Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number

Smith, Caroline J.; Kingsbury, Marcy A.; Dziabis, Julia E.; Hanamsagar, Richa; Malacon, Karen; Tran, Jessica J.; Norris, Haley A.; Gulino, Mary; Bordt, Evan A.; Bilbo, Staci D.

doi:10.1016/j.bbi.2020.08.013

Cited by 27 publications

(30 citation statements)

References 79 publications

(104 reference statements)

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“…However, relatedly, the effect of a single LPS challenge during the postnatal period has been examined in mice, and differential effects have been found in males in females regarding effects on adult social behavior ( 149 ). More specifically, neonatal LPS treatment decreased sociability in adult female, but not male mice.…”

Section: Microglial Mechanisms Regulate Social Behaviormentioning

confidence: 99%

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Loth

Donaldson

2020

Endocrinology

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Pair bonds represent some of the strongest attachments we form as humans. These relationships positively modulate health and well-being. Conversely, the loss of a spouse is an emotionally painful event that leads to numerous deleterious physiological effects, including increased risk for cardiac dysfunction and mental illness. Much of our understanding of the neuroendocrine basis of pair bonding has come from studies of monogamous prairie voles (Microtus ochrogaster), laboratory-amenable rodents that, unlike laboratory mice and rats, form lifelong pair bonds. Specifically, research using prairie voles has delineated a role for multiple neuromodulatory and neuroendocrine systems in the formation and maintenance of pair bonds, including the oxytocinergic, dopaminergic, and opioidergic systems. However, while these studies have contributed to our understanding of selective attachment, few studies have examined how interactions among these 3 systems may be essential for expression of complex social behaviors, such as pair bonding. Therefore, in this review, we focus on how the social neuropeptide, oxytocin, interacts with classical reward system modulators, including dopamine and endogenous opioids, during bond formation and maintenance. We argue that an understanding of these interactions has important clinical implications and is required to understand the evolution and encoding of complex social behaviors more generally. Finally, we provide a brief consideration of future directions, including a discussion of the possible roles that glia, specifically microglia, may have in modulating social behavior by acting as a functional regulator of these 3 neuromodulatory systems.

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Section: Microglial Mechanisms Regulate Social Behaviormentioning

confidence: 99%

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Loth

Donaldson

2020

Endocrinology

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“…Whether hippocampal immune tolerance is beneficial or harmful to neonates is not known. Neonatal inflammation is a well-established mediator of brain injury resulting in poorer behavioral outcomes in humans and preclinical models [ 6 – 10 , 24 , 48 , 49 ]. Preclinical studies show that attenuation of the neuroinflammatory response, by inducing tolerance or inhibiting inflammatory cell activity, is associated with improved developmental outcomes [ 43 , 50 – 52 ].…”

Section: Discussionmentioning

confidence: 99%

Fetal inflammation induces acute immune tolerance in the neonatal rat hippocampus

Singh

Segura

Georgieff

et al. 2021

J Neuroinflammation

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Background Infants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and then by subsequent postnatal infections. FIRS and postnatal systemic inflammatory events independently contribute to poor neurocognitive outcomes of preterm infants. Developmental integrity of the hippocampus is crucial for intact neurocognitive outcomes in preterms and hippocampally dependent behaviors are particularly vulnerable to preterm systemic inflammation. How FIRS modulates the hippocampal immune response to acute postnatal inflammatory events is not well understood. Methods Prenatal LPS exposed (FIRS) and control neonatal rats received i.p. LPS or saline at postnatal day (P) 5. On P7, immune response was evaluated in the hippocampus of four treatment groups by measuring gene expression of inflammatory mediators and cytosolic and nuclear NFκB pathway proteins. Microglial activation was determined by CD11b+ and Iba1+ immunohistochemistry (IHC) and inflammatory gene expression of isolated microglia. Astrocyte reactivity was measured using Gfap+ IHC. Results Postnatal LPS resulted in a robust hippocampal inflammatory response. In contrast, FIRS induced by prenatal LPS attenuated the response to postnatal LPS exposure, evidenced by decreased gene expression of inflammatory mediators, decreased nuclear NFκB p65 protein, and fewer activated CD11b+ and Iba1+ microglia. Isolated microglia demonstrated inflammatory gene upregulation to postnatal LPS without evidence of immune tolerance by prenatal LPS. Conclusion Prenatal LPS exposure induced immune tolerance to subsequent postnatal LPS exposure in the hippocampus. Microglia demonstrate a robust inflammatory response to postnatal LPS, but only a partial immune tolerance response.

