Breathing is essential to life. At birth, the brain quickly adapts and learns to control breathing in different situations. This adaptability is called neuroplasticity. Most breathing-related adjustments in the brain are short-term, like breathing faster during exercise. The brain can also learn from prior experience to prepare for future situations. For example, intermittent exposure to low oxygen causes long-term changes in signals from the brain to muscles controlling breathing, which may help them prepare for future low oxygen situations. This is called long-term facilitation (LTF). This neuroplasticity may also help the brain to compensate or stabilize breathing during an illness or injury.

Illnesses shortly after birth can affect how the brain controls breathing and may contribute to respiratory diseases later in life. They may also have lasting effects on the ability to of the brain to learn and respond to stress, and may even contribute to psychiatric disorders or age-related cognitive decline.

Now, Hocker et al. show that inflammation shortly after birth has effects on breathing control that extend into adulthood. In the experiments, rats were injected four days after birth with either saline solution or a drug causing inflammation. When the rats grew into adults, their ability to make long-term breathing adjustments, or LTF, was assessed. In the rats exposed to early life inflammation two important pathways that enable LTF were eliminated. One pathway was restored when the rats received an anti-inflammatory treatment. Activating nerve cells reinstated the other pathway, suggesting these cells are not impaired.

The experiments suggest inflammation during early life impairs breathing control later on and may contribute to adult respiratory disease. Inflammation is common among infants in their first year, particularly among those born prematurely. This early-life inflammation may put them at risk of diseases associated with breathing control, like sleep apnoea, later in life. More studies are needed to understand the relationship between early life inflammation, respiratory control, and respiratory disease later in life.

At birth, neonates transition from a sterile maternal environment into an environment filled with pathogens, microbes, and toxins and must simultaneously begin robust, rhythmic breathing. Respiratory problems represent a significant clinical problem for neonatologists (Martin et al., 2012), especially in preterm infants where breathing is unstable (Poets and Southall, 1994; Poets et al., 1994) and infections are common (Stoll et al., 2002; Stoll et al., 2004). Further, inflammation appears to augment respiratory dysfunction in neonates, whereby inflammation depresses hypoxic responses (Olsson et al., 2003; Rourke et al., 2016) and induces recurrent apneas (Hofstetter et al., 2007). Despite the prevalence of early life inflammation, little is known about the long-lasting consequences of neonatal inflammation on adult neurorespiratory control.

We are beginning to understand the potential for long-term consequences of early life inflammation in other physiological systems. Neonatal inflammation blunts adult immune function (Bilbo et al., 2010; Mouihate et al., 2010; Spencer et al., 2011), increases adult stress reactivity (Shanks et al., 2000; Wang et al., 2013; Grace et al., 2014), impairs adult learning and hippocampal plasticity (Bilbo, 2005a; Bilbo et al., 2006), increases the risk of neuropsychiatric disorders (Rantakallio et al., 1997; Hornig et al., 1999), and worsens age-related cognitive decline (Bilbo, 2010). Yet, we know very little about the long-term effects of neonatal inflammation on adult neurorespiratory control.

