult CNS. We found that exposure to an enriched environment induces significant morphological changes of Purkinje and precerebellar axon terminals in the cerebellar nuclei, accompanied by a conspicuous reduction of perineuronal nets. In the animals reared in an enriched environment, cerebellar nuclear neurons show decreased expression of mRNAs coding for key matrix components (as shown by real time PCR experiments), and enhanced activity of matrix degrading enzymes (matrix metalloproteinases 2 and 9), which was assessed by in situ zymography. Accordingly, we found that in mutant mice lacking a crucial perineuronal net component, cartilage link protein 1, perineuronal nets around cerebellar neurons are disrupted and plasticity of Purkinje cell terminal is enhanced. Moreover, all the effects of environmental stimulation are amplified if the afferent Purkinje axons are endowed with enhanced intrinsic growth capabilities, induced by overexpression of GAP-43. Our observations show that the maintenance and growth-inhibitory function of perineuronal nets are regulated by a dynamic interplay between pre- and postsynaptic neurons. External stimuli act on this interaction and shift the balance between synthesis and removal of matrix components in order to facilitate neuritic growth by locally dampening the activity of inhibitory cues

Effect of skilled and unskilled training on nerve regeneration and functional recovery

The most disabling aspect of human peripheral nerve injuries, the majority of which affect the upper limbs, is the loss of skilled hand movements. Activity-induced morphological and electrophysiological remodeling of the neuromuscular junction has been shown to influence nerve repair and functional recovery. In the current study, we determined the effects of two different treatments on the functional and morphological recovery after median and ulnar nerve injury. Adult Wistar male rats weighing 280 to 330 g at the time of surgery (N = 8-10 animals/group) were submitted to nerve crush and 1 week later began a 3-week course of motor rehabilitation involving either “skilled” (reaching for small food pellets) or “unskilled” (walking on a motorized treadmill) training. During this period, functional recovery was monitored weekly using staircase and cylinder tests. Histological and morphometric nerve analyses were used to assess nerve regeneration at the end of treatment. The functional evaluation demonstrated benefits of both tasks, but found no difference between them (P > 0.05). The unskilled training, however, induced a greater degree of nerve regeneration as evidenced by histological measurement (P < 0.05). These data provide evidence that both of the forelimb training tasks used in this study can accelerate functional recovery following brachial plexus injury

Long-Term Consequences of Developmental Alcohol Exposure on Brain Structure and Function: Therapeutic Benefits of Physical Activity

Developmental alcohol exposure both early in life and during adolescence can have a devastating impact on normal brain structure and functioning, leading to behavioral and cognitive impairments that persist throughout the lifespan. This review discusses human work as well as animal models used to investigate the effect of alcohol exposure at various time points during development, as well as specific behavioral and neuroanatomical deficits caused by alcohol exposure. Further, cellular and molecular mediators contributing to these alcohol-induced changes are examined, such as neurotrophic factors and apoptotic markers. Next, this review seeks to support the use of aerobic exercise as a potential therapeutic intervention for alcohol-related impairments. To date, few interventions, behavioral or pharmacological, have been proven effective in mitigating some alcohol-related deficits. Exercise is a simple therapy that can be used across species and also across socioeconomic status. It has a profoundly positive influence on many measures of learning and neuroplasticity; in particular, those measures damaged by alcohol exposure. This review discusses current evidence that exercise may mitigate damage caused by developmental alcohol exposure and is a promising therapeutic target for future research and intervention strategies