Invited review: Neural network plasticity in respiratory control.

Respiratory network plasticity is a modification in respiratory control that persists longer than the stimuli that evoke it or that changes the behavior produced by the network. Different durations and patterns of hypoxia can induce different types of respiratory memories. Lateral pontine neurons are required for decreases in respiratory frequency that follow brief hypoxia. Changes in synchrony and firing rates of ventrolateral and midline medullary neurons may contribute to the long-term facilitation of breathing after brief intermittent hypoxia. Long-term changes in central respiratory motor control may occur after spinal cord injury, and the brain stem network implicated in the production of the respiratory rhythm could be reconfigured to produce the cough motor pattern. Preliminary analysis suggests that elements of brain stem respiratory neural networks respond differently to hypoxia and hypercapnia and interact with areas involved in cardiovascular control. Plasticity or alterations in these networks may contribute to the chronic upregulation of sympathetic nerve activity and hypertension in sleep apnea syndrome and may also be involved in sudden infant death syndrome.     

Long-term effects of the perinatal environment on respiratory control.

The respiratory control system exhibits considerable plasticity, similar to other regions of the nervous system. Plasticity is a persistent change in system behavior triggered by experiences such as changes in neural activity, hypoxia, and/or disease/injury. Although plasticity is observed in animals of all ages, some forms of plasticity appear to be unique to development (i.e., "developmental plasticity"). Developmental plasticity is an alteration in respiratory control induced by experiences during "critical" developmental periods; similar experiences outside the critical period will have little or no lasting effect. Thus complementary experiments on both mature and developing animals are generally needed to verify that the observed plasticity is unique to development. Frequently studied models of developmental plasticity in respiratory control include developmental manipulations of respiratory gas concentrations (O(2) and CO(2)). Environmental factors not specifically associated with breathing may also trigger developmental plasticity, however, including psychological stress or chemicals associated with maternal habits (e.g., nicotine, cocaine). Despite rapid advances in describing models of developmental plasticity in breathing, our understanding of fundamental mechanisms giving rise to such plasticity is poor; mechanistic studies of developmental plasticity are of considerable importance. Developmental plasticity may enable organisms to "fine tune" their phenotype to optimize the performance of this critical homeostatic regulatory system. On the other hand, developmental plasticity could also increase the risk of disease later in life. Future directions for studies concerning the mechanisms and functional implications of developmental plasticity in respiratory motor control are discussed.     

Invited review: Intermittent hypoxia and respiratory plasticity.

Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.     

ADAMTS expression and function in central nervous system injury and disorders

The components of the adult extracellular matrix in the central nervous system form a lattice-like structure that is deposited as perineuronal nets, around axon initial segments and as synapse-associated matrix. An abundant component of this matrix is the lecticans, chondroitin sulfate-bearing proteoglycans that are the major substrate for several members of the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) family. Since lecticans are key regulators of neural plasticity, ADAMTS cleavage of lecticans would likely also contribute to neuroplasticity. Indeed, many studies have examined the neuroplastic contribution of the ADAMTSs to damage and recovery after injury and in central nervous system disease. Much of this data supports a role for the ADAMTSs in recovery and repair following spinal cord injury by stimulating axonal outgrowth after degradation of a glial scar and improving synaptic plasticity following seizure-induced neural damage in the brain. The action of the ADAMTSs in chronic diseases of the central nervous system appears to be more complex and less well-defined. Increasing evidence indicates that lecticans participate in synaptic plasticity in neurodegenerative disease states. It will be interesting to examine how ADAMTS expression and action would affect the progression of these diseases.     

Spinal cord regeneration: A brief overview of the present scenario and a sneak peek into the future

The central nervous system (CNS) portrays appreciable complexity in developing from a neural tube to controlling major functions of the body and orchestrated co-ordination in maintaining its homeostasis. Any insult or pathology to such an organized tissue leads to a plethora of events ranging from local hypoxia, ischemia, oxidative stress to reactive gliosis and scarring. Despite unravelling the pathophysiology of spinal cord injury (SCI) and linked cellular and molecular mechanism, the over exhaustive inflammatory response at the site of injury, limited intrinsic regeneration capability of CNS, and the dual role of glial scar halts the expected accomplishment. The review discusses major current treatment approaches for traumatic SCI, addressing their limitation and scope for further development in the field under three main categories- neuroprotection, neuro-regeneration, and neuroplasticity. We further propose that a multi-disciplinary combinatorial treatment approach exploring any two or all three heads simultaneously might alleviate the inhibitory milieu and ameliorate functional recovery.     

