Functional neuropathology of neonatal hypoxia-ischemia by single-mouse longitudinal electroencephalography.

OBJECTIVE: Neonatal cerebral hypoxia-ischemia (HI) results in symptomatic seizures and long-term neurodevelopmental disability. The Rice-Vannucci model of rodent neonatal HI has been used extensively to examine and translate the functional consequences of acute and chronic HI-induced encephalopathy. Yet, longitudinal electrophysiological characterization of this brain injury model has been limited by the size of the neonatal mouse's head and postnatal maternal dependency. We overcome this challenge by employing a novel method of longitudinal single-mouse electroencephalography (EEG) using chronically implanted subcranial electrodes in the term-equivalent mouse pup. We characterize the neurophysiological disturbances occurring during awake and sleep states in the acute and chronic phases following newborn brain injury. METHODS: C57BL/6 mice underwent long-term bilateral subcranial EEG and electromyographic electrode placement at postnatal day 9 followed by unilateral carotid cauterization and exposure to 40 minutes of hypoxia the following day. EEG recordings were obtained prior, during, and intermittently after the HI procedure from postnatal day 10 to weaning age. Quantitative EEG and fast Fourier transform analysis were used to evaluate seizures, cortical cerebral dysfunction, and disturbances in vigilance states. RESULTS: We observed neonatal HI-provoked electrographic focal and bilateral seizures during or immediately following global hypoxia and most commonly contralateral to the ischemic injury. Spontaneous chronic seizures were not seen. Injured mice developed long-term asymmetric EEG background attenuation in all frequencies and most prominently during non-rapid eye movement (NREM) sleep. HI mice also showed transient impairments in vigilance state duration and transitions during the first 2 days following injury. SIGNIFICANCE: The functional burden of mouse neonatal HI recorded by EEG resembles closely that of the injured human newborn. The use of single-mouse longitudinal EEG in this immature model can advance our understanding of the developmental and pathophysiological mechanisms of neonatal cerebral injury and help translate novel therapeutic strategies against this devastating condition.

Longitudinal analysis of developmental changes in electroencephalography patterns and sleep-wake states of the neonatal mouse.

The neonatal brain undergoes rapid maturational changes that facilitate the normal development of the nervous system and also affect the pathological response to brain injury. Electroencephalography (EEG) and analysis of sleep-wake vigilance states provide important insights into the function of the normal and diseased immature brain. While developmental changes in EEG and vigilance states are well-described in people, less is known about the normal maturational properties of rodent EEG, including the emergence and evolution of sleep-awake vigilance states. In particular, a number of developmental EEG studies have been performed in rats, but there is limited comparable research in neonatal mice, especially as it pertains to longitudinal EEG studies performed within the same mouse. In this study, we have attempted to provide a relatively comprehensive assessment of developmental changes in EEG background activity and vigilance states in wild-type mice from postnatal days 9-21. A novel EEG and EMG method allowed serial recording from the same mouse pups. EEG continuity and power and vigilance states were analyzed by quantitative assessment and fast Fourier transforms. During this developmental period, we demonstrate the timing of maturational changes in EEG background continuity, frequencies, and power and the emergence of identifiable wake, NREM, and REM sleep states. These results should serve as important control data for physiological studies of mouse models of normal brain development and neurological disease.