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

Discussion meeting


The Royal Society, London, 6-9 Carlton House Terrace, London, SW1Y 5AG


Scientific discussion meeting organised by Dr Amy L Milton and Professor Emily Holmes.

Credit: Abigail Reynolds 'Mirror Benrath'. Image courtesy of the artist.

Basic and clinical neuroscientists pioneering research into mental health disorders have much to learn from each other, but opportunities for interaction are limited. This meeting will bring these investigators together, highlighting commonalities in approach and facilitating dialogue between them, to aid in the development of new, fully translational models that will promote our understanding and treatment of mental health disorders.

The schedule of talks and speaker biographies are available below. Speaker abstracts will be available closer to the meeting date. Recorded audio of the presentations will be available on this page after the meeting has taken place. Meeting papers will be published in a future issue of Philosophical Transactions B.

Poster session - deadline extended

There will be a poster session at 17.00 on Monday 24 April 2017. If you would like to apply to present a poster please submit your proposed title, abstract (no more than 200 words), author list, name of proposed presenter and institution to the Scientific Programmes team no later than Friday 10 March 2017. Please include the text 'Poster abstract submission' in the email subject line. Please note that places are limited and posters are selected at the scientific organisers' discretion. Poster abstracts will only be considered if the presenter is registered to attend the meeting.

Attending this event

This event is intended for researchers in relevant fields.

  • Free to attend
  • Limited places, advanced registration essential
  • An optional lunch can be purchased during registration

An evening poster session and optional drinks reception will be held following the close of the meeting on 24 April. Whilst the posters are free to view for all registered participants, the corresponding optional drinks reception is ticketed. Drinks tickets can be purchased in advance during registration.

Enquiries: Contact the Scientific Programmes team

Event organisers

Select an organiser for more information

Schedule of talks

24 April

Session 1 09:00-17:00

Stress and anxiety disorders

9 talks Show detail Hide detail


Dr Amy L. Milton, University of Cambridge, UK

09:05-09:45 Mental health and mental health science: opportunity for treatment innovation

Professor Emily Holmes, Karolinska Institute, Sweden

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09:45-10:30 Memory boundaries: an opportunistic therapeutic window

Professor Marie Monfils, The University of Texas, USA


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.

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10:30-11:00 Coffee

11:00-11:45 Optimising extinction learning during exposure therapy

Professor Michelle Craske, University of California Los Angeles, USA


The therapeutic strategy of repeated exposure to fear producing stimuli is effective for fears and anxiety disorders, but a substantial number of individuals fail to respond or show a return of fear. Translation from the basic science of fear extinction inhibitory retrieval models, and inhibitory regulation, offers strategies for increasing response rates and decreasing relapse following exposure therapy. The underlying theories and evidence for these strategies will be presented, as well as their contrast with ‘fear habituation’ approaches for conducting exposure therapy. The strategies that optimise inhibitory learning/regulation include violation of expectancies by designing exposures to provide evidence that disconfirms expectancies, and by presenting multiple feared stimuli simultaneously as well as occasional exposures to aversive outcomes. Attention to the feared stimuli is considered critical to these processes while cognitive restructuring can be an impediment. Methods for rehearsal and other forms of consolidation following exposure therapy will be discussed. Variability in stimuli and context throughout exposure, utilisation of retrieval cues, and methods for limiting hippocampal activation during exposure offer the potential to increase generalisation of extinction/exposure therapy and limit return of fear. Strategies for increasing the valence of feared stimuli also reduce vulnerability to return of fear. Finally, affect labelling (or labelling emotional responses), an implicit inhibitory regulation strategy, will be presented.

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11:45-12:30 The secret life of emotional memories

Professor Merel Kindt, University of Amsterdam, The Netherlands

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12:30-13:30 Lunch

13:30-14:15 Rewrite or overwrite: identifying neuromolecular mechanisms of remote fear memory attenuation

Dr Johannes Gräff, École Polytechnique Fédérale de Lausanne, Switzerland


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. 

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14:15-15:00 Professor Susan Mineka, Northwestern University, USA

15:00-15:30 Tea

15:30-16:15 Can we bridge psychological and pharmacological views of depression and its treatment? 

Professor Catherine Harmer, University of Oxford, UK


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.

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16:15-17:00 Development of translational new approaches to investigating mood disorders in rodents

Dr Emma Robinson, University of Bristol, UK


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.

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Poster session

25 April

Session 2 09:00-13:15

Compulsive disorders

5 talks Show detail Hide detail


Professor Emily Holmes, Karolinska Institute, Sweden

09:00-09:45 Neuroimaging in drug addiction: an eye towards intervention purposes

Professor Rita Goldstein, Icahn School of Medicine at Mount Sinai, USA


Drug addiction is a chronically relapsing disorder characterised by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, Dr Goldstein will present results of human neuroimaging studies, utilising a multimodal approach (neuropsychology, functional magnetic resonance imaging, positron emission tomography, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, Dr Goldstein’s multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk Dr Goldstein will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behaviour compromises in treatment seeking cocaine addicted individuals. Promising novel fMRI studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging in the empirical guidance for the development of effective neurorehabilitation strategies in cocaine addiction.

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09:45-10:30 Addictive behaviour in experimental animals: prospects for translation

Professor Barry Everitt FMedSci FRS, University of Cambridge, UK

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10:30-11:15 Neurobiology of compulsive eating

Dr Pietro Cottone, Boston University, USA


Compulsive eating behaviour is a transdiagnostic construct that is characteristic of medical and psychiatric conditions such as forms of obesity and eating disorders. It has been hypothesised that one of the mechanisms underlying compulsive eating involves highly palatable food acquiring negative reinforcing properties; that is, the need to alleviate a negative emotional state induced by withdrawal from high palatable food drives overeating. The group observed that rats undergoing chronic, intermittent access to highly palatable food showed hypophagia and decreased motivation for a less palatable food alternative. Withdrawal from palatable food was associated with spontaneous emotional signs of palatable food-withdrawal, including anxiety- and depressive-like behaviour. In addition, cycling rats showed a weakened ability for contextual spatial processing during withdrawal. According to a negatively reinforced mechanism, renewing access to highly palatable food normalised all withdrawal-dependent maladaptive behavioural outcomes, and induced overeating. Palatable-food withdrawal was also found to be accompanied by increased corticotropin-releasing factor (CRF) expression in the central nucleus of the amygdala and administration of a selective CRF1 receptor antagonist directly into this brain area was able to block both the overeating of palatable food and the negative emotional state. Interestingly, diet cycled rats also showed reduced expression of immature neurons in the dentate gyrus of the hippocampus, as well as a withdrawal-dependent decrease of proliferating cells. These results suggest that withdrawal from palatable food, analogous to abstinence from abused drugs, causes profound behavioural and molecular neuroadaptations which promote and sustain compulsive eating.

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11:15-11:45 Coffee

11:45-12:30 Deep Brain Stimulation in obsessive compulsive disorder: a decade of experience

Professor Damiaan Denys, University of Amsterdam, The Netherlands


OCD is considered one of the most disabling psychiatric disorders, causing serious impairment in patients’ daily functioning and affecting professional, social, and personal lives. Thanks to a wide range of available pharmacologic treatments and cognitive behavioural therapy (CBT), most patients can be treated to a satisfactory level. However, 10% of patients experience inadequate response and remain severely ill. In the last decades, neuromodulating techniques have emerged as promising alternatives for the treatment of OCD. Different from the rather aspecific pharmacologic modulation of drug therapy, neuromodulation techniques enable modulation of distinct neuronal circuits by targeting specific brain structures. OCD may be particularly suitable for these interventions because of its strong link to discrete neuro-anatomic networks. Neuroimaging studies have consistently related OCD to aberrant activity within the orbitofronto-striato-thalamo-cortical (CSTC) network. A major advantage of neuromodulation is its potential of adjustable and reversible brain network manipulation. This lecture reviews studies on DBS for OCD.

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12:30-13:15 Dissecting OCD mechanisms using advanced technologies in mice

Dr Susanne Ahmari, University of Pittsburgh, USA


Ahmari and colleagues explore the neural mechanisms underlying perseverative thoughts and actions. This topic is of general importance because compulsive behaviours are a central component of Obsessive Compulsive Disorder (OCD), as well as prominent, disabling, and notoriously-treatment resistant symptoms of many severe psychiatric disorders, including autism, schizophrenia, and addiction. Although OCD symptoms have been broadly linked to abnormal activity in cortical-basal ganglia circuits via human imaging studies, there is still a quite limited understanding of how maladaptive repetitive behaviours are encoded in the brain. The Ahmari lab is therefore using novel technologic approaches and statistical strategies to determine: 1) which neural circuits underlie maladaptive repetitive behaviours, 2) how these behaviours are encoded in the brain, and 3) when the neural code changes as these behaviours develop and resolve.

In previous work the Ahmari lab demonstrated that repeated pulses of brief but abnormal activity delivered by optogenetic stimulation of projections from orbitofrontal cortex (OFC) to ventromedial striatum (VMS) leads to long-lasting perseverative grooming, a mouse behaviour linked to OCD. This compulsive grooming behaviour was associated with increased neural activity in the striatum. Dr Ahmari will discuss how her lab is now using advanced in vivo approaches including optogenetics, electrophysiology, and head-mounted microscopy to identify the specific activity patterns, cell-types, and circuits responsible for this pathologic plasticity in the brain. She will also describe approaches to ground basic neuroscience experiments in findings from clinical studies.

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Session 3 14:15-15:45


2 talks Show detail Hide detail


Dr Amy L. Milton, University of Cambridge, UK

14:15-15:00 Modelling DISC1 and EIF4E mutations in mice

Professor David St Clair, University of Aberdeen, UK


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.

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15:00-15:45 Using human brain imaging studies as a guide toward animal models of schizophrenia

Professor Christoph Kellendonk, Columbia University, USA


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.

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15:45-16:15 Tea

Session 4 16:15-17:00

General discussion

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Professor Emily Holmes, Karolinska Institute, Sweden

16:15-17:00 From basic disease mechanisms to therapeutics: making a new map

Professor Steven Hyman, Harvard University, USA


Genetic analyses of schizophrenia and other psychiatric disorders are yielding exciting initial results. It is sobering, however, to contemplate the implications of the genetic risk architecture of psychiatric disorders for biological investigation, given the goals of elucidating disease mechanisms and informing discovery of biomarkers and new drug targets. Risk of common psychiatric disorders involves heterogeneous combinations of low penetrance gene variants (alleles) associated with many hundreds of genes. The successful reductionist approaches long used to interrogate gene function—introduction of penetrant transgenes into inbred mouse strains—simply will not work. In different inbred strains, penetrant mutations yield different phenotypes, belying the possibility of generalisation across Mus musculus let alone to Homo sapiens. Moreover, except for rare, severe neurodevelopmental conditions, there are no penetrant mutations to interrogate.  We must therefore develop robust and translatable biological systems in which to study the actions of risk genes. Important steps on the way will include (1) Pushing human genetics to the point of diminishing biological returns to permit discovery of convergence of risk gene expression on specific cell types and pathways; (2) Advancing the utility of human cellular models in vitro (3) As ethically and pragmatically possible using transplantation of human pluripotent cells or neurons  into animal brains and genetically humanising model organisms; (4) Developing robust and high throughput assays relevant to pathophysiology.

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Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists The Royal Society, London 6-9 Carlton House Terrace London SW1Y 5AG UK