Studies on Aplysia neurons suggest treatments for chronic human disorders

For decades, the marine snail Aplysia has proven to be a powerful system for analyzing basic neurobiological mechanisms, particularly cellular and molecular mechanisms of neural plasticity. Three new findings on Aplysia may be relevant for the understanding and treatment of chronic human disorders. This research on this simple molluscan nervous system may lead to new therapeutic approaches for spinal cord injury, Fragile X syndrome, and genetic learning deficits more generally.     

TGF-beta in neural stem cells and in tumors of the central nervous system

Mechanisms that regulate neural stem cell activity in the adult brain are tightly coordinated. They provide new neurons and glia in regions associated with high cellular and functional plasticity, after injury, or during neurodegeneration. Because of the proliferative and plastic potential of neural stem cells, they are currently thought to escape their physiological control mechanisms and transform to cancer stem cells. Signals provided by proteins of the transforming growth factor (TGF)-beta family might represent a system by which neural stem cells are controlled under physiological conditions but released from this control after transformation to cancer stem cells. TGF-beta is a multifunctional cytokine involved in various physiological and patho-physiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegeneration when it modulates and dampens inflammatory responses. After injury, although TGF-beta is neuroprotective, it may limit the self-repair of the brain by inhibiting neural stem cell proliferation. Similar to its effect on neural stem cells, TGF-beta reveals anti-proliferative control on most cell types; however, paradoxically, many brain tumors escape from TGF-beta control. Moreover, brain tumors develop mechanisms that change the anti-proliferative influence of TGF-beta into oncogenic cues, mainly by orchestrating a multitude of TGF-beta-mediated effects upon matrix, migration and invasion, angiogenesis, and, most importantly, immune escape mechanisms. Thus, TGF-beta is involved in tumor progression. This review focuses on TGF-beta and its role in the regulation and control of neural and of brain-cancer stem cells. This work was supported by the German Federal Ministry of Education and Research (BMBF no. 01GA0510 and no. 0312134) and by the Bavarian State Ministry of Sciences, Research and the Arts, "Forneurocell grant".     

Influence of the environment on adult CNS plasticity and repair

During developmental critical periods, external stimuli are crucial for information processing, acquisition of new functions or functional recovery after CNS damage. These phenomena depend on the capability of neurons to modify their functional properties and/or their connections, generally defined as "plasticity". Although plasticity decreases after the closure of critical periods, the adult CNS retains significant capabilities for structural remodelling and functional adaptation. At the molecular level, structural modifications of neural circuits depend on the balance between intrinsic growth properties of the involved neurons and growth-regulatory cues of the extracellular milieu. Interestingly, experience acts on this balance, so as to create permissive conditions for neuritic remodelling. Here, we present an overview of recent findings concerning the effects of experience on cellular and molecular processes responsible for producing structural plasticity of neural networks or functional recovery after an insult to the adult CNS (e.g. traumatic injury, ischemia or neurodegenerative disease). Understanding experience-dependent mechanisms is crucial for the development of tailored rehabilitative strategies, which can be exploited alone or in combination with specific therapeutic interventions to improve neural repair after damage.     

Neurobiology of exercise

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.     

Respiratory plasticity in response to changes in oxygen supply and demand

Aerobic organisms maintain O₂ homeostasis by responding to changesin O₂ supply and demand in both short and long time domains.In this review, we introduce several specific examples of respiratoryplasticity induced by chronic changes in O₂ supply (environmentalhypoxia or hyperoxia) and demand (exercise-induced and temperature-inducedchanges in aerobic metabolism). These studies reveal that plasticityoccurs throughout the respiratory system, including modificationsto the gas exchanger, respiratory pigments, respiratory muscles,and the neural control systems responsible for ventilating thegas exchanger. While some of these responses appear appropriate(e.g., increases in lung surface area, blood O₂ capacity, andpulmonary ventilation in hypoxia), other responses are potentiallyharmful (e.g., increased muscle fatigability). Thus, it maybe difficult to predict whole-animal performance based on theplasticity of a single system. Moreover, plastic responses maydiffer quantitatively and qualitatively at different developmentalstages. Much of the current research in this field is focusedon identifying the cellular and molecular mechanisms underlyingrespiratory plasticity. These studies suggest that a few keymolecules, such as hypoxia inducible factor (HIF) and erythropoietin,may be involved in the expression of diverse forms of plasticitywithin and across species. Studying the various ways in whichanimals respond to respiratory challenges will enable a betterunderstanding of the integrative response to chronic changesin O₂ supply and demand.     

