Our previous study showed that treatment with α-phenyl-n-tert-butyl-nitrone (PBN) after exposure to lipopolysaccharide (LPS) reduced LPS-induced white matter injury in the neonatal rat brain.The object of the current study was to further examine whether PBN has long-lasting protective effects and ameliorates LPS-induced neurological dysfunction. Intracerebral (i.c.) injection of LPS (1 mg/kg) was performed in postnatal day (P) 5 Sprague Dawley rat pups and PBN (100 mg/kg) or saline was administered intraperitoneally 5 min after LPS injection. The control rats were injected (i.c.) with sterile saline. Neurobehavioral tests were carried out from P3 to P21, and brain injury was examined after these tests. LPS exposure resulted in severe brain damage, including enlargement of ventricles bilaterally, loss of mature oligodendrocytes, impaired myelination as indicated by the decrease in myelin basic protein immunostaining, and alterations in dendritic processes in the cortical gray matter of the parietal cortex. Electron microscopic examination showed that LPS exposure caused impaired myelination as indicated by the disintegrated myelin sheaths in the juvenile rat brain. LPS administration also significantly affected neurobehavioral functions such as performance in righting reflex, wire hanging maneuver, cliff avoidance, negative geotaxis, vibrissa-elicited forelimb-placing test, beam walking, and gait test. Treatment with PBN, a free radical scavenger and antioxidant, provided protection against LPS-induced brain injury and associated neurological dysfunction in juvenile rats, suggesting that antioxidation might be an effective approach for therapeutic treatment of neonatal brain injury induced by infection/ inflammation. Keywordswhite matter injury; lipopolysaccharide; impaired myelination; neurobehavioral performance; antioxidant Maternal or placental infection plays an important role in the pathogenesis of periventricular leukomalacia (PVL), a form of white matter disease closely associated with cerebral palsy (Hagberg et al., 2002;Rezaie and Dean, 2002;Volpe, 2003 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript damage to developing oligodendrocytes (OLs) during a specific prenatal window of vulnerability (24-32 weeks' gestation) as a significant underlying factor in the pathogenesis of PVL is usually accompanied by the development of several types of lesions within the central nervous system in the infant brain (Back et al., 2001(Back et al., , 2002Rezaie and Dean, 2002). Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, is responsible for most of the inflammatory effects of infection from these bacteria. LPS has been detected in amniotic fluid of patients with gram-negative intra-amniotic infection (Romero et al., 1987). It is possible the LPS may reach the fetal brain during maternal infection. Therefore, LPS has been extensively used to study the possible link between inflammation and perinatal brain injury with different ways of administration ...
Key points The locus coeruleus (LC) contains noradrenergic (NA) neurons that respond to novel stimuli in the environment with phasic activation to initiate an orienting response; phasic LC activation is also triggered by stimuli, representing the outcome of task‐related decision processes, to facilitate ensuing behaviours and help optimize task performance. Here, we report that LC‐NA neurons exhibit bursts of action potentials in vitro resembling phasic LC activation in vivo, and the activity is gated by inhibitory interneurons (I‐INs) located in the peri‐LC. We also observe that inhibition of peri‐LC I‐INs enhances prepulse inhibition and axons from cortical areas that play important roles in evaluating the cost/reward of a stimulus synapse on both peri‐LC I‐INs and LC‐NA neurons. The results help us understand the cellular mechanisms underlying the generation and regulation of phasic LC activation with a focus on the role of peri‐LC I‐INs. Abstract Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behaviour or stimuli representing the outcome of task‐related decision processes to facilitate ensuing behaviours and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. We report here that LC‐NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation‐pause profile observed in animals. The activity was referred to as phasic‐like activity (PLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory–inhibitory balance of the circuit. In support of this notion, we located a population of inhibitory interneurons (I‐INs) in the medial part of the peri‐LC that exerted feedforward inhibition of LC‐NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri‐LC I‐INs with chemogenetic methods could enhance PLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri‐LC I‐INs and LC‐NA neurons. These observations demonstrate functional roles of peri‐LC I‐INs in integrating inputs of the frontal cortex onto LC‐NA neurons and gating the phasic LC output.
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