Repeated recall, extinction and reconsolidation in behaviorally conditioned immunosuppression

Manfred Schedlowski

Institute of Medical Psychology and Behavioral Immunobiology, Germany

Immune responses can be modulated via associative learning paradigms. We have established a model of behaviorally conditioned suppression of immune functions in rodents and healthy humans, employing the immunosuppressant cyclosporine A as an unconditioned stimulus, by demonstrating a behaviorally conditioned suppression of T cell proliferation and cytokine production. This learned immune response is mediated centrally via the insular cortex and the amygdala as well as on the efferent arm via the splenic nerve, through noradrenaline and adrenoceptor-dependent mechanisms and is sufficient to prolong heart allograft survival in rats. The learned immunosuppression can be reproduced during a second, unreinforced re-exposition to the conditioned stimulus (CS). Moreover, extinction of learned immunosuppression can be inhibited by employing subtherapeutical doses of the drug together with the CS. These data provide a basis for employing learning paradigms in clinical situations as supportive therapy together with standard pharmacological regimens, the aim being to maximize the therapeutic outcome for the patient’s benefit.

Immune modulation of memory, neural plasticity and neurogenesis

Raz Yirmiya, Ph.D.

The Hebrew University of Jerusalem, Israel

Over the past two decades it became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. Under normal quiescent conditions, immune mechanisms are activated by environmental stimuli and positively regulate the remodeling of neural circuits, promoting memory consolidation, hippocampal long-term potentiation and neurogenesis. These beneficial effects are mediated by complex interactions among neurons, astrocytes, microglia, neural precursor cells and peripheral immune cells (particularly T cells). These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters and hormones, as well as the responsiveness of neurons and glia to low levels of inflammatory cytokines, particularly interleukin (IL)-1, IL-6 and TNF alpha.  In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, brain immune cells, particularly microglia, change their morphology and functioning and secrete high levels of pro-inflammatory cytokines and prostaglandins, which disrupt the delicate balance needed for the neurophysiological actions of immune processes and produce direct detrimental effects on memory, neural plasticity and neurogenesis. These effects are mediated by inflammation-induced neuronal hyper-excitability and adrenocortical stimulation, followed by reduced production of neurotrophins and other plasticity-related molecules. Such immune-mediated changes facilitate many forms of neuropathology associated with normal aging as well as neurodegenerative and neuropsychiatric diseases, including Alzheimer's disease and major depression.

Peripheral inflammation impairs human spatial memory

Neil Harrison

Brighton and Sussex Medical School

Inflammation impairs cognitive performance and is implicated in the progression of neurodegenerative disorders. Rodent studies demonstrate key roles for inflammatory mediators in many processes critical to memory, including long-term potentiation, synaptic plasticity, and neurogenesis. Here I will review human data demonstrating acute sensitivity of human medial temporal lobe to even mild peripheral inflammation, giving rise to functional impairment in the form of reduced spatial memory performance. These data suggest a potential mechanism for the observed epidemiologic link between inflammation and risk of age-related cognitive decline and progression of neurodegenerative disorders including Alzheimer’s disease.

The biological and clinical outcomes of immunotherapy in Alzheimer’s disease

Clive Holmes

University of Southampton

In Alzheimer’s Disease a major focus of therapeutic development has been on the prevention of the deposition of amyloid protein in the brain which, is seen as having a major role in the development and progression of the disease. However, in clinical trials the modification of amyloid production does not appear to have had any beneficial clinical effects. Indeed emerging evidence shows that, in some cases, therapeutic interventions aimed at removing amyloid may lead marked bystander tissue damage.

The alternative hypothesis that pro-inflammatory drive is detrimental to the progression of AD has been advocated for many years but enthusiasm for this approach has been dampened by a large number of negative clinical trials of a wide variety of anti-inflammatory agents. However, interest has become rekindled due to the advent of genome wide association studies showing that inflammatory pathways are key to the development of late onset Alzheimer’s Disease.

