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.

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.

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.

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. 

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.

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.

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.

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.