Respiratory plasticity is an important feature of the neural control of breathing, providing adaptability and maintenance of breathing when the respiratory system is challenged (Fuller and Mitchell, 2017). Phrenic long-term facilitation (pLTF) is a frequently studied adult model of respiratory motor plasticity (Mitchell and Johnson, 2003) and is elicited by at least two distinct cellular signaling pathways: the Q-pathway and the S-pathway (reviewed in Dale-Nagle et al., 2010). The Q-pathway is evoked by moderate acute intermittent hypoxia (mAIH; 3 × 5 min hypoxic episodes, PaO₂35–45 mmHg) and is serotonin dependent, while the S-pathway is evoked by severe AIH (sAIH, PaO₂25–35 mmHg) and is adenosine dependent (Nichols et al., 2012). Interestingly, Q-pathway-evoked plasticity is undermined by even low levels of acute, adult, systemic inflammation and restored by the non-steroidal anti-inflammatory, ketoprofen (Vinit et al., 2011; Huxtable et al., 2013; Hocker and Huxtable, 2018), while S-pathway-evoked adult plasticity is inflammation resistant (Agosto-Marlin et al., 2017). Though we are beginning to understand more about the mechanisms of acute, adult inflammation on respiratory motor plasticity (Hocker et al., 2017; Hocker and Huxtable, 2018), we do not know how inflammation in early postnatal life impacts respiratory motor plasticity in the adult. Furthermore, few studies have investigated sex-differences in pLTF (Behan et al., 2002; Dougherty et al., 2017) and we know even less about sex-differences in respiratory control in response to inflammation. Additionally, males are more sensitive acutely to neonatal inflammation leading to higher male mortality in neonates (Bouman et al., 2005; Kentner et al., 2010; Rathod et al., 2017), but our understanding of other sex-differences after neonatal inflammation are unknown. Given the profound effects of neonatal inflammation on other physiological systems, we tested the hypothesis that neonatal inflammation undermines Q-pathway, but not S-pathway, respiratory motor plasticity in adult male and female rats.

Our results indicate that one neonatal inflammatory challenge completely abolishes adult, AIH-induced Q-pathway and S-pathway respiratory motor plasticity. Despite no lasting increases in adult, inflammatory gene expression, Q-pathway impairment is inflammation-dependent and is restored by acute adult anti-inflammatory treatment. Conversely, S-pathway impairment is inflammation-independent, but can be evoked by intermittent adenosine receptor agonism, suggesting phrenic motor neurons are not impaired. Since astrocytes are a primary source of adenosine during hypoxia (Takahashi et al., 2010; Angelova et al., 2015), they are likely impaired by neonatal inflammation and contributing to impairment of respiratory plasticity. These studies are the first steps toward understanding the lasting effects of neonatal inflammation on adult respiratory plasticity and suggest neonatal inflammation induces lasting-changes, increasing susceptibility to adult ventilatory control disorders.

Although neonatal inflammation is common (Stoll et al., 2002; Stoll et al., 2004), little is known concerning how neonatal inflammation alters ventilatory control. Here, we investigated the long-term consequences of neonatal systemic inflammation on adult respiratory motor plasticity, a key feature of the neural control of breathing providing adaptability to respiratory system challenges (Mitchell and Johnson, 2003). We show for the first time that a single inflammatory challenge to neonates completely abolishes AIH-induced Q-pathway and S-pathway-evoked respiratory motor plasticity in adult males and females. Our results indicate a persistent change in adult inflammatory signaling contributes to this impairment since adult anti-inflammatory treatment restores Q-pathway-evoked, but not S-pathway-evoked, pLTF. Further, this is the first evidence of impairment of S-pathway-evoked motor plasticity, suggesting neonatal inflammation likely leads to a further vulnerable adult as this pathway was thought of as a ‘backup pathway’ after acute, adult inflammation (Agosto-Marlin et al., 2017). However, we demonstrate S-pathway plasticity can be revealed by intermittent, spinal adenosine receptor agonism, suggesting astrocyte dysfunction after neonatal inflammation since they are the likely source of adenosine during hypoxia (Takahashi et al., 2010; Angelova et al., 2015). These studies are the first steps toward understanding the lasting effects of neonatal inflammation on adult neurorespiratory control and suggest neonatal inflammation may increase susceptibility to adult ventilatory control disorders.