We have argued that the chronic build up of amyloid in the brains of elderly subjects leads to a down regulated phenotype but in which microglial cells are primed. In these circumstances microglial cells are exquisitely sensitive to even modest pro-inflammatory signals leading to microglial activation with a marked increase in pro-inflammatory signalling and parenchymal damage. Importantly in these circumstances peripheral pro-inflammatory signals become a major contributor to disease progression in AD subjects. This hypothesis has been supported by a number of clinical studies, an understanding of which may lead to a number of novel therapeutic and preventative strategies.

Inflammation And Depression: Where Do We Stand?

Robert Dantzer

M.D. Anderson Cancer Center, Department of Symptom Research, Houston.

There is a general agreement on a role for inflammation in the pathophysiology of depression despite the fact that depression is not always associated with inflammation and vice versa inflammation does not always lead to depression. At the preclinical level, acute as well as chronic inflammation induces behavioral alterations that are labeled "depression-like behaviors" because they occur in animal tests of antidepressant action and are sensitive to antidepressants. At the clinical level, inflammation induces symptoms of depression in naive subjects but the emergence of a full-blown episode of depression requires the presence of the usual risk factors for depression. Recent behavioral and biochemical studies of inflammation-associated depression have helped to put the relationship between inflammation and depression in a new perspective, the implications of which for biomarkers and depression will be discussed.

Funded by the University of Texas MD Anderson Cancer Center and National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants R01-NS073939 and R01-NS074999]. The work of A.K. is also supported by a STARS [“Science and

Technology Acquisition and Retention”] award of the University of Texas System. R.D. worked as a consultant for Ironwood Pharma (Cambridge, MA)

The delirium dementia interface: vulnerability as a key determinant of the impact of systemic inflammation on central nervous system function

Colm Cunningham

Trinity College Dublin

It has been clear for many years that systemic inflammation can signal to the brain by a number of routes and that this inflammatory communication to the brain is essential to initiate the sickness behaviour syndrome (SBS). This periphery to brain communication involves the pro-inflammatory cytokines IL-1b, TNF-a and IL-6 as well as multiple prostaglandins. However, the arrival of these systemic inflammatory signals to the aged or neurodegenerative brain induces exaggerated CNS pro-inflammatory cytokine responses due to priming of the microglial population by aging and degenerative changes and this is associated with exaggerated sickness responses. These exaggerated sickness behaviours provide a conceptual framework by which we may begin to delineate aspects of delirium induced by systemic inflammation in such vulnerable populations. When superimposed on models of chronic progressive neurodegeneration and on basal forebrain cholinergic neurodegeneration systemic inflammatory insults produce robust cognitive/attentional dysfunction that is not observed during systemic inflammation in normal animals and these model systems have good construct and face validity for studying delirium during dementia. Using these models we have shown that IL-1b, COX-1-mediated prostaglandin synthesis and dysfunction in the cholinergic system all have clear roles in acute cognitive dysfunction induced by systemic inflammation. The progression of degeneration appears to progressively increase the risk for acute exacerbations of function in mice and humans. The continuing study of sickness behaviour syndrome and its interaction with multiple neurotransmitter systems that become dysfunctional with progressing disease will likely reveal important mechanistic insights into delirium and progression of dementia.

Inflammation in chronic neurodegeneration and the contribution of systemic inflammation.

V. Hugh Perry

University of Southampton

During the  progression of a number of neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, and prion diseases there is an innate immune response in the brain. This innate immune response is characterised by an increase in the density of the microglia, and their activation as judged by alterations in their morphology and the upregulation or de novo synthesis of macrophage antigens. The proliferation of microglia is driven by cytokines CSF1 and IL-34 acting on the CSF1-receptor. This pathway also primes the microglia. We have shown that systemic inflammation has a profound impact on the phenotype of these primed microglia, switching them to an aggressive tissue-damaging phenotype with exaggerated cytokine synthesis in the brain relative to naive animals.  The increased levels of cytokines are associated with exaggerated sickness behaviours and acceleration of disease progression. Understanding how systemic co-morbidities contribute to progression of chronic neurodegenerative disease offers a route to slowing disease progression and improving the quality of life of those with neurodegenerative disease.

