Complement C3 and C3aR mediate different aspects of emotional behaviours; relevance to risk for psychiatric disorder.

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR-/-) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3-/-) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms. Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology.

Enduring neuroimmunological consequences of developmental experiences: From vulnerability to resilience.

The immune system is crucial for normal neuronal development and function (neuroimmune system). Both immune and neuronal systems undergo significant postnatal development and are sensitive to developmental programming by environmental experiences. Negative experiences from infection to psychological stress at a range of different time points (in utero to adolescence) can permanently alter the function of the neuroimmune system: given its prominent role in normal brain development and function this dysregulation may increase vulnerability to psychiatric illness. In contrast, positive experiences such as exercise and environmental enrichment are protective and can promote resilience, even restoring the detrimental effects of negative experiences on the neuroimmune system. This suggests the neuroimmune system is a viable therapeutic target for treatment and prevention of psychiatric illnesses, especially those related to stress. In this review we will summarise the main cells, molecules and functions of the immune system in general and with specific reference to central nervous system development and function. We will then discuss the effects of negative and positive environmental experiences, especially during development, in programming the long-term functioning of the neuroimmune system. Finally, we will review the sparse but growing literature on sex differences in neuroimmune development and response to environmental experiences.

Aging with a traumatic brain injury: Could behavioral morbidities and endocrine symptoms be influenced by microglial priming?

A myriad of factors influence the developmental and aging process and impact health and life span. Mounting evidence indicates that brain injury, even moderate injury, can lead to lifetime of physical and mental health symptoms. Therefore, the purpose of this mini-review is to discuss how recovery from traumatic brain injury (TBI) depends on age-at-injury and how aging with a TBI affects long-term recovery. TBI initiates pathophysiological processes that dismantle circuits in the brain. In response, reparative and restorative processes reorganize circuits to overcome the injury-induced damage. The extent of circuit dismantling and subsequent reorganization depends as much on the initial injury parameters as other contributing factors, such as genetics and age. Age-at-injury influences the way the brain is able to repair itself, as a result of developmental status, extent of cellular senescence, and injury-induced inflammation. Moreover, endocrine dysfunction can occur with TBI. Depending on the age of the individual at the time of injury, endocrine dysfunction may disrupt growth, puberty, influence social behaviors, and possibly alter the inflammatory response. In turn, activation of microglia, the brain's immune cells, after injury may continue to fuel endocrine dysfunction. With age, the immune system develops and microglia become primed to subsequent challenges. Sustained inflammation and microglial activation can continue for weeks to months post-injury. This prolonged inflammation can influence developmental processes, behavioral performance and age-related decline. Overall, brain injury may influence the aging process and expedite glial and neuronal alterations that impact mental health.

Microglial morphometric analysis: so many options, so little consistency.

Quantification of microglial activation through morphometric analysis has long been a staple of the neuroimmunologist's toolkit. Microglial morphological phenomics can be conducted through either manual classification or constructing a digital skeleton and extracting morphometric data from it. Multiple open-access and paid software packages are available to generate these skeletons via semi-automated and/or fully automated methods with varying degrees of accuracy. Despite advancements in methods to generate morphometrics (quantitative measures of cellular morphology), there has been limited development of tools to analyze the datasets they generate, in particular those containing parameters from tens of thousands of cells analyzed by fully automated pipelines. In this review, we compare and critique the approaches using cluster analysis and machine learning driven predictive algorithms that have been developed to tackle these large datasets, and propose improvements for these methods. In particular, we highlight the need for a commitment to open science from groups developing these classifiers. Furthermore, we call attention to a need for communication between those with a strong software engineering/computer science background and neuroimmunologists to produce effective analytical tools with simplified operability if we are to see their wide-spread adoption by the glia biology community.

Early-Career Complementologists (ECCO) - Past achievements and future directions.

The Early-Career Complementologists (ECCO) is a task force that was established, in close collaboration with the European Complement Network (ECN) and the International Complement Society (ICS), with the specific mission to support and connect early-career researchers (ECRs) in the complement field. ECRs are junior scientists at the early stages of their training which include undergraduate as well as graduate students, Ph.D. graduates, and post-doctoral fellows. This unique population within the scientific community represents the next generation of scientific leaders. However, ECRs are faced with key challenges and the COVID-19 pandemic has disproportionately impacted them. In this paper, we provide further insight into specific needs and challenges of ECRs in the complement field. We surveyed 52 ECRs in the complement field and assessed their perceptions of 1) mentor and peer support, 2) working conditions as well as 3) career interests and prospects. Furthermore, we review the various activities carried out by ECCO over the past years such as our social media presence, social events, and newly-created awards. We also discuss the future activities and events to be carried out by ECCO. Through these initiatives and activities, ECCO strives to boost collaborations between ECRs, provide recognition, and improve the visibility of their work. In addition, continuous joint efforts must also be made by the scientific community, research institutes, and funding organizations to nurture and invest in ECRs.

ECCO - A new initiative to support early-career researchers in the complement field.

Research on the complement system, like most areas of immunology, has seen tremendous progress over the last decades. Further advances in the complement field will rely on the next generation of scientific leaders, which are today's early-career researchers (ECRs). ECRs are emerging scientists who obtained their PhD degree within the past five years. They represent a distinct population within the scientific community, and accordingly have unique needs. Unfortunately, ECRs are faced with significant challenges that require customized solutions. The current paper provides a snapshot of the major obstacles ECRs face, such as an unhealthy work-life balance, lack of mentor and peer support, and uncertain career prospects. Efforts must consequently be taken to ensure stability and success of ECRs, not only to benefit these researchers in the early stages of their career, but the entire field of complement research. The Early-Career Complementologists (ECCO) was, therefore, launched as a new Task Force to support ECRs in the complement field. This new initiative aims to support and connect ECRs in the complement field worldwide. Furthermore, ECCO is supported by both the International Complement Society (ICS) and the European Complement Network (ECN); two professional societies led by scientists investigating the complement system.

Neuroimmunological effects of early life experiences.

Exposure to adverse experiences during development increases the risk of psychiatric illness later in life. Growing evidence suggests a role for the neuroimmune system in this relationship. There is now substantial evidence that the immune system is critical for normal brain development and behaviour, and responds to environmental perturbations experienced early in life. Severe or chronic stress results in dysregulated neuroimmune function, concomitant with abnormal brain morphology and function. Positive experiences including environmental enrichment and exercise exert the opposite effect, promoting normal brain and immune function even in the face of early life stress. The neuroimmune system may therefore provide a viable target for prevention and treatment of psychiatric illness. This review will briefly summarise the neuroimmune system in brain development and function, and review the effects of stress and positive environmental experiences during development on neuroimmune function. There are also significant sex differences in how the neuroimmune system responds to environmental experiences early in life, which we will briefly review.