LPS-induced neonatal inflammation transiently upregulates cytokines in regions involved in respiratory control and plasticity (N. Morrison, S. Johnson, J. Watters, A. Huxtable, unpublished observations), consistent with inflammatory profiles in other CNS regions (Wang et al., 2006; Schwarz and Bilbo, 2011; Bilbo and Schwarz, 2012; Jafri et al., 2013). Neonatal inflammation also increases male mortality, consistent with clinical male mortality after neonatal inflammation (Person et al., 2014) and is relevant to the increased risk of sudden infant death syndrome for males (Kinney and Thach, 2009). However, similar to other studies (Bilbo et al., 2005b; Mouihate et al., 2010; Smith et al., 2014), we found no measurable adult changes in cytokines, or glial number or morphology despite a lasting inflammation-dependent impairment in Q-pathway-evoked pLTF. While we have previously demonstrated adult Q-pathway pLTF is sensitive to low levels of acute, systemic inflammation (Huxtable et al., 2011; Huxtable et al., 2013; Huxtable et al., 2015; Huxtable et al., 2018a; Vinit et al., 2011; Hocker and Huxtable, 2018), this is the first study to demonstrate neonatal inflammation induces lasting changes in inflammatory signaling to undermine adult Q-pathway-evoked pLTF. Additionally, S-pathway-evoked pLTF is not restored by even the high dose of ketoprofen used here, but is revealed by intermittent adenosine 2A receptor agonism on phrenic motor neurons (Seven et al., 2018). Thus, these results indicate phrenic motor neurons are not impaired after neonatal inflammation and the loss of S-pathway-evoked plasticity is likely due to impaired adenosine signaling during hypoxia. Furthermore, a likely source of adenosine during hypoxia is astrocytes (Takahashi et al., 2010; Angelova et al., 2015), suggesting neonatal inflammation induces lasting astrocyte-specific changes in the adult spinal cord to impair adult S-pathway-evoked pLTF. Further understanding the mechanisms impairing distinct forms of respiratory motor plasticity is required to develop plasticity as a therapeutic tool, such as for spinal cord injury and amyotrophic lateral sclerosis (Mitchell, 2008; Gonzalez-Rothi et al., 2015). Additionally, considering the cross-talk between Q- and S-pathways (Dale-Nagle et al., 2010; Fields and Mitchell, 2015; Perim et al., 2018), the response of the respiratory control system likely depends on the functional status of both Q- and S-pathways. Thus, future studies are needed to understand how inflammation modifies cross-talk between Q- and S-pathways and how respiratory motor plasticity can be exploited therapeutically (Gonzalez-Rothi et al., 2015).

The timing of neonatal inflammation is likely a significant factor in how neonatal inflammation impacts adult physiology. Low-levels of cytokines are important for neurodevelopment (Bilbo and Schwarz, 2009), and perturbing the balance of neonatal cytokines during development leads to lasting aberrant effects on neural circuits and developing cells (Reemst et al., 2016). Furthermore, while many components of the respiratory system begin developing in utero (Prakash et al., 2000; Pagliardini et al., 2003; Mantilla and Sieck, 2008; Johnson et al., 2018), the respiratory control system undergoes significant postnatal maturation. In these studies, we induced systemic inflammation with LPS at P4, similar to other studies showing long-term consequences of neonatal inflammation in other physiological systems (Shanks et al., 2000; Walker et al., 2006; Fan et al., 2008; Kohman et al., 2008; Bilbo, 2010), supporting the idea that important neural changes occur within the first week of life. Yet, it remains to be determined whether there is a precise critical period where neonatal inflammation impacts respiratory control circuits. However, our data on male mortality after neonatal LPS are consistent with other critical developmental windows, including a male-specific sensitive period to LPS (Rourke et al., 2016), disproportionate male mortality from neonatal inflammation (Person et al., 2014), the increased risk of sudden infant death syndrome for males (Kinney and Thach, 2009), and increased incidence of obstructive sleep apnea in adults after neonatal inflammation (McNamara and Sullivan, 2000). Thus, these data have important implications for understanding the sex-specific impairment early in life and into adulthood. Additionally, we and others (Spencer et al., 2006) observed a short delay in weight gain after neonatal inflammation, which normalized by weaning, suggesting no lasting effects on growth. Future studies are needed to refine our understanding of the critical periods during development when early-life inflammation induces long-lasting physiological changes to improve our understanding of adult disease and better understand important developmental processes.

