Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists

First, a warm welcome to ‘From mice to mental health’ at the Royal Society – an interdisciplinary meeting of researchers who range from basic scientists to clinicians – yet who bring together their different methods to a shared goal. Our common approach is to understand and improve mental health treatments via mental health science (Holmes, Craske and Graybiel, 2014, Nature). 

Clinicians and scientists must work together to understand and improve mental health treatments. Mental–health disorders now account for more than 15% of the disease burden in developed countries, more than all forms of cancer. Even the best mental health treatments demand improvement – for example to increase the proportion of patients who achieve a clinically meaningful reduction in symptoms or full remission. Mental health science has an important role to play in improving treatments of all types, whether psychological, pharmacological or their combination. Basic and clinical neuroscientists pioneering research into mental health disorders have much to learn from each other, but opportunities for interaction are limited. A culture gap means both sides are often unaware of what the other is doing. Therefore, it is hoped this meeting facilitates dialogue – ultimately to aid in the development of translational models for mental health. 

Second, Professor Holmes will discuss work from her group. The group’s core interests are (1) psychological trauma and mental imagery; (2) translating experimental psychopathology for psychological treatment development. Intrusive memories of psychological trauma comprise mental images. Mental imagery involves an experience like perception in the absence of a percept, such as ‘seeing in our mind’s eye’. Intrusive memories that ‘flash back’ to past trauma occur in post-traumatic stress disorder (PTSD) while images that ‘flash forwards’ to the future can occur in bipolar disorder. 

To better understand and treat maladaptive mental imagery, the group is curious about what can be learned from animal and human neuroscience. Here Professor Holmes will discuss work concerning intrusive memory encoding using human fMRI (Clark et al, 2016, Psych Med); and a behavioural method (dual task interference) to disrupt memory re-consolidation which reduces the frequency of intrusive memories of experimental trauma in humans, yet is informed by animal models (James et al, 2015, Psych Sci). Finally, she will discuss the successful translation of this intervention (memory activation plus Tetris gameplay) to patients (Iyadurai et al, 2017, Molecular Psychiatry). Results show a brief intervention delivered in a hospital emergency department after a traumatic motor vehicle accident reduces the number of intrusive memories of trauma. Results have replicated in a different traumatised population (Horsch et al, in press, Behaviour Research and Therapy). Given the scale of trauma world wide – from accidents to refugees who have experienced war- the need for new effective treatments after trauma that can reach a large population has never been greater.

Professor Emily Holmes, Karolinska Institute, Sweden

Professor Emily Holmes, Karolinska Institute, Sweden

Emily is Professor of Psychology at the Karolinska Institutet in Stockholm. She is a clinical psychologist and cognitive neuroscientist. The work in her research group is underpinned by a core interest in mental health science, and the translation of basic findings to create innovations to improve psychological treatments to reach more people. The research takes an interdisciplinary approach including psychology, psychiatry, cognitive science, neuroscience and so forth. Her group is particularly interested in the powerful impact of mental imagery on emotion. This research is being used to develop solutions in areas where we lack treatments – such as to prevent the build-up of symptoms soon after a traumatic event, and innovative treatments for refugee trauma - approaches which ultimately can help benefit the many people affected by trauma worldwide.

Emily is also a Visiting Professor in Clinical Psychology at the Department of Psychiatry at the University of Oxford, holds an Honorary Appointment at the MRC Cognition and Brain Sciences, Cambridge, UK and is a Fellow of Clare Hall, University of Cambridge. She is Associate Editor of 'Behaviour Research and Therapy'. Her research has been recognised by the British Psychological Society’s Spearman Medal (2010), Humboldt Foundation Friedrich Wilhelm Bessel Research Award (2013), and the American Psychological Association (2014). She is on the Board of Trustees and Chair of the Fellows Committee of the research charity ‘MQ; transforming mental health.’

Dysregulation of the fear system is at the core of many psychiatric disorders. When fear memories are formed, they are initially fragile, but become progressively strengthened into persistent traces via the synthesis of new proteins (a process called consolidation). Later retrieval of a consolidated fear memory engages two seemingly opposing mechanisms: reconsolidation and extinction. Manipulations based on each of these approaches are routinely used to attenuate fear memories. Many factors account for how well individuals respond to treatments aimed to reduce acquired fears, such as genetic variability, learning capacity and conditions under which an intervention is administered. Here, Professor Monfils describes how reconsolidation and extinction-based interventions can be employed to optimise fear reduction, in rats and humans, and propose that while they may both be effective under certain conditions, they differ in the groups they target.