Subjective health perception, inflammation and brain function

Mats Lekander

Stress Research Institute, Stockholm University, and Osher Center for Integrative Medicine, Karolinska Institute, Stockholm, Sweden.

Subjectively perceived health and bodily symptoms are central for wellbeing and health care seeking behaviors, but are also predictive of objective outcomes such as morbidity and mortality. In addition, how we perceive other individuals’ health status is important to regulate approach-avoidance behaviors and may affect clinical judgment. Along with an increased understanding of the role of the immune system in signaling the brain to regulate behavior, the role of inflammation in health perception can start to be delineated. The present talk will summarize models and findings, and discuss the link between inflammation, brain function, and subjective health perception.

Stress in Puberty Unmasks Latent Neuropathological Consequences of Prenatal Immune Activation in Mice

Urs Meyer

Physiology and Behaviour Laboratory, Switzerland

Prenatal infection and exposure to traumatizing experiences in peripubertal life have each been associated with increased risk for neuropsychiatric disease, especially schizophrenia and related psychotic illnesses. We have recently developed a translational mouse model of combined expo exposure to prenatal immune challenge and peripubertal stress to study possible neuropathological synergisms between these two adverse environmental factors. In this two-hit model, the first environmental hit is composed of prenatal viral-like immune activation induced by maternal administration of the synthetic double-stranded RNA poly(I:C) (polyriboinosinic-polyribocytidilic acid) during mid-gestation. The resulting offspring are then either left undisturbed or exposed to subchronic unpredictable stress during puberty. Using this two-hit environmental model, we reveal that prenatal immune activation and pubertal stress synergistically interact with each other to facilitate the emergence of schizophrenia-relevant behavioural and neurochemical abnormalities, including sensorimotor gating deficiency, hypersensitivity to psychotomimetic drugs, and dopaminergic imbalances in striatal and hippocampal areas. We further find that the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. In particular, offspring subjected to combined prenatal immune challenge and peripubertal stress show signs of neuroinflammation that are characterized by microglia activation and hypersecretion of brain inflammatory cytokines. Based on these latter findings, we have recently begun to test whether normalizing acute neuroinflammation in the event of peripubertal stress exposure may prevent the subsequent emergence of schizophrenia-relevant deficits in prenatally primed offspring. As a first proof-of principle supporting this hypothesis, we reveal that the adult onset of behavioural abnormalities induced by combined prenatal immune challenge and peripubertal stress can be prevented by administration of the broad-spectrum antibiotic minocycline during the course of peripubertal stress exposure. This intervention also prevents activation of microglia and altered pro-inflammatory cytokine secretion in prenatally primed offspring experiencing additional stress in puberty. Our experimental data highlight that stress exposure in puberty can unmask latent neuropathological consequences of early prenatal environmental insults such as prenatal maternal infection. Furthermore, anti-inflammatory strategies may represent a valid pharmacological approach to prevent full-blown brain abnormalities emerging in subjects exposed to multiple environmental hits such as prenatal infection and pubertal stress.

Stress, Immunity and the Microbiota-Gut Brain Axis in Early-Life: Priming for Health and Disease

Prof. John F. Cryan

University College Cork, Cork, Ireland

Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Regulation of the microbiome-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. The microbiota undergoes a vigorous process of development throughout lifespan and establishes its symbiotic rapport with the host early in life. Early-life perturbations of the developing gut microbiota can impact neurodevelopment and potentially lead to adverse mental health outcomes later in life. Moreover, there is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Research has focused on how the microbiota communicates with the CNS and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus, the concept of a microbiome-brain-gut axis is emerging which suggests that modulation of the gut microflora may be a tractable strategy for developing novel therapeutics for complex stress-related CNS disorders where there is a huge unmet medical need.

Immune-to-brain communication: relevance for neuropsychiatric  comorbidity in metabolic disorders

Lucile Capuron

INRA, Bordeaux.