While other reports have shown sex differences in neonatal programming of adult neuro-inflammatory responses (LaPrairie and Murphy, 2007; Rana et al., 2012), we observed no sex-differences in the effects of neonatal inflammation on adult plasticity. Importantly, this is the first evidence of inflammation abolishing pLTF in females and the first to report sAIH-induced respiratory motor plasticity in females. Females exhibited greater acute hypoxic phrenic amplitude responses relative to males, consistent with previous findings (Mortola and Saiki, 1996; Bavis et al., 2004), despite variability in reports of sex differences in hypoxic ventilatory responses (Behan and Kinkead, 2011). In contrast to our results following neonatal inflammation, neonatal stress alters adult hypoxic responses in a sex-dependent manner, whereby male responses are enhanced and female responses are blunted (Rousseau et al., 2017). Thus, the long-term effects on respiratory control may be dependent on the type of stressors in early life. Importantly, our experiments were performed in adult, ovariectomized females with exogenously restored estradiol levels to permit respiratory motor plasticity (Behan et al., 2002; Zabka et al., 2003; Dougherty et al., 2017). Therefore, as sex hormones are known to modulate respiratory control and hypoxic responses (Nelson et al., 2011; Behan and Kinkead, 2011), we cannot rule out a confounding role for exogenous estradiol supplementation after ovariectomy. Finally, after neonatal inflammation, we found no differences in adult hypoxic responses, suggesting no lasting change in carotid body responses due to neonatal inflammation. Accordingly, the deficit in adult respiratory motor plasticity after neonatal inflammation is likely a consequence of long-term changes in the spinal cord where pLTF occurs (Baker-Herman et al., 2004; Devinney et al., 2015; Dale et al., 2017).

While adult anti-inflammatory treatment restored Q-pathway-evoked pLTF, we did not observe increases in inflammatory gene expression in adult medullary or cervical spinal cord homogenates. Thus, while inflammatory signaling contributes to the impairment of adult plasticity, the source of this signaling change remains unclear and will be the topic of future studies. Similarly, others demonstrated no changes in baseline CNS inflammatory markers after neonatal inflammation, but observed priming of glial responses to adult stimuli (Bilbo et al., 2005b; Mouihate et al., 2010; Smith et al., 2014), suggesting lasting changes in glia have the potential to underlie impairments in adult respiratory plasticity. Contrary to other reports (Boissé et al., 2005; Kentner et al., 2010), we found spinal COX-2 gene expression was decreased in adulthood, suggesting a decrease in inflammatory signaling, which is unlikely to contribute to the lasting inflammation-dependent impairment in plasticity. Further, the acute inflammatory impairment of adult respiratory plasticity is COX-independent (Huxtable et al., 2018a), emphasizing a role for other inflammatory molecules mediating the lasting impairment in respiratory motor plasticity. Unmeasured inflammatory genes or post-transcriptional changes in inflammatory proteins may be responsible for undermining adult pLTF after neonatal inflammation. Conversely, other perinatal stimuli involving inflammatory signaling, such as maternal care and diet, do have lasting programming effects on adult inflammatory cytokine expression (Bilbo and Schwarz, 2009), but are more complex stimuli than the acute neonatal inflammation in our study. We also observed no change in microglial or astrocyte density and no obvious qualitative changes in morphology in adult medullas or spinal cords after neonatal inflammation. Thus, there are no obvious signs of inflammation in regions contributing to pLTF despite the restoration of Q-pathway-evoked pLTF with ketoprofen. Furthermore, the abolition of S-pathway-evoked pLTF is likely due to lasting changes in adenosine signaling from astrocytes, suggesting an astrocyte-specific change underlies this impairment. Thus, future studies are needed to identify inflammatory mechanisms undermining the Q-pathway and further details of the inflammation-independent mechanism responsible for undermining S-pathway-evoked motor plasticity.

