Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity

Abstract

Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in motor dysfunction and dopaminergic neuronal injury in the juvenile rat brain. To further examine whether neonatal LPS exposure has persisting effects in adult rats, motor behaviors were examined from postnatal day 7 (P7) to P70 and brain injury was determined in P70 rats following an intracerebral injection of LPS (1 mg/kg) in P5 Sprague-Dawley male rats. Although neonatal LPS exposure resulted in hyperactivity in locomotion and stereotyped tasks, and other disturbances of motor behaviors, the impaired motor functions were spontaneously recovered by P70. On the other hand, neonatal LPS-induced injury to the dopaminergic system such as the loss of dendrites and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra persisted in P70 rats. Neonatal LPS exposure also resulted in sustained inflammatory responses in the P70 rat brain, as indicated by an increased number of activated microglia and elevation of interleukin-1β and interleukin-6 content in the rat brain. In addition, when challenged with methamphetamine (METH, 0.5 mg/kg) subcutaneously, rats with neonatal LPS exposure had significantly increased responses in METH-induced locomotion and stereotypy behaviors as compared to those without LPS exposure. These results indicate that although neonatal LPSinduced neurobehavioral impairment is spontaneously recoverable, the LPS exposure-induced persistent injury to the dopaminergic system and the chronic inflammation may represent the existence of silent neurotoxicity. Our data further suggest that the compromised dendritic mitochondrial function might contribute, at least partially, to the silent neurotoxicity.

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

“…Specifically, adult nLPS males who received exposure to a three-day stress protocol (restraint stress, isolation stress) spent less time in the open arms (exhibiting anxiogenic effect) compared to nLPS females and all other treatment groups (Walker et al, 2009). Lastly, Fan et al (2011) reported that nLPS (P5) male and female rats on P21 showed anxiolytic effects (spent more time in the open arms) on the EPM compared to nSal controls (Fan et al, 2011). The anxiolytic effects observed have been previously seen by others (Imhof et al, 1993;Masur et al, 1980;Walker et al, 2004).…”

“…Kohman et al found that nLPS (P4 and P5) treated male mice performed significantly fewer avoidance responses than saline treated males in a two-way active avoidance paradigm, a finding not observed in nLPS treated females on P70 (Kohman et al, 2008a;Kohman et al, 2008b). In another study however, no sex effects were detected on performance in a passive avoidance test in P21 rats administered LPS intracerebrally (1 mg/kg) on P5 (Fan et al, 2011). The authors found learning and memory deficits on this task in both nLPS males and females relative to nSal controls.…”

“…Walker et al (2009) found that only nLPS (P3 and P5) male rats exposed to repeated stress over 3 days in adulthood were less active than male controls and female counterparts in an OFT (Walker et al, 2009). Hyperactivity in an OFT was observed in male and female nLPS (P5) treated rats on P13-P17 (Fan et al, 2011).…”

“…Neonatal immune activation has been associated with such psychiatric disorders as Alzheimer's disease, schizophrenia, cerebral palsy and autism (Garnier et al, 2003;Hornig et al, 1999;Huleihel et al, 2004;Nelson and Willoughby, 2000;Rantakallio et al, 1997;Shi et al, 2003). Cytoarchitectural changes can also be seen in the adult animals exposed to immunogen as neonates such as enlargement of bilateral ventricles and alterations in axonal and dendritic arborization in the parietal cortex and substantia nigra (Fan et al, 2011). Common functional deficits seen in rodent offspring exposed to prenatal or neonatal immune activation include cognitive and social dysfunctions (Bilbo et al, 2005;Bitanihirwe et al, 2010;Ibi et al, 2009;Wang et al, 2010).…”

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

“…One of the main alterations following perinatal infection/inflammation is a persistent low-grade inflammation characterized by higher expression of inflammatory mediators and also microglial reactivity during adulthood [236]. Adult rodent exposed during early-life to LPS-enhanced expression of CD11b, IL-1β and IL-6 and also more activated microglia in the hippocampus, the striatum and substantia nigra/ventral tegmental area [239,240]. This persistent low-grade inflammation sensitizes the brain to secondary injuries, which can lead to neurological disorders such as cerebral palsy, mood disorder, schizophrenia, or Parkinson disease [241].…”