Targeting novel synaptic pathways in trauma-related psychiatric disorder: a Clinical Research Priority Program 2019-2021 funded by University of Zurich

In today’s turbulent world, psychological trauma and early-life adversity have emerged as major risk factors for various psychiatric disorders. Across the entire spectrum of trauma-related disorders, cognitive-behavioural psychotherapy, which seeks to modify aversive memories (Milad and Quirk, 2012), is currently the recommended treatment by national and international guidelines. Yet, in clinical practice the majority of patients remain symptomatic (Loerinc et al., 2015; Yehuda et al., 2015). This has led to high-profile calls for developing adjunct pharmacological therapies (Krystal et al., 2017). During the same time, our understanding of synaptic biology has increased exponentially, yielding a wide range of compounds that modify synapses themselves, the surrounding extracellular matrix that shapes their properties (Huntley, 2012), and the daily rhythms of sleep and wake that govern their strength (Chen et al., 2013).

This CRPP connects these disparate strands and delivers a novel approach to alter aversive memories with pharmacological agents. The conceptual idea, already established in pre-clinical (Lee et al., 2017) and clinical models (Brunet et al., 2018), is to activate synapses through psychotherapeutic intervention, and then modify them pharmacologically. While previous models for pharmacological intervention targeted synapses indirectly via neurotransmitters, this CRPP focuses on directly targeting molecular pathways involved in degrading old, and shaping new, synaptic connections. In humans, the CRPP will use several candidate drugs already approved for other indications, one of which has already been shown to impact on human fear memory (Bach et al., 2017). The CRPP will further strive to identify new mechanisms of action in non-human models.

Contact

Prof. Dr. Dominik R Bach
Department of Psychiatry, Psychotherapy, and Psychosomatics
Psychiatric Hospital, University of Zurich
Lenggstrasse 31
8032 Zurich
Switzerland

Principal Investigators

Dominik Bach, Assistant Professor for Clinical Psychiatry Research, Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Zurich

Birgit Kleim, Professor for Experimental Psychopathology and Psychotherapy, Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Zurich

Steven Brown, Professor for Chronobiology and Sleep Research, Institute of Pharmacology and Toxicology, University of Zurich

Shiva Tyagarajan, Assistant Professor for Neurodevelopmental Pharmacology, Institute of Pharmacology and Toxicology, University of Zurich

Co-Investigator

Erich Seifritz, Professor for Psychiatry and Director of the Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Zurich

Advisory Board

Emily Holmes, Karolinska Institute Stockholm

Kai Kaila, University of Helsinki

Rafael Kalisch, University of Mainz

Andreas Maercker, University of Zurich

PhD and MD/PhD opportunities (starting 01. January 2019)

We are hiring 5 PhD or MD/PhD students to work on clinical, human behavioural, animal sleep, and molecular neuroscience. Two of the positions will involve both animal and human research. The CRPP involves shared student supervision between clinician and basic scientists, and regular teachings between the 4 partner labs based in psychiatry and pharmacology.

Please address informal enquiries to the respective PI(s). Please send your application to the email address stated in the advert, merging into one PDF your CV, BSc/MSc certificates, statement of research interest, and a motivation letter pointing out why you think this CRPP is the ideal place for your PhD thesis. Please state in the email subject which of the below projects you are applying for.

1 Altering trauma memories with synaptic plasticity interventions (PI Birgit Kleim)

Summary: We will translate promising findings on synaptic plasticity inhibition of aversive memories from the laboratory to the clinic.

Scientific Background: Targeting synaptic plasticity has recently been shown to reduce human aversive memory acquisition. However, this finding is so far restricted to a simple experimental fear-learning model and we aim to extend this to a trauma memory context. Following trauma, a significant number of those affected develop intrusive fear memories, a hallmark of PTSD. We will draw on an experimental trauma model that induces involuntary memories and thus resembles PTSD symptoms (James et al., 2016; Kleim et al., 2016). This model offers an experimental psychopathology model to study both exposure to trauma and acquisition of trauma memories, as well as their change over time. Healthy individuals watch an aversive movie. Based on previous results, many individuals will temporarily develop involuntary trauma memories following this exposure. We will measure these memories with an intrusion interview, as well as with so-called ecological momentary assessments (i.e. experience sampling) to investigate the impact of a plasticity intervention (versus placebo) on development and reconsolidation of intrusive trauma memories. We will then conduct a clinical study in PTSD patients to investigate the impact of the same plasticity intervention during trauma memory reactivation on trauma memories and clinical PTSD symptoms.

Planned studies: 2 experimental trauma studies in healthy volunteers, one clinical study in N = 60 PTSD patients, one open-label case study in PTSD patients.

Information on how to apply: contact Prof. Birgit Kleim

2 Role of sleep and circadian timing on human plasticity intervention and underlying synaptic function (PIs Birgit Kleim & Steven Brown)

Details TBA

Information on how to apply: contact Prof. Birgit Kleim or Prof. Steven Brown

3 Synaptic protein network adaptations as a basis for human memory reconsolidation (PIs Shiva Tyagarajan & Dominik Bach)

Summary: Using rodent models this project will investigate how Swissmedic-approved drugs that modify extracellular matrix affect synaptic protein networks in animal models of aversive and non-aversive memory. After identification of synaptic mechanism(s) downstream of Swissmedic-approved drug, we will pharmacologically block the mechanism and evaluate its psychophysiological and neuropsychological impact in humans after aversive memory.