The adult respiratory control network is vulnerable to early life stressors (Bavis et al., 2004; Genest et al., 2004; Fournier et al., 2011), which may undermine the ability to compensate during adult ventilatory control disorders. Our study is the first to demonstrate lasting consequences of neonatal inflammation on adult respiratory control. These deficits in respiratory control are independent of later life events, in contrast to other studies in which the physiological effects of early life inflammation are not revealed until after an adult stimulus (Bilbo et al., 2005b; Bilbo, 2010). We found a single episode of neonatal systemic inflammation induced lasting impairment of both Q- and S-pathway-evoked respiratory motor plasticity in adults. Our results suggest the adult impairment of Q-pathway plasticity is dependent on acute inflammatory signaling; however, we observed no lasting increase in adult inflammatory gene expression or the density of astrocytes and microglia. The pharmacological induction of S-pathway-evoked pLTF demonstrates phrenic motor neurons are capable of plasticity and suggest upstream impairment, such as the source of adenosine. While strong evidence supports astrocytes as the primary source of adenosine during hypoxia (Takahashi et al., 2010; Angelova et al., 2015), we cannot rule out other sources of adenosine. Identifying cell-type specific changes underlying lasting physiological impairments will be explored in future studies. Future studies will investigate the lasting effects of neonatal inflammation on isolated microglia and astrocytes to uncover potential mechanisms of adult impairments after neonatal inflammation.

Together, these results indicate two mechanistic pathways to spinal motor plasticity induced by AIH are undermined by neonatal inflammation in rats. Our experimental approach assessed phrenic nerve output in anesthetized rats and may not be generalizable to respiratory control in freely behaving animals or to other forms of motor plasticity. However, AIH induces long-term facilitation of ventilation in humans (Mateika and Komnenov, 2017) and strengthens corticospinal pathways to non-respiratory motor-neurons (Christiansen et al., 2018), suggesting our results likely have relevance to mechanisms of human spinal motor plasticity after AIH. While AIH-induced respiratory motor plasticity does not necessarily alter normal homeostatic control of ventilation, the general facilitation of spinal motor output has significant therapeutic potential for treating patients with respiratory and non-respiratory motor limitations (Trumbower et al., 2012; Trumbower et al., 2017; Nichols et al., 2013; Hayes et al., 2014)

In conclusion, this basic science study has major implications for the understanding the neonatal origins of adult ventilatory control disorders. These studies are the first evidence that one neonatal inflammatory exposure induces long-term impairments in adult respiratory control with potential relevance to many respiratory disorders. These findings are particularly relevant since inflammation is common in neonates (Person et al., 2014), especially those born prematurely who are at higher risk for adult disease (Luu et al., 2016). Improving our appreciation of how early life inflammation can influence adult respiratory control will have important consequences for understanding adult disease and susceptibility to respiratory disorders. Additionally, AIH-induced spinal motor plasticity is also a promising therapy to enhance motor recovery after spinal injury (Trumbower et al., 2012). However, not all patients respond to AIH (Hayes et al., 2014; Trumbower et al., 2017) and our findings suggest neonatal inflammatory exposure could contribute to these therapeutic limitations and understanding the mechanisms undermining plasticity will increase the therapeutic potential of AIH-induced spinal motor plasticity.

All experiments were approved by the Institutional Animal Care and Use Committees at the University of Oregon and the University of Wisconsin-Madison and conformed to the policies of the National Institute of Health Guide for the Care and Use of Laboratory Animals. Male and female Sprague Dawley rats (Envigo Colony 217 and 206) were housed under standard conditions (12:12 hr light/dark cycle) with food and water ad libitum.

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data are available for all figures.

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Author details

1. Austin D Hocker

   Department of Human Physiology, University of Oregon, Eugene, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2941-2581

2. Sarah A Beyeler

   Department of Human Physiology, University of Oregon, Eugene, United States

   Contribution

   Investigation, Visualization, Writing—original draft

   Competing interests

   No competing interests declared

3. Alyssa N Gardner

   Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Stephen M Johnson

   Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, United States

   Contribution

   Conceptualization, Resources, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

5. Jyoti J Watters

   Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, United States

   Contribution

   Conceptualization, Resources, Data curation, Funding acquisition, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

6. Adrianne G Huxtable

   Department of Human Physiology, University of Oregon, Eugene, United States

   Contribution

   Conceptualization, Resources, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   huxtable@uoregon.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8745-2231

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