Intermittent hypoxia: cell to system

This symposium was organized to present research dealing with the effects of intermittent hypoxia on cardiorespiratory systems and cellular mechanisms. The pattern of neural impulse activity has been shown to be critical in the induction of genes in neuronal cells and involves distinct signaling pathways. Mechanisms associated with different patterns of intermittent hypoxia might share similar mechanisms. Chronic intermittent hypoxia selectively augments carotid body sensitivity to hypoxia and causes long-lasting activation of sensory discharge. Intermittent hypoxia also activates hypoxia-inducible factor-1. Reactive oxygen species are critical in altering carotid body function and hypoxia-inducible factor-1 activation caused by intermittent hypoxia. Blockade of serotonin function in the spinal cord prevents long-term facilitation in respiratory motor output elicited by episodic hypoxia and requires de novo protein synthesis. Chronic intermittent hypoxia leads to sustained elevation in arterial blood pressure and is associated with upregulation of catecholaminergic and renin-angiotensin systems and downregulation of nitric oxide synthases.     

Heart rate during exercise with leg vascular occlusion in spinal cord-injured humans.

Feed-forward and feedback mechanisms are both important for control of the heart rate response to muscular exercise, but their origin and relative importance remain inadequately understood. To evaluate whether humoral mechanisms are of importance, the heart rate response to electrically induced cycling was studied in participants with spinal cord injury (SCI) and compared with that elicited during volitional cycling in able-bodied persons (C). During voluntary exercise at an oxygen uptake of approximately 1 l/min, heart rate increased from 66 +/- 4 to 86 +/- 4 (SE) beats/min in seven C, and during electrically induced exercise at a similar oxygen uptake in SCI it increased from 73 +/- 3 to 110 +/- 8 beats/min. In contrast, blood pressure increased only in C (from 88 +/- 3 to 99 +/- 4 mmHg), confirming that, during exercise, blood pressure control is dominated by peripheral neural feedback mechanisms. With vascular occlusion of the legs, the exercise-induced increase in heart rate was reduced or even eliminated in the electrically stimulated SCI. For C, heart rate tended to be lower than during exercise with free circulation to the legs. Release of the cuff elevated heart rate only in SCI. These data suggest that humoral feedback is of importance for the heart rate response to exercise and especially so when influence from the central nervous system and peripheral neural feedback from the working muscles are impaired or eliminated during electrically induced exercise in individuals with SCI.     

Spinal cord injury-induced changes in breathing are not due to supraspinal plasticity in turtles (Pseudemys scripta)

After occurrence of spinal cord injury, it is not known whether the respiratory rhythm generator undergoes plasticity to compensate for respiratory insufficiency. To test this hypothesis, respiratory variables were measured in adult semiaquatic turtles using a pneumotachograph attached to a breathing chamber on a water-filled tank. Turtles breathed room air (2 h) before being challenged with two consecutive 2-h bouts of hypercapnia (2 and 6% CO2 or 4 and 8% CO2). Turtles were spinalized at dorsal segments D8-D10 so that only pectoral girdle movement was used for breathing. Measurements were repeated at 4 and 8 wk postinjury. For turtles breathing room air, breathing frequency, tidal volume, and ventilation were not altered by spinalization; single-breath (singlet) frequency increased sevenfold. Spinalized turtles breathing 6-8% CO2 had lower ventilation due to decreased frequency and tidal volume, episodic breathing (breaths/episode) was reduced, and singlet breathing was increased sevenfold. Respiratory variables in sham-operated turtles were unaltered by surgery. Isolated brain stems from control, spinalized, and sham turtles produced similar respiratory motor output and responded the same to increased bath pH. Thus spinalized turtles compensated for pelvic girdle loss while breathing room air but were unable to compensate during hypercapnic challenges. Because isolated brain stems from control and spinalized turtles had similar respiratory motor output and chemosensitivity, breathing changes in spinalized turtles in vivo were probably not due to plasticity within the respiratory rhythm generator. Instead, caudal spinal cord damage probably disrupts spinobulbar pathways that are necessary for normal breathing.     