Professor Marie Monfils, The University of Texas, USA

Professor Marie Monfils, The University of Texas, USA

Marie Monfils is currently an Associate Professor in the Department of Psychology at the University of Texas at Austin, where she heads the Monfils Fear Memory Lab. She received her Ph.D. in Behavioural Neuroscience from the Canadian Centre for Behavioural Neuroscience, under the supervision of Bryan Kolb and Jeffrey Kleim, and her Master’s degree from the University of Calgary with Cam Teskey. She conducted a postdoctoral fellowship at New York University with Joseph LeDoux. Dr. Monfils’ lab is currently examining the mechanisms by which post-consolidation manipulations can persistently attenuate fear memories, and isolating the factors that underlie the social transmission of fear.

At the turn of this century, a major breakthrough in neuroscience was achieved with the discovery that once (fear) memories are retrieved, they may enter a labile, protein synthesis dependent state, rendering it amenable to change. This process is referred to as memory reconsolidation and offers a window of opportunity to target fear memories with amnesic agents. Evidence for pharmacologically induced fear amnesia has progressed from animals to humans. In a series of laboratory experiments, the group has convincingly demonstrated that disrupting the process of memory reconsolidation erased the affective component from a fear memory, without changing the actual recollection of the threatening event. These laboratory findings hint at the prospect of a revolutionary new treatment for disorders of emotional memory. The reconsolidation intervention challenges the dominant psychological and pharmacological models of treatment. Instead of multiple sessions of cognitive behavioural treatment or daily drug intake with a gradual reduction of symptoms, it involves one single intervention that leads to a sudden decline in fear. And the intervention is only effective when the drug is given in conjunction with memory reactivation during a specific time window, while a modification of cognitive processes is not necessary to change fear. But irrespective of these therapeutic potentials, an obvious limitation in human memory research is that the underlying neurobiological processes of memory reconsolidation can neither be directly observed nor locally targeted. Hence, the critical conditions for harnessing memory reconsolidation in humans are still largely unknown.

Professor Merel Kindt, University of Amsterdam, The Netherlands

Professor Merel Kindt, University of Amsterdam, The Netherlands

Merel Kindt (1967) is full Professor of Experimental Clinical Psychology at the University of Amsterdam. It is her mission to understand mechanisms of change, and to build on fundamental brain and cognition science in order to shape clinical interventions. In 2008, she started an innovative research programme on the plasticity of fear memory, which challenged the prevailing cognitive behavioural hypothesis that emotional memories are fixated in the physical architecture of the brain. She has used and developed a vast array of experimental methods to study the formation, consolidation and plasticity of emotional memory in humans. The potential of her research program lies in the bidirectional translational approach. It builds on fundamental insights from animal and human neuroscience literature, as well as clinical observations. These insights and observations provide operational tools to test novel hypotheses at different levels of analysis.

How to attenuate traumatic memories has long been the focus of intensive research efforts, as traumatic memories are extremely persistent and heavily impinge on the quality of life. Yet, surprisingly few studies have investigated treatment options for remote, i.e. long-lasting forms of traumata in animal models. The few that have unanimously concluded that exposure therapy-based treatments, the most successful behavioural intervention for the attenuation of recent traumata in humans, fail to effectively reduce remote fear memories.

Recently, the group has described a pharmacological approach by which even remote fear memories become amenable to attenuation: By combining exposure therapy-like approached with histone deacetylase inhibitors in mice, chromatin-templated neuroplasticity could be reinstated, which resulted in persistent fear reduction (Gräff et al., Cell, 2014).

Notwithstanding, the physiological substrates of such persistent fear reduction remain unclear. In particular, it is still open whether successful attenuation of remote fear memories is driven by a new memory trace of safety or by a re-learning of the original memory trace of fear. In the current project, the group is in the process of investigating this question in a cell type-specific manner using transgenic mice that allow for the visualisation of remote fear memory traces. 