Scientific background: Doxycycline is clinically used as an antibiotic. Recently, Bach laboratory has demonstrated doxycycline effectively reduces aversive fear anxiety in humans. Extracellular matrix protease, MMP-9, facilitates synapse adaptations in basolateral and central amygdala during delay fear conditioning paradigm. Interestingly, Doxycycline inhibits MMP-9; however, the impact of doxycycline treatment on synaptic protein adaptations is currently unexplored. If psychological trauma associated memories are a product of both context and mechanisms underlying synaptic plasticity, then doxycycline is an ideal candidate drug to test this hypothesis.

Planned experiments: Neuro-morphological and functional studies of synapses in rodent brains with or without Doxycycline treatment during aversive learning (eg. foot shock). Phospho-proteome analysis of synapses in various animal models of aversive and non-aversive memory. Identify novel drug target for synaptic plasticity changes and evaluate its psychophysiological and neuropsychological impact on aversive memory in humans.

Information on how to apply: http://bachlab.org/opportunities

4 Synaptic plasticity interventions to block human memory reconsolidation

Summary: This project will investigate to what extent various human aversive and non-aversive memory models are malleable by synaptic plasticity interventions, using psychophysiological and neuropsychological measurements. Afterwards, we seek to test at least one novel synaptic-plasticity inhibitor in humans.

Scientific background: Current evidence for the clinical potential of synaptic plasticity inhibition with the MMP-9 inhibitor doxycycline comes from simple delay fear conditioning paradigm which is known to require synaptic changes in basolateral and central amygdala. However, psychological trauma memory involves context-dependent and perceptually complex memories, which are likely to (additionally) require synaptic plasticity in macroscopically different neural circuits with distinct histological and functional properties such as hippocampus and sensory cortex. It is unclear to what extent these synapses can be modified with MMP-9 inhibitors, and what the boundary conditions of memory modification are

Planned experiments: Investigation of different aversive memory paradigms that presumably require plasticity in different circuits, as well as other memory systems (spatial, semantic, motor).

Information on how to apply: http://bachlab.org/opportunities

5 Molecular and synaptic roles of sleep and circadian timing in memory reconsolidation (PI Steven Brown)

Summary: Using cellular model and then an animal one, this project will systematically explore the influence of sleep pressure and time of day upon synaptic long-term potentiation (LTP) and aversive memory retrieval. Then, using these data, it will test the effects of reconsolidation blockade upon such memories using Swissmedic-approved drugs modifying extracellular matrix proteins.

Scientific Background: Within the mammalian brain, both cellular physiology and network activity is heavily influenced by both time of day (thanks to an endogenous circadian clock) and sleep pressure (through a homeostatic sleep-wake mechanism). As a result, the processes of memory storage and memory retrieval vary greatly with both time of day and sleep-wake state. In this project, these mechanisms will be explored in molecular detail, specifically in terms of memory reconsolidation, the strengthening or weakening of an existing memory when it is accessed. This aspect is particularly relevant to the treatment of post-traumatic stress disorder. Though no animal model effectively recapitulates all aspects of PTSD, by far the most accepted and widely used model is that of aversive learning, which shows dramatic circadian modulation. Supporting our model, optogenetic induction of long-term depression effectively “erases” aversive memory in mice, while induction of long-term potentiation prolongs it.

Planned Experiments: Examination of LTP in acute hippocampal slice models via multielectrode arrays, and its modification by circadian phase and candidate drugs; Measurement of extinction of aversive memories in mice, as influenced by time of day, sleep pressure, and candidate drugs.

Information on how to apply: contact Prof. Steven Brown

References

Bach DR, Tzovara A, Vunder J (2017) Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline. Molecular psychiatry.

Brunet A, Saumier D, Liu A, Streiner DL, Tremblay J, Pitman RK (2018) Reduction of PTSD Symptoms With Pre-Reactivation Propranolol Therapy: A Randomized Controlled Trial. Am J Psychiatry:appiajp201717050481.

Chen Z, Yoo SH, Takahashi JS (2013) Small molecule modifiers of circadian clocks. Cell Mol Life Sci 70:2985-2998.

Huntley GW (2012) Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13:743-757.

Krystal JH, Davis LL, Neylan TC, M AR, Schnurr PP, Stein MB, Vessicchio J, Shiner B, Gleason TD, Huang GD (2017) It Is Time to Address the Crisis in the Pharmacotherapy of Posttraumatic Stress Disorder: A Consensus Statement of the PTSD Psychopharmacology Working Group. Biological psychiatry 82:e51-e59.

Lee JLC, Nader K, Schiller D (2017) An Update on Memory Reconsolidation Updating. Trends in cognitive sciences 21:531-545.

Loerinc AG, Meuret AE, Twohig MP, Rosenfield D, Bluett EJ, Craske MG (2015) