The Laboratory of Neuroimmunology
- Animal models of psychopathology
- Early childhood stress and altered psychophysiological reactivity in chronic pain
- Prenatal infection on schizophrenia
- Programming of pain responses by early life infection
- Prophylactic role of Maternal probiotic intervention in the prevention of endocrine, immune and gut alterations induced by early life stress
The observation that the drug phencyclidine has psychotomimetic effects and that it noncompetitively blocks N-methyl-D-aspartate (NMDA)-type glutamate receptors has led to models of the aetiology and pathophysiology of schizophrenia focussing on glutamate and NMDA receptor hypofunction (Catts & Catts, 2010; Javitt & Zukin, 1991). Given the importance of NMDA receptors to developmental plasticity (Cotman, Monaghan, & Ganong, 1988; Monyer, Burnashev, Laurie, Sakmann, & Seeburg, 1994), we propose a novel approach of examining the effects of early life infection on NMDA-sensitive measures in the rodent that are homologous to the human (Bickel & Javitt, 2009) and which are established schizophrenia endophenotypes. These are the mismatch negativity (MMN) and the N1 component of auditory event-related potentials (ERPs) (Javitt, 2009). Birth cohort studies suggest that maternal viral infection during pregnancy increases the risk of schizophrenia (Brown, 2006). Importantly, in animals, maternal viral infection results in NMDA-related behavioural and neurochemical abnormalities in adult offspring (Meyer, Nyffeler, Yee, Knuesel, & Feldon, 2008). Over the past years, we have been establishing rodent models of schizophrenia focussed on the effects of early life infection on NMDA receptor functioning and auditory ERPs. We are currently verifying the NMDA receptor involvement and determining the specificity of NMDA receptor changes to maternal viral infection.
Our working premise is that adverse childhood events can reprogramme the psychophysiological reactivity of individuals such that in later adulthood, they are more prone to various stressors, including chronic pain. Chronic pain syndrome, which is associated with higher levels of disability, independent of reported levels of pain intensity, is characterized by an inability to adjust to and accommodate the limitations associated with persistent pain. This inability to adjust is not readily discerned, and many years of failed interventions may ensue. It is anticipated that the altered psychophysiological reactivity can be reliably assessed and then used as a thumbprint, to identify such individuals early in their rehabilitative journey, so they can be selected for more tailored treatment.
Disturbance of normal brain development is implicated in a number of neuropsychiatric disorders, including autism and schizophrenia. Both are characterized by a heterogeneous group of symptoms with relatively ill-defined aetiologies. Besides a clear genetic contribution, various environmental factors appear to increase the risk for schizophrenia and/or related disorders. Many of these factors operate at prenatal stages of life, that is, during the critical periods of central nervous system development. Epidemiological research over the past two decades has indicated that the risk for schizophrenia is enhanced in offspring exposed to viral or bacterial infections in utero. Thus, we propose to investigate the effects of a well-established rodent model of prenatal infection (i.e. polyinosinic-polycytidylic acid (poly I:C) treatment - a synthetic analogue of double-stranded RNA, which induces similar effects as a true viral infection in rodent models) in two species of rodents (Wistar rats and C57BL/6 mice) on schizophrenia-like behaviours and NMDA receptor functioning (see the "Animal models of psychopathology" section for rats). We also have collaboration with Dr Tim Karl and his team at the Neuroscience Research Australia where we are investigating the effects of poly I: C to genetic mouse model of schizophrenia [i.e. neuregulin 1 (Nrg1) mutant mouse model]. This will represent the two-hit hypothesis of schizophrenia stating that a combination of e.g. a genetic predisposition for the illness together with an environmental insult "later" in life (e.g. prenatally) will increase the risk of developing schizophrenia.
Chronic pain has major negative effects on millions of people worldwide and a huge social cost for modern societies. The failure of current therapies implies that the traditional view of pain as being purely an unpleasant sensory and an emotional experience produced solely by the activation of a direct line pathway from nociceptors (pain receptors) to the brain, has failed. A substantial body of evidence now points toward the critical role played by the immune system in modulating pain sensitivity. It is well established that Glia (astrocytes and microglia) in the spinal cord as well as in brain areas processing pain, participate in the maintenance and modulation of pain. Under activation, these cells release a plethora of pro-inflammatory cytokines such as TNFα, IL-1β or IL-6 which not only sensitize nociceptors but also enhance the discharge of dorsal horn neurons leading to a state of hyperalgesia or increased pain sensitivity. Infection during pregnancy is a common event and neonatal infection has been demonstrated to be associated with activation of Glia and increased pain sensitivity in rats subjected to bacterial infection during the first weeks of development. Of particular interest no other laboratory worldwide has addressed the question of the impact of prenatal infection on pain sensitivity later in life. Since we have demonstrated that prenatal exposure to infection alters cytokines production and that cytokines modulate pain, we hypothesize that in utero exposure to bacteria will alter pain sensitivity in offspring rats from endotoxin-challenged mothers and that this alteration is due, in part, to activation of immune cells which release pro-inflammatory cytokines and induce hyperalgesia. This project is aiming at elucidating the mechanisms underlying the modulation of pain after in utero exposure to bacteria, notably by determining the role played by the immune system. This new theory of pain mechanisms will help developing new therapeutic approaches that will target the immune system decreasing thus the psychological, social and physiological suffering induced by chronic pain.
Prophylactic role of Maternal probiotic intervention in the prevention of endocrine, immune and gut alterations induced by early life stress
Neonatal stress is a common early life event which alters the development of the endocrine and immune systems. Specifically, exposure to neonatal stress results in alterations to the hypothalamic-pituitary-adrenal (HPA) axis resulting in offspring who hyper-respond to stress in adulthood. Recently, this concept has been applied to the ontogeny of functional gastrointestinal (GI) disturbances such as irritable bowel syndrome (IBS). The high prevalence of this disorder and the ineffectiveness of current treatments results in high direct and indirect costs to the society. Therefore, developing preventive modalities/strategies in the management of IBS will have advantages over the current treatment procedures. Recently, administration of probiotics to neonates has been used as a safe and cost-effective preventive strategy to revoke the long term unfavourable imprinting induced on the gastrointestinal system by early life stress rats. It is not as yet known however, whether maternal supplementary probiotics may also contribute to improved GI integrity and gut-associated immune functioning in stressed neonates, if these possible improvements persist into adulthood, and how this possible protective effect may be mediated. The project has focussed on whether maternal probiotic intervention can act prophylactically to prevent endocrine, immune and colonic dysfunctions provoked by early life stress in Wistar rats.