Cardiac arrest-induced global brain hypoxia-ischemia during development affects spontaneous activity organization in rat sensory and motor thalamocortical circuits during adulthood

Normal maturation of sensory information processing in the cortex requires patterned synaptic activity during developmentally regulated critical periods. During early development, spontaneous synaptic activity establishes required patterns of synaptic input, and during later development it influences patterns of sensory experience-dependent neuronal firing. Thalamocortical neurons occupy a critical position in regulating the flow of patterned sensory information from the periphery to the cortex. Abnormal thalamocortical inputs may permanently affect the organization and function of cortical neuronal circuits, especially if they occur during a critical developmental window. We examined the effect of cardiac arrest (CA)-associated global brain hypoxia-ischemia in developing rats on spontaneous and evoked firing of somatosensory thalamocortical neurons and on large-scale correlations in the motor thalamocortical circuit. The mean spontaneous and sensory-evoked firing rate activity and variability were higher in CA injured rats. Furthermore, spontaneous and sensory-evoked activity and variability were correlated in uninjured rats, but not correlated in neurons from CA rats. Abnormal activity patterns of ventroposterior medial nucleus (VPm) neurons persisted into adulthood. Additionally, we found that neurons in the entopeduncular nucleus (EPN) in the basal ganglia had lower firing rates yet had higher variability and higher levels of burst firing after injury. Correlated levels of power in local field potentials (LFPs) between the EPN and the motor cortex (MCx) were also disrupted by injury. Our findings indicate that hypoxic-ischemic injury during development leads to abnormal spontaneous and sensory stimulus-evoked input patterns from thalamus to cortex. Abnormal thalamic inputs likely permanently and detrimentally affect the organization of cortical circuitry and processing of sensory information. Hypoxic-ischemic injury also leads to abnormal single neuron and population level activity in the basal ganglia that may contribute to motor dysfunction after injury. Combination of deficits in sensory and motor thalamocortical circuit function may negatively impact sensorimotor integration in CA survivors. Modulation of abnormal activity patterns post-injury may represent a novel therapeutic target to improve neurologic function in survivors

Long-term deficits in cortical circuit function after asphyxial cardiac arrest and resuscitation in developing rats

AbstractCardiac arrest is a common cause of global hypoxic-ischemic brain injury. Poor neurologic outcome among cardiac arrest survivors results not only from direct cellular injury but also from subsequent long-term dysfunction of neuronal circuits. Here, we investigated the long-term impact of cardiac arrest during development on the function of cortical layer IV (L4) barrel circuits in the rat primary somatosensory cortex. We used multielectrode single-neuron recordings to examine responses of presumed excitatory L4 barrel neurons to controlled whisker stimuli in adult (8 ± 2-mo-old) rats that had undergone 9 min of asphyxial cardiac arrest and resuscitation during the third postnatal week. Results indicate that responses to deflections of the topographically appropriate principal whisker (PW) are smaller in magnitude in cardiac arrest survivors than in control rats. Responses to adjacent whisker (AW) deflections are similar in magnitude between the two groups. Because of a disproportionate decrease in PW-evoked responses, receptive fields of L4 barrel neurons are less spatially focused in cardiac arrest survivors than in control rats. In addition, spiking activity among L4 barrel neurons is more correlated in cardiac arrest survivors than in controls. Computational modeling demonstrates that experimentally observed disruptions in barrel circuit function after cardiac arrest can emerge from a balanced increase in background excitatory and inhibitory conductances in L4 neurons. Experimental and modeling data together suggest that after a hypoxic-ischemic insult, cortical sensory circuits are less responsive and less spatially tuned. Modulation of these deficits may represent a therapeutic approach to improving neurologic outcome after cardiac arrest.</jats:p

Emergency Neurological Life Support: Intracranial Hypertension and Herniation

Sustained intracranial hypertension and acute brain herniation are “brain codes,” signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, a brain code mandates the organized implementation of a stepwise management algorithm. The goal of this emergency neurological life support protocol is to implement an evidence-based, standardized approach to the evaluation and management of patients with intracranial hypertension and/or herniation

Thalamocortical dysfunction and thalamic injury after asphyxial cardiac arrest in developing rats

Global hypoxia-ischemia interrupts oxygen delivery and blood flow to the entire brain. Previous studies of global brain hypoxia ischemia have primarily focused on injury to the cerebral cortex and to the hippocampus. Susceptible neuronal populations also include inhibitory neurons in the thalamic Reticular Nucleus. We therefore investigated the impact of global brain hypoxia-ischemia on the thalamic circuit function in the somatosensory system of young rats. We used single neuron recordings and controlled whisker deflections to examine responses of thalamocortical neurons to sensory stimulation in rat survivors of 9 min of asphyxial cardiac arrest incurred on post-natal day 17. We found that 48–72 hours after cardiac arrest, thalamocortical neurons demonstrate significantly elevated firing rates both during spontaneous activity and in response to whisker deflections. The elevated evoked firing rates persist for at least 6–8 weeks after injury. Despite the overall increase in firing, by 6 weeks, thalamocortical neurons display degraded receptive fields, with decreased responses to adjacent whiskers. Nine min of asphyxial cardiac arrest was associated with extensive degeneration of neurites in the somatosensory nucleus as well as activation of microglia in the Reticular Nucleus. Global brain hypoxia-ischemia during cardiac arrest has a long-term impact on processing and transfer of sensory information by thalamic circuitry. Thalamic circuitry and normalization of its function may represent a distinct therapeutic target after cardiac arrest

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest–derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre(+);Rb1(fl/fl) mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS

Organization of sensory feature selectivity in the whisker system

Our sensory receptors are faced with an onslaught of different environmental inputs. Each sensory event or encounter with an object involves a distinct combination of physical energy sources impinging upon receptors. In the rodent whisker system, each primary afferent neuron located in the trigeminal ganglion innervates and responds to a single whisker and encodes a distinct set of physical stimulus properties – features – corresponding to changes in whisker angle and shape and the consequent forces acting on the whisker follicle. Here we review the nature of the features encoded by successive stages of processing along the whisker pathway. At each stage different neurons respond to distinct features, such that the population as a whole represents diverse properties. Different neuronal types also have distinct feature selectivity. Thus, neurons at the same stage of processing and responding to the same whisker nevertheless play different roles in representing objects contacted by the whisker. This diversity, combined with the precise timing and high reliability of responses, enables populations at each stage to represent a wide range of stimuli. Cortical neurons respond to more complex stimulus properties – such as correlated motion across whiskers – than those at early subcortical stages. Temporal integration along the pathway is comparatively weak: neurons up to barrel cortex are sensitive mainly to fast (tens of milliseconds) fluctuations in whisker motion. The topographic organization of whisker sensitivity is paralleled by systematic organization of neuronal selectivity to certain other physical features, but selectivity to touch and to dynamic stimulus properties is distributed in “salt-and-pepper” fashion

Neonatal and Pediatric Cerebro-Cardiopulmonary Resuscitation

Pediatric resuscitation medicine has witnessed significant advances with improved understanding of the pathophysiology of cardiac arrest and resuscitation. Multiple mechanisms of neurological injury have been identified, outlining potential avenues for neuroprotection following cardiac arrest. Resuscitation science exists at multiple levels of analysis, from biomechanics of chest compressions to implementation of best training procedures in real time, from epidemiology of cardiac arrest survival to molecular mechanisms of cellular injury due to ischemia and reperfusion. What next steps in research and in clinical practice will ensure the best possible neurologic outcome among children who survive cardiac arrest? How can we leverage novel technologies in neuroimaging, nanomaterials, drug delivery, biomarker-based risk stratification and next generation sequencing, among others, to resuscitate and to protect the Central Nervous System (CNS)? How can we improve clinical trial design and data analyses to maintain a robust clinical research infrastructure and to ensure validity and applicability? These are just some of the questions will addressed in this Research Topic. Using evidence-based algorithms and public health approaches to disseminate them, the last decade has seen a paradigm shift in pediatric resuscitation with significantly improved survival from pediatric cardiac arrests. However, neurologic outcome in survivors remains far from optimal. High quality CPR is increasingly recognized as a key factor for improving neurologic outcomes. Advanced technologies allow monitoring the quality of CPR and just-in-time feedback to improve the quality of CPR. Further research is needed to evaluate impact of these technologies on neurologic outcome. The recent American Heart Association CPR guidelines emphasis on Circulation-Airway-Breathing (CAB) approach to CPR needs a careful evaluation in children, in whom timely airway and breathing support are as important as circulation. The growing controversy regarding use of epinephrine, and alternative routes of administration of epinephrine during CPR, warrants further evaluation in the setting of pediatric CPR. Improved outcome of hemodynamic goal-directed CPR over standard CPR in animal models of cardiac arrest has initiated interest in physiology-based CPR, especially in the in-hospital cardiac arrest. Basic and applied-science research have become relevant for specific subpopulations of pediatric cardiac arrest victims and circumstances (e.g., ventricular fibrillation, neonates, congenital heart disease, extracorporeal cardiopulmonary resuscitation). Just-in-time and just-in-place simulation training, which have evolved as training strategies to improve quality of CPR, are being evaluated for outcomes. The concept of just-in-time and just-in-place coaching of CPR providers on high quality CPR is a novel concept which has emerged recently and remains unstudied. Whilst there have been significant advances in newborn stabilization over the last decade many questions remain unanswered. These include the role of delayed cord clamping in preterm infants and term newborns requiring resuscitation, the role of sustained inflations as a method of respiratory support and the role of epinephrine and volume administration in neonatal resuscitation. Novel methods of assessment including the use of end tidal CO2 monitoring, respiratory function monitoring and near infrared spectroscopy warrant further evaluation. The use of transitioning animal models that accurately replicate the newborn circulation with patent fetal shunts are emerging but more assessments in these are required to better establish CPR strategies in newborn infants. Newborn resuscitation training programs have resulted in a reduction in neonatal mortality in the developing world, but key questions remain around the frequency of training, team training methods and the role of simulation training. Post resuscitation interventions, in particular therapeutic hypothermia, has resulted in significant improvements in long-term outcome and there is now a growing interest in adjunct therapies, such as use of melatonin, erythropoietin, or other neuroprotective molecules to improve therapeutic benefits of cooling. Therapeutic hypothermia did not provide any higher benefit than normothermia in children following out of hospital cardiac arrest, although three is considerable debate in the community whether 14% probability of observing a similar outcome if the study were repeated a 100 times applies to an individual child in the PICU. Exciting research is occurring in unraveling connection between inflammation, immune dysregulation and neuroinjury. This will further support research on the use of anti-inflammatory agents and immunomodulators for neuroprotection after cardiac arrest and birth asphyxia