Ongoing Research Projects
Gut-brain interactions in brain function and behaviour
The human gut contains an enormous number of microorganisms referred to as commensal bacteria, or gut microbiota. Without this microbiome, we would be unable to digest plant polysaccharides and would have trouble extracting lipids from our diet. Several studies have now established clear evidence linking gut microbiota to mental health.
Our research in the gut-brain was the first to link microbiota to anxiety-like behaviour (Neufeld et al, 2011a). These first experiments followed on the observation that germ-free mice showed enhanced stress-reactivity (Sudo et al., 2004) and we sought to determine if this resulted in changes in stress-related behaviours. Surprisingly, our results revealed that germ-free mice showed reduced anxiety-like behaviour in the elevated plus maze, a well established behavioural test that examines approach and avoidance behaviour in mice, in comparison to specific pathogen free (SPF) mice. The low anxiety-like behavioural phenotype observed in germ-free mice was accompanied by long-term changes in plasticity-related genes in the hippocampus and amygdala (Neufeld et al., 2011a). Interestingly, the low anxiety-like behavioural phenotype observed in germ-free mice persisted after colonization with normal intestinal microbiota demonstrating that gut-brain interactions influence CNS wiring early in life (Neufeld et al., 2011b). This seminal work in the area of gut-brain interactions has received considerable attention in the scientific and public domain in the past few years. The initial paper demonstrating this link was featured in the March issue of Neurogastro Motility, with a research highlight article by Dr. John Cryan from Cork University, Ireland. In addition, it received the “Most cited paper award” as the most cited paper in Neurogastro Motility in 2010-2012. The related press release from that paper was picked up by numerous news agencies and was featured locally in both print newspaper and radio interview.
Our ongoing work examines whole brain structure using high resolution ex vivo magnetic resonance imaging (MRI with Jason Lerch at Sick Kids) to determine the association of microbiota and brain structure. Different mouse strains show natural differences in anxiety-related behaviour and therefore, we are studying different strains of mice as a naturalist approach to examine the link between microbiota, brain, and behaviour. Further our integrated analysis will consider the role of stress and host genetics on central circuits of stress and how these factors influence behaviour.
Overall, research in the last decade has established a bottom up link between gut microbiota and brain function. Our findings demonstrate that gut microbiota are important during early development and can influence brain wiring and behaviour; however, in order to determine the importance of this influence, the mechanisms of action and the nature of the interactions (causal or not) must be considered.
See below for a talk given by Dr. Jane Foster at the 2015 POND Parent Information Day.
Our research in the gut-brain was the first to link microbiota to anxiety-like behaviour (Neufeld et al, 2011a). These first experiments followed on the observation that germ-free mice showed enhanced stress-reactivity (Sudo et al., 2004) and we sought to determine if this resulted in changes in stress-related behaviours. Surprisingly, our results revealed that germ-free mice showed reduced anxiety-like behaviour in the elevated plus maze, a well established behavioural test that examines approach and avoidance behaviour in mice, in comparison to specific pathogen free (SPF) mice. The low anxiety-like behavioural phenotype observed in germ-free mice was accompanied by long-term changes in plasticity-related genes in the hippocampus and amygdala (Neufeld et al., 2011a). Interestingly, the low anxiety-like behavioural phenotype observed in germ-free mice persisted after colonization with normal intestinal microbiota demonstrating that gut-brain interactions influence CNS wiring early in life (Neufeld et al., 2011b). This seminal work in the area of gut-brain interactions has received considerable attention in the scientific and public domain in the past few years. The initial paper demonstrating this link was featured in the March issue of Neurogastro Motility, with a research highlight article by Dr. John Cryan from Cork University, Ireland. In addition, it received the “Most cited paper award” as the most cited paper in Neurogastro Motility in 2010-2012. The related press release from that paper was picked up by numerous news agencies and was featured locally in both print newspaper and radio interview.
Our ongoing work examines whole brain structure using high resolution ex vivo magnetic resonance imaging (MRI with Jason Lerch at Sick Kids) to determine the association of microbiota and brain structure. Different mouse strains show natural differences in anxiety-related behaviour and therefore, we are studying different strains of mice as a naturalist approach to examine the link between microbiota, brain, and behaviour. Further our integrated analysis will consider the role of stress and host genetics on central circuits of stress and how these factors influence behaviour.
Overall, research in the last decade has established a bottom up link between gut microbiota and brain function. Our findings demonstrate that gut microbiota are important during early development and can influence brain wiring and behaviour; however, in order to determine the importance of this influence, the mechanisms of action and the nature of the interactions (causal or not) must be considered.
See below for a talk given by Dr. Jane Foster at the 2015 POND Parent Information Day.
Class I MHC & neuroplasticity, a novel role for a classical immune molecule
Several immune molecules are produced in neurons and are known to be important to neuronal function. One of the most interesting and least well understood is class I major histocompatability complex (MHC). Class I MHC has emerged as a key regulator of synaptic function plasticity mechanisms in developing and adult brain. As we consider new concepts related to neuroimmune interactions, it is important to better understand the role of neuronal class I MHC in response to daily life stressors, such as infection or immune challenge. Such work will provide new knowledge to improve our understanding of the changes that may occur in the CNS between healthy and pathological states.
The Foster Lab has developed a productive research program that straddles immunology and neuroscience. We hope that by improving our understanding of how immune molecules contribute to normal brain function, we may in the end provide novel ideas and concepts about how these systems fail in disease. The lab has examined the long-term impact of an early immune challenge on molecular and behavioural phenotypes associated with stress-related behaviours (Sidor et al., 2010, Amath et al., 2012). These studies suggest that early life activation of the innate immune system influences wiring the brain’s stress system, however, our work to date has not identified the CNS molecules involved. We are particularly interested in immune molecules that are expressed in neurons in the CNS, such as class I MHC as our previous work has suggested this molecule may play a role in the CNS response to immune challenge (Foster et al., 2002).
Recently, we have examined mice lacking functional class I MHC (β2microglobulin[B2M]-/- transporter of antigen processing [TAP]-/-) and observed differences in basal exploratory behaviour. These mice also showed an exaggerated stress response (behavioural and physiological) to a normally innocuous saline injection suggesting that wiring of the stress system may be influenced by class I MHC (Sankar et al., 2012). Ongoing and future experiments will continue this work in vivo and in vitro in order to investigate the cellular and molecular mechanisms regulation immune signaling in the CNS.
The Foster Lab has developed a productive research program that straddles immunology and neuroscience. We hope that by improving our understanding of how immune molecules contribute to normal brain function, we may in the end provide novel ideas and concepts about how these systems fail in disease. The lab has examined the long-term impact of an early immune challenge on molecular and behavioural phenotypes associated with stress-related behaviours (Sidor et al., 2010, Amath et al., 2012). These studies suggest that early life activation of the innate immune system influences wiring the brain’s stress system, however, our work to date has not identified the CNS molecules involved. We are particularly interested in immune molecules that are expressed in neurons in the CNS, such as class I MHC as our previous work has suggested this molecule may play a role in the CNS response to immune challenge (Foster et al., 2002).
Recently, we have examined mice lacking functional class I MHC (β2microglobulin[B2M]-/- transporter of antigen processing [TAP]-/-) and observed differences in basal exploratory behaviour. These mice also showed an exaggerated stress response (behavioural and physiological) to a normally innocuous saline injection suggesting that wiring of the stress system may be influenced by class I MHC (Sankar et al., 2012). Ongoing and future experiments will continue this work in vivo and in vitro in order to investigate the cellular and molecular mechanisms regulation immune signaling in the CNS.
Immune role in mental illness
Historically the brain and the immune system were studied separately and it was widely believed that the immune system and its related signaling did not exist within the healthy central nervous system (CNS). However, in the last few decades the field of neuroimmunology has expanded considerably and the importance of immune-brain communication is increasing. Immune functioning has been linked to mood, behaviour, and psychiatric illnesses. Immune-brain interactions are continual and bidirectional. Early postnatal life represents a critical period during which immune-brain communication may influence the developmental trajectory of the brain. Molecules originally thought to be unique to the immune system are present and functional in the brain. In fact, the brain and immune system share many molecules including neurotransmitters and their receptors, cytokines and chemokines and their receptors, integrins, and cell adhesion molecules to name a few. What is exciting in the field of neuroimmune research is work suggesting that immune molecules in the CNS are, in fact, important to neuronal function including aspects of neuronal development, neuronal excitability, and neurotransmission. This discovery changes the way that we may think about the immune system and has stimulated new research directions aimed at identifying novel roles for immune molecules in normal brain function and has provided an opportunity to consider how immune dysfunction during development may alter the trajectory of brain development and increase risk of mental illness.
Researchers in psychiatry and behavioural neuroscience are increasingly recognizing the importance of the adaptive immune system in behaviour. Our behavioural work using immunocompromised mice has included GF mice, mice lacking T cell receptor β and δ chains (TCRβ-/- δ-/-); mice lacking both β-2microglobulin and transporter associated with antigen processing genes (β2M−/−TAP−/−), resulting in the loss of functional class I MHC molecules and depleted CD8 T cells, and B cell deficient mice. Our recent work showed that mice deficient of T cells (TCRβ-/- δ-/-) showed reduced anxiety-like behaviour in the elevated plus maze, light/dark test, and open field, whereas these behavioural differences are not observed in B cell deficient mice (Rilett et al, 2015). An interesting observation in our study with β2M-/-TAP-/- mice was that we observed a loss of sexual dimorphism in activity, exploratory, and anxiety-like behaviours compared to wild type mice (Sankar et al, 2012). This was also observed in TCRβ-/- δ-/- mice. Considering the evidence of sexually dimorphisms in immune functioning, it is seems reasonable and necessary to further examine a role for immune phenotype in sex differences in behaviour.
In collaboration with our clinical networks, POND (http://pond-network.ca/) and CAN-BIND (http://www.canbind.ca/), we are examining the role of inflammatory mediators in psychiatric illnesses including neurodevelopmental disorders and depression.
Researchers in psychiatry and behavioural neuroscience are increasingly recognizing the importance of the adaptive immune system in behaviour. Our behavioural work using immunocompromised mice has included GF mice, mice lacking T cell receptor β and δ chains (TCRβ-/- δ-/-); mice lacking both β-2microglobulin and transporter associated with antigen processing genes (β2M−/−TAP−/−), resulting in the loss of functional class I MHC molecules and depleted CD8 T cells, and B cell deficient mice. Our recent work showed that mice deficient of T cells (TCRβ-/- δ-/-) showed reduced anxiety-like behaviour in the elevated plus maze, light/dark test, and open field, whereas these behavioural differences are not observed in B cell deficient mice (Rilett et al, 2015). An interesting observation in our study with β2M-/-TAP-/- mice was that we observed a loss of sexual dimorphism in activity, exploratory, and anxiety-like behaviours compared to wild type mice (Sankar et al, 2012). This was also observed in TCRβ-/- δ-/- mice. Considering the evidence of sexually dimorphisms in immune functioning, it is seems reasonable and necessary to further examine a role for immune phenotype in sex differences in behaviour.
In collaboration with our clinical networks, POND (http://pond-network.ca/) and CAN-BIND (http://www.canbind.ca/), we are examining the role of inflammatory mediators in psychiatric illnesses including neurodevelopmental disorders and depression.
Translational Research Collaborations
Province of Ontario Neurodevelopmental Disorders (POND) Network
The overall aim of the POND network is to enable medical discoveries and personalized treatments of neurological disorders to come about rapidly. To meet this challenge, my lab, in collaboration with Jason Lerch’s group at Sick Kids, utilizes a number of mouse models of these neurodevelopmental disorders. This project examines gene-environment interactions on behavior and brain structure and is clinically important to childhood disorders including autism, obsessive compulsive disorder, attention deficit disorders, Fragile X, Rett syndrome, Tourette’s, and intellectual disability. My lab has developed tools to examine early life growth and development, stress responsivity, activity, and social behaviours prior to puberty in mice. In collaboration with the Lerch lab, we will link our behavioral observations with brain structure. In the past 3 years, we have completed the early life behavioural analysis and related brain imaging on over 1100 mice, sampled across 7 strains/genotypes. The ongoing integrated analysis will link host genetics and target disease-related genes to behaviour and brain structure. In parallel, we have measures of microbiota composition and diversity in selected subsets of mice and measures of stress reactivity and immune signaling. In collaboration with other POND investigators, we are initiating studies to study immune dysfunction in children in the POND network in parallel with ongoing immunophenotyping in mice.
Canadian Biomarker Integration Network in Depression
The CAN-BIND program vision is to define the biological signatures of currently uncharacterized subtypes of major depressive disorder (MDD) to provide an accurate and rapid diagnosis that informs appropriate treatment selection. This vision will be achieved through the development of a standardized platform for integrated clinical, molecular and imaging data collection. My lab is part of the collaborative team that is examining inflammatory markers in MDD patients and healthy volunteers. In addition, I have contributed significantly to the development of reverse translation approaches, particularly in zebra fish. An active collaboration with Xiao-Yan Wen at the La Ka Shing Knowledge Institute at St. Michael’s Hospital will use miRNA targets identified as treatment response biomarkers in our clinical population and generate reporter fish for high-throughput screening for drug discovery . Importantly, several of our ongoing mouse studies are aligned with the clinical outcomes of CAN-BIND and this component of our research program will continue to expand in the next few years.
The overall aim of the POND network is to enable medical discoveries and personalized treatments of neurological disorders to come about rapidly. To meet this challenge, my lab, in collaboration with Jason Lerch’s group at Sick Kids, utilizes a number of mouse models of these neurodevelopmental disorders. This project examines gene-environment interactions on behavior and brain structure and is clinically important to childhood disorders including autism, obsessive compulsive disorder, attention deficit disorders, Fragile X, Rett syndrome, Tourette’s, and intellectual disability. My lab has developed tools to examine early life growth and development, stress responsivity, activity, and social behaviours prior to puberty in mice. In collaboration with the Lerch lab, we will link our behavioral observations with brain structure. In the past 3 years, we have completed the early life behavioural analysis and related brain imaging on over 1100 mice, sampled across 7 strains/genotypes. The ongoing integrated analysis will link host genetics and target disease-related genes to behaviour and brain structure. In parallel, we have measures of microbiota composition and diversity in selected subsets of mice and measures of stress reactivity and immune signaling. In collaboration with other POND investigators, we are initiating studies to study immune dysfunction in children in the POND network in parallel with ongoing immunophenotyping in mice.
Canadian Biomarker Integration Network in Depression
The CAN-BIND program vision is to define the biological signatures of currently uncharacterized subtypes of major depressive disorder (MDD) to provide an accurate and rapid diagnosis that informs appropriate treatment selection. This vision will be achieved through the development of a standardized platform for integrated clinical, molecular and imaging data collection. My lab is part of the collaborative team that is examining inflammatory markers in MDD patients and healthy volunteers. In addition, I have contributed significantly to the development of reverse translation approaches, particularly in zebra fish. An active collaboration with Xiao-Yan Wen at the La Ka Shing Knowledge Institute at St. Michael’s Hospital will use miRNA targets identified as treatment response biomarkers in our clinical population and generate reporter fish for high-throughput screening for drug discovery . Importantly, several of our ongoing mouse studies are aligned with the clinical outcomes of CAN-BIND and this component of our research program will continue to expand in the next few years.
References:
Amath A, Foster JA, Sidor MM (2012) Developmental alterations in CNS stress-related gene expression following postnatal immune activation. Neuroscience 220:90-99.
Foster JA, Quan N, Stern EL, Kristensson K, Herkenham M (2002) Induced neuronal expression of class I major histocompatibility complex mRNA in acute and chronic inflammation models. J Neuroimmunol 131:83-91.
Neufeld KM, Kang N, Bienenstock J, Foster JA (2011a) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23:255-264, e119.
Neufeld KA, Kang N, Bienenstock J, Foster JA (2011b) Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol 4:492-494.
Rilett, K.C., J. Ellegood, M. Friedel, R.N. MacKenzie, J.P. Lerch, and J.A. Foster. 2015. Loss of T cells significantly alters sex differences in behaviour and brain structure. Brain Behav Imm 46:649-657. Epub Feb 26 2015
Sankar A, Mackenzie RN, Foster JA (2012) Loss of class I MHC function alters behavior and stress reactivity. J Neuroimmunol 244:8-15.
Sidor MM, Amath A, MacQueen G, Foster JA (2010) A developmental characterization of mesolimbocortical serotonergic gene expression changes following early immune challenge. Neuroscience 171:734-746.
Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558:263-275.
Amath A, Foster JA, Sidor MM (2012) Developmental alterations in CNS stress-related gene expression following postnatal immune activation. Neuroscience 220:90-99.
Foster JA, Quan N, Stern EL, Kristensson K, Herkenham M (2002) Induced neuronal expression of class I major histocompatibility complex mRNA in acute and chronic inflammation models. J Neuroimmunol 131:83-91.
Neufeld KM, Kang N, Bienenstock J, Foster JA (2011a) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23:255-264, e119.
Neufeld KA, Kang N, Bienenstock J, Foster JA (2011b) Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol 4:492-494.
Rilett, K.C., J. Ellegood, M. Friedel, R.N. MacKenzie, J.P. Lerch, and J.A. Foster. 2015. Loss of T cells significantly alters sex differences in behaviour and brain structure. Brain Behav Imm 46:649-657. Epub Feb 26 2015
Sankar A, Mackenzie RN, Foster JA (2012) Loss of class I MHC function alters behavior and stress reactivity. J Neuroimmunol 244:8-15.
Sidor MM, Amath A, MacQueen G, Foster JA (2010) A developmental characterization of mesolimbocortical serotonergic gene expression changes following early immune challenge. Neuroscience 171:734-746.
Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558:263-275.