Dr Johannes Gräff, École Polytechnique Fédérale de Lausanne, Switzerland

Dr Johannes Gräff, École Polytechnique Fédérale de Lausanne, Switzerland

Johannes Gräff is an Assistant Professor on tenure track at the Brain Mind Institute at EPFL, Switzerland. He obtained his PhD from ETH Zürich under the supervision of Isabelle Mansuy before conducting his postdoc at MIT under the guidance of Li-Huei Tsai. A main research focus of his lab is how long-term traumatic memories can be overcome. To answer this question, the Gräff lab uses mouse behaviour in combination with brain circuit and molecular analyses. Particular focus is paid to the emerging field of neuroepigenetics. Epigenetic mechanisms are at once dynamic and stable, and thus harbour the potential to better explain the molecular processes that govern learning, memory and memory loss. In extension, because epigenetic mechanisms are also amenable to pharmacological intervention, they might constitute a novel angle on how to counteract memory loss and resilient traumatic memories.

Disrupted in Schizophrenia one (DISC1) and Eukaryote Initiation factor 4 E (EIF4E) genes are candidate genes for major psychiatric disorders.They were first identified through their disruption by balanced translocations in two Scottish families.The former involved an inherited 1:11 translocation cosegregating with multiple cases of major affective disorders and schizophrenia.The latter a de novo 4q:5q translocation in a boy with severe autism. Two further families with mutations of the promoter causing overexpression of EIF4E were also reported.

To model DISC1 mutation in mice, Shen et al generated Disc1tr transgenic mice expressing 2 copies of truncated Disc1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, they discovered a range of phenotypes including a series of novel features not previously reported. Disc1tr transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviourally, transgenic mice exhibit increased immobility and reduced vocalisation in depression-related tests, and impairment in conditioning of latent inhibition.

Overexpression of eIF4e in mice  results in exaggerated cap dependent translation and a range of repetitive and perseverative behaviours and social interaction deficits reminiscent of autism and are accompanied by synaptic pathophysiology in medial prefrontal cortex, striatum and hippocampus. The autistic behaviours are corrected by intracerebral infusion of cap dependent translation inhibitor 4EG1-1.

Although Disc1 and Eif4 E genes do not show up in GWAS studies, these rare high penetrant mutations modelled in mice have provided important insights into key molecular pathways involved in major psychiatric disorders.

Professor David St Clair, University of Aberdeen, UK

Professor David St Clair, University of Aberdeen, UK

Professor David St Clair is a clinical academic psychiatrist. He holds a tenured clinical professorship at the University of Aberdeen UK and honorary consultant position at the Royal, Cornhill Hospital.He is adjunct professor at Columbia University, New York and advisory professor at Shanghai Jiaotong University.

With over 250 scientific publications in psychiatric genetics, molecular neuroscience, psychophysiology and epidemiology, he is best known for his ground breaking work on DISC1 gene, copy number variations, event related potentials and eye movements as trait markers, and prenatal malnutrition and risk of schizophrenia.

From Jan 2010 to Jan 2012 Dr St Clair was visiting scientist NIMH/NIH, Bethesda MD,USA.

Professor St Clair is chief scientific officer and cofounder of Saccade Diagnostics a spin out company of Aberdeen University whose aim is to develop eye tracking technology for use in routine psychiatric practise. A large component of this work is currently funded by Wellcome Trust and Department of Health: Health Innovation Challenge Fund (HICF) award.

Schizophrenia is a heterogeneous mental disorder that is presently defined by its behavioural symptoms. Advances in genetic, epidemiological and brain imaging techniques in the last 30 years, however, have significantly advanced our understanding of the underlying biology of the disorder. Despite these advances clinical research remains limited in its power to establish the causal relationships that link aetiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about potential biological processes that are disrupted in the disorder. At the meeting Professor Kellendonk will present an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. Specifically, he will describe two mouse models that were generated and studied based on two imaging findings in patients: enhanced striatal dopamine D2 receptor activation and decreased thalamo-prefrontal circuit function. By modelling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioural consequences, and (2) to determine whether this brain abnormality can cause alterations in other brain areas that are thought to be affected in patients.

Professor Christoph Kellendonk, Columbia University, USA

Professor Christoph Kellendonk, Columbia University, USA

Dr Kellendonk obtained his PhD from the University of Heidelberg in Germany where he employed genetic tools to study glucocorticoid receptor function in the mouse. He then joined Dr Eric Kandel’s laboratory at Columbia University in New York as a postdoctoral researcher. There he started to develop mouse models with relevance for schizophrenia. Since 2008 Dr Kellendonk has led his own laboratory in the Departments of Psychiatry and Pharmacology at Columbia University and the New York State Psychiatric Institute. Using the mouse as an animal model he hopes to A) better understand basic mechanisms that regulate cognitive and motivated behaviours relevant for schizophrenia, B) inspire new human studies based on outcomes from these models and C) develop new treatment strategies for enhancing cognition and motivation.

