Cardiac Arrest-Induced Global Brain Hypoxia-Ischemia during Development Affects Spontaneous Activity Organization in Rat Sensory and Motor Thalamocortical Circuits during Adulthood.

Michael Shoykhet,Jason W Middleton

doi:10.3389/fncir.2016.00068

Abstract

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.

Highlights

Acute brain injury disrupts sensory processing, motor function, cognition and behavior in survivors (Volpe et al, 1984; Graves et al, 1997; Schreckinger et al, 2007)
We previously reported that coherence between entopeduncular nucleus (EPN) and motor cortex (MCx) local field potential (LFP) is decreased in CA survivors
Disruption of these mechanisms during different developmental periods by neuronal injury can have long lasting functional consequences as we have observed in a model of pediatric hypoxia-induced ischemic injury

Summary

Introduction

Acute brain injury (e.g., hypoxia-ischemia due to stroke or cardiac arrest [CA]) disrupts sensory processing, motor function, cognition and behavior in survivors (Volpe et al, 1984; Graves et al, 1997; Schreckinger et al, 2007). In order to develop better therapeutic and rehabilitative interventions, we must understand how neural injury during development affects maturation and functional organization of neuronal circuits in adulthood. Evidence that ongoing spontaneous activity during development exerts a lasting effect on the organization and function of neuronal circuits in adulthood has emerged from both sensory and motor systems. Before the onset of visual experience, retinal ganglion cells fire spontaneous bursts of action potentials that contribute to coherent propagating waves of activity across the retina (Wong et al, 1993). These waves can engage burst-dependent Hebbian synaptic plasticity rules to refine retinogeniculate synapses (Butts et al, 2007). In the developing motor cortex (MCx), spontaneous gamma and spindle bursts correlate with motor and sensory inputs associated with movement (An et al, 2014)

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