A Murine Model of Cervical Spinal Cord Injury to Study Post-lesional Respiratory Neuroplasticity

A cervical spinal cord injury induces permanent paralysis, and often leads to respiratory distress. To date, no efficient therapeutics have been developed to improve/ameliorate the respiratory failure following high cervical spinal cord injury (SCI). Here we propose a murine pre-clinical model of high SCI at the cervical 2 (C2) metameric level to study diverse post-lesional respiratory neuroplasticity. The technique consists of a surgical partial injury at the C2 level, which will induce a hemiparalysis of the diaphragm due to a deafferentation of the phrenic motoneurons from the respiratory centers located in the brainstem. The contralateral side of the injury remains intact and allows the animal recovery. Unlike other SCIs which affect the locomotor function (at the thoracic and lumbar level), the respiratory function does not require animal motivation and the quantification of the deficit/recovery can be easily performed (diaphragm and phrenic nerve recordings, whole body ventilation). This pre-clinical C2 SCI model is a powerful, useful, and reliable pre-clinical model to study various respiratory and non-respiratory neuroplasticity events at different levels (molecular to physiology) and to test diverse putative therapeutic strategies which might improve the respiration in SCI patients.     

Brain and spinal cord interaction: protective effects of exercise prior to spinal cord injury

We have investigated the effects of a spinal cord injury on the brain and spinal cord, and whether exercise provided before the injury could organize a protective reaction across the neuroaxis. Animals were exposed to 21 days of voluntary exercise, followed by a full spinal transection (T7-T9) and sacrificed two days later. Here we show that the effects of spinal cord injury go beyond the spinal cord itself and influence the molecular substrates of synaptic plasticity and learning in the brain. The injury reduced BDNF levels in the hippocampus in conjunction with the activated forms of p-synapsin I, p-CREB and p-CaMK II, while exercise prior to injury prevented these reductions. Similar effects of the injury were observed in the lumbar enlargement region of the spinal cord, where exercise prevented the reductions in BDNF, and p-CREB. Furthermore, the response of the hippocampus to the spinal lesion appeared to be coordinated to that of the spinal cord, as evidenced by corresponding injury-related changes in BDNF levels in the brain and spinal cord. These results provide an indication for the increased vulnerability of brain centers after spinal cord injury. These findings also imply that the level of chronic activity prior to a spinal cord injury could determine the level of sensory-motor and cognitive recovery following the injury. In particular, exercise prior to the injury onset appears to foster protective mechanisms in the brain and spinal cord.     

Molecular mechanisms of neuroplasticity: An expanding universe

Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different “hot points” in the research area of biochemical mechanisms supporting neuroplasticity.     

Ubiquitin proteasome system-mediated degradation of synaptic proteins: An update from the postsynaptic side

The ubiquitin proteasome system is one of the principle mechanisms for the regulation of protein homeostasis in mammalian cells. In dynamic cellular structures such as neuronal synapses, ubiquitin proteasome system and protein translation provide an efficient way for cells to respond promptly to local stimulation and regulate neuroplasticity. The majority of research related to long-term plasticity has been focused on the postsynapses and has shown that ubiquitination and subsequent degradation of specific proteins are involved in various activity-dependent plasticity events. This review summarizes recent achievements in understanding ubiquitination of postsynaptic proteins and its impact on synapse plasticity and discusses the direction for advancing future research in the field.     

Cervical spinal cord injury alters the pattern of breathing in anesthetized rats.

The mechanisms by which chronic cervical spinal cord injury alters respiratory function and plasticity are not well understood. We speculated that spinal hemisection at C(2) would alter the respiratory pattern controlled by vagal mechanisms. Expired volume (V(E)) and respiratory rate (RR) were measured in anesthetized control and C(2)-hemisected rats at 1 and 2 mo postinjury. C(2) hemisection altered the pattern of breathing at both postinjury time intervals. Injured rats utilized a higher RR and lower V(E) to maintain the same minute ventilation as control rats. After bilateral vagotomy, the pattern of breathing in injured rats was not different from controls. The frequency of augmented breaths was higher in injured rats at 2 mo postinjury before vagotomy; however, the V(E) of augmented breaths was not different between groups. In conclusion, C(2) hemisection alters the pattern of breathing at 1 and 2 mo postinjury via vagal mechanisms.