Potent interactions between the immune system and the brain provide the basis for understanding mechanisms of the influence of immune processes on behavioral symptoms. Inflammatory cytokines released by activated immune cells are notorious for causing neuropsychiatric symptoms, including fatigue, cognitive dysfunction and mood alterations. Metabolic disorders such as obesity or the metabolic syndrome are characterized by a chronic low-grade inflammatory state, with an over-expression of circulating inflammatory factors to the detriment of anti-inflammatory factors. Not surprisingly, these conditions are also associated with an increased prevalence of neuropsychiatric symptoms. In order to assess the contribution of systemic inflammation to neuropsychiatric comorbidity in these conditions, clinical studies were conducted in patients suffering from metabolic disorders, including obesity, type 2 diabetes and/or the metabolic syndrome. Results indicate that chronically activated inflammatory processes, in conjunction with separate vulnerability factors, are associated with significant alterations in the activity of metabolic and enzymatic pathways involved in the biosynthesis of neurotransmitters that may contribute to the pathophysiology of neuropsychiatric symptoms. Given the increasing incidence of overweight and obesity worldwide, strategies to regulate chronic inflammatory processes in these conditions and to prevent inflammation-related metabolic/enzymatic changes and neuropsychiatric disturbances may be of particular relevance.

Inflammation and the generation of neurotoxins: can the activation of the tryptophan-kynurenine pathway in depression suggest novel targets for psychotropic drug development?

Aye-Mu Myint

Ludwig-Maximilian University, Munich, Germany and School for Mental Health and Neuroscience, Maastricht University, The Netherlands

Inflammation and the generation of neurotoxins: can the activation of the tryptophan-kynurenine pathway in depression suggest novel targets for psychotropic drug development?

Psychiatric disorders are highly heterogeneous and quite often become chronic or comorbid with physical illnesses. Treatment resistance to antidepressants is an important issue and new treatment targets are necessary. The use of biomarkers to single out patients for particular treatment of care is also an option to handle the issue of treatment resistance. Activation of inflammatory response system is well documented in depression and inflammatory process can cause accumulation of kynurenines. Kynurenines are the neuroactive metabolites from tryptophan metabolism which play a role in glial-neuronal network in the brain and also in the link between body immune system, neuroplasticity and ageing.

Series of studies have been performed regarding the profile of kynurenines in the serum/plasma and cerebrospinal fluid in patients with mood disorders. The changes in kynurenines and related molecules were shown to be associated with subgroup of depression, specific symptoms and response to antidepressant treatment.

We proposed that kynurenines and inflammatory related biomarkers can be applied in personalized medicine in future psychiatry.

Molecular mechanisms linking brain response to peripheral inflammation.

Jonathan Cavanagh

University of Glasgow

Part of the increasingly compelling evidence base supporting an association between inflammation and mood disorder is that anti-inflammatory drugs may have anti-depressant effects. This is supported by a number of clinical trails but mechanisms underpinning this remain unclear.

Pro-inflammatory cytokines (e.g. TNFα) have previously been shown to increase the activity and availability of the serotonin transporter (SERT), a protein central to the neuropharmacology of SSRI antidepressants. Availability of highly specific cytokine antagonists (biologicals) affords the possibility to explore the impact of peripheral modulation of cytokines on brain SERT expression. We therefore predicted that given evidence that cytokines up-regulate SERT selective cytokine antagonism will down regulate or reverse this.

In an initial proof of concept study, we showed that SERT availability was reduced following 4 weeks of the human monoclonal drug Adalimumab in a sample of patients with rheumatoid arthritis. This has since been replicated with another drug (Etancercept) in a different clinical population (Psoriatic Arthritis). Here we found that pre-Etanercept TNF correlated positively with pre-Etanercept SERT. Also higher SERT availability mediated the relationship between peripheral inflammatory markers and depression. Treatment with anti-inflammatory biological was associated with decrease in SERT as was a reduction in BDI.

In this presentation I will explore the implications of this finding as well as data from preclinical models implicating chemokines.

Glucocorticoids, cytokines and brain abnormalities in depression

Carmine M. Pariante

Institute of Psychiatry, King’s College London

This talk will offer support to the notion that increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and of peripheral inflammation is on the causal pathway to depression. In particular, this talk will discuss our recent findings, from both experimental and clinical research, showing that high levels of cortisol and of pro-inflammatory cytokines, such as interleukin-1 and IL-6, directly affect brain function by reducing hippocampal size, by decreasing neurogenesis and by stimulating the production of neurotoxic and depressogenic metabolites. Moreover, increased pro-inflammatory cytokines predict which depressed patients are less likely to respond to conventional antidepressants. These HPA axis and inflammation abnormalities seem to be particularly important for a more “developmental” form of depression, originating in early life trauma.  In conclusion, twenty years of research on depression, the HPA axis and the immune system are finally bringing “personalised medicine” right into the core of psychiatry research and patients’ care.

Effects Of Interferon-Alpha Treatment On Cortical Glutamatergic Function

Matthew Taylor

Institute of Psychiatry, King's College London

The development of depressive symptoms is a significant complication of treatment with the cytokine, interferon-α, with up to 40% of patients developing major depression over three months of therapy.

We studied 12 patients with hepatitis C receiving pegylated-interferon-α and ribavirin. Glutamate and glutamine measurements were obtained from anterior cingulate cortex before and after 4-6 weeks treatment with interferon.

Treatment led to an increase in cortical levels of glutamine (p= 0.02) and a significant elevation in the ratio of glutamine to glutamate (p<.01). Changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan.

These data indicate that treatment with interferon-α is associated with MRS-visible changes in glutamatergic metabolism. The changes seen differ from those reported in major depression. The pathophysiology of interferon-induced depression may differ from that of major depression, and be more similar to the pattern of effect seen in bipolar disorder.

Neuroimmune Signaling creates the Neurobiology of Alcohol Dependence

Fulton T. Crews

University of North Carolina School of Medicine

Our experiments modeling alcoholic binge drinking have led to thae hypothesis that neuroimmune gene induction contributes to addiction neurobiology and neurodegeneration.  Neuroimmune genes are generally associated with monocyte innate immune responses, but are expressed in brain.  These genes include cytokines-chemokines, toll-like receptors (TLR), oxidases such as COX, NOX and iNOS, proteases and high mobility group box 1(HMGB1-amphoterin), an endogenous TLR4 agonist cytokine.  Neuroimmune genes share signaling mechanisms that activate NFkappaB, a transcription factor that increases expression of most neuroimmune genes and their receptors which further activate NFkappaB creating amplifying loops.  Multiple mechanisms can contribute to neuroimmune activation.  One mechanism involves acute high dose ethanol, stress or other factors that increase gut permeability leaking bacterial factors that activate liver innate immune genes that contribute to activation of brain responses.  Another mechanism involves neuronal excitation releasing HMGB1 from neurons that activate TLR4 and other receptors.  Genetic studies find NFkB as a central gene related to alcohol drinking and stimulant preferring transcriptomes in rodents.  Opiates also interact with TLR4 receptors and naltrexone, a pharmacotherapy for alcoholism, blocks HMGB1-TLR4 signaling. Transgenic mice lacking neuroimmune genes drink less alcohol and induction of neuroimmune genes with endotoxin in normal mice increases alcohol preference and drinking for months. Neuroimmune genes are hypothesized to disrupt frontal cortical circuits due to hyperexcitability, reducing behavioral flexibility and increasing negative affect increasing risks of abuse in heavy drinkers. 

An early age of drinking onset is associated with increased risk of alcohol dependence during the lifetime.  Adolescent binge drinking models find persistent and progressive increases in neuroimmune gene expression that last long into adulthood and are associated with alterations in choline acetyltransferase and tyrosine hydroxylase expression as well as a persistent loss of hippocampal neurogenesis.   Adolescent binge drinking exposure also leads to adult delayed discounting dysfunction, sleep disturbances, perseveration and a persistence of adolescent phenotype, perhaps defining an Adolescent Binge Alcohol Syndrome.  Studies of post-mortem human brain find alcoholics have increased neuroimmune gene expression in orbital frontal cortex.  HMGB1 and TLR expression in OFC correlates across all human subjects with age of drinking onset and lifetime alcohol consumption consistent with the progressive and persistent induction of neuroimmune signaling contributing to the chronic relapsing nature of dependence.  Neuroimmune signaling may be an important target for pharmacotherapies for dependence.