Cognitive and pharmacological approaches to depression are often considered independently from one another and can be viewed as competing explanations. However, recent evidence challenges this division and shows that antidepressants affect cognitive mechanisms important for the maintenance of depression very early in treatment.  For example, a single dose of an antidepressant reduces negative affective bias in depression by increasing the recognition of positive facial expressions and enhancing memory for positive vs negative information. At a neural level, these early changes in emotional processing are related to re-tuning fronto-limbic circuitry important for the detection and response to biologically salient information. Although these changes in neurocognitive processing occur before clinical changes in depression are seen, they are predictive of later clinical response. These results are therefore consistent with the view that antidepressants work via early correction of negative bias and the delay in response reflects the need for changes in processing to interact with everyday events, stressors and cues. As such, antidepressants may not be direct mood enhancers but work in a more similar way to targets of psychological treatments such as Cognitive Behavioural Therapy (CBT). This approach offers a framework by which novel treatment approaches may be formulated and screened. In particular, this approach offers hypotheses about how to best combine psychological and pharmacological strategies for depression and anxiety.

Professor Catherine Harmer, University of Oxford, UK

Professor Catherine Harmer, University of Oxford, UK

Catherine Harmer is a Professor of Cognitive Neuroscience at the University Department of Psychiatry in Oxford. She directs a multidisciplinary team of researchers in the Psychopharmacology and Emotion Research Lab (PERL) using a variety of techniques such as fMRI, MEG, TMS, psychopharmacological challenge techniques and neuropsychological assessments. Her work has led to the novel idea that antidepressants may work by rapidly resolving negative affective bias in depression which leads to gradual improvements in mood, social dysfunction and other key symptoms of depression over time. This concept has stimulated new research approaches for the treatment of depression with implications for stratification of treatment, early prediction of therapeutic response and identification of novel therapeutic targets. Catherine Harmer has been awarded prizes from the British Association for Psychopharmacology and the Royal College of Psychiatrists for this research and is the 2013 recipient of the AE Bennett award from the Society of Biological Psychiatry.

Studies in animals are essential in the understanding of disease processes and the development of new treatments. This is particularly the case where they utilise methods which cannot be applied to humans due to ethical and/or practical constraints. In psychiatry, animal studies have been heavily criticised due to concerns that the methods used, and results obtain, fail to translate to the clinical condition. Translating subjective, self-report measures used in the diagnosis of depression into valid animal models is not possible. In contrast, objective, neuropsychological methods provide a much more realistic starting point. This talk will describe results from our novel rodent behavioural tasks developed to more closely reflect the neuropsychological impairments reported in major depressive disorder (MDD). The work build on the clinical literature which shows how emotional states alter cognitive processes. These affective biases have been shown to influence a wide range of cognitive processes including learning and memory and decision-making. Animal studies now suggest that similar affective biases are observed across a wide range of species and tasks to quantify these biases may provide a novel approach to studying MDD. This presentation will include validation data for a wide range of antidepressant and pro-depressant manipulations. Dr Robinson will also discuss evidence which suggests that distinct neuropsychological mechanisms explain the differences in effects seen with delayed versus rapid onset antidepressants. The final part of the talk will discuss the relationship between affective biases and anticipation of reward and their possible roles in the symptoms of MDD.

Dr Emma Robinson, University of Bristol, UK

Dr Emma Robinson, University of Bristol, UK

Emma completed her BSc(Hons) in Pharmacology in Bristol in 1995 and PhD in Psychopharmacology in 1999. In 2005, she was awarded an RCUK Academic Fellowship which included an opportunity to work at the University of Cambridge, Experimental Psychology Department. Now based in Bristol’s School of Physiology, Pharmacology and Neuroscience, Emma’s research focuses on studies to investigate the neural and neurochemical mediators of normal cognitive and emotional behaviour and how these may be disrupted in psychiatric disorders such as depression, anxiety and addiction. Her recent work has focused on the development and validation of novel methods to study emotional behaviour in rodents, in particular, investigating affective biases associated with mood disorders.