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“…Interestingly, late gestational Poly I:C (on the last day of pregnancy) induces social deficits in both male and female offspring ( 184 ), which may suggest that sex-specific vulnerability is sensitive to gestational age. Similarly, in rodents, administration of a low dose of LPS between postnatal days (PND) 3–5 has been shown to decrease social behavior in both males and females in adolescence ( 30 , 178 ) and only in females in adulthood ( 111 ), while a high dose of LPS administered at PND 9 only decreases social behavior in adulthood in males ( 69 ). Thus, either a viral or bacterial infection may alter social behavior in males and females, but the magnitude of these effects differs between the sexes and changes along developmental trajectories.…”

Section: Critical Periods and Chronic Illness: The Breakdown Of Adaptmentioning

confidence: 98%

“…Microglia, the resident immune cells of the brain, are also important mediators of the relationship between infection and social behavior. Peripheral LPS injection increases IL-1β and TNFα mRNA in microglia ( 109 – 111 ). Since LPS does not cross the blood brain barrier, it is likely that local cytokine release by microglia at least partially mediates the impact of immune activation on social behavior.…”

Section: What Are the Neuroimmune Mechanisms Mediating The Relationshmentioning

confidence: 99%

“…However, when immune challenges occur during developmental critical periods or lead to chronic inflammation, they can have long-lasting and maladaptive consequences for social dysfunction—even after the acute illness has passed ( 95 , 177 ). Immune challenges during the perinatal period disrupt adult social functioning in both males and females, but these effects appear to depend on a variety of factors including developmental timing of the challenge, drug dose, and the nature of the challenge itself ( 30 , 68 , 69 , 111 , 178 , 179 ). For instance, maternal immune activation with influenza virus ( 70 ) or Poly I:C during pregnancy leads to social deficits in adult offspring in both rodents and primates ( 68 , 70 , 180 – 182 ).…”

Section: Critical Periods and Chronic Illness: The Breakdown Of Adaptmentioning

confidence: 99%

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Sickness and the Social Brain: Love in the Time of COVID

Smith

Bilbo

2021

Front. Psychiatry

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As a highly social species, inclusion in social networks and the presence of strong social bonds are critical to our health and well-being. Indeed, impaired social functioning is a component of numerous neuropsychiatric disorders including depression, anxiety, and substance use disorder. During the current COVID-19 pandemic, our social networks are at risk of fracture and many are vulnerable to the negative consequences of social isolation. Importantly, infection itself leads to changes in social behavior as a component of “sickness behavior.” Furthermore, as in the case of COVID-19, males and females often differ in their immunological response to infection, and, therefore, in their susceptibility to negative outcomes. In this review, we discuss the many ways in which infection changes social behavior—sometimes to the benefit of the host, and in some instances for the sake of the pathogen—in species ranging from eusocial insects to humans. We also explore the neuroimmune mechanisms by which these changes in social behavior occur. Finally, we touch upon the ways in which the social environment (group living, social isolation, etc.) shapes the immune system and its ability to respond to challenge. Throughout we emphasize how males and females differ in their response to immune activation, both behaviorally and physiologically.

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Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number

Cited by 27 publications

References 79 publications

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Fetal inflammation induces acute immune tolerance in the neonatal rat hippocampus

Sickness and the Social Brain: Love in the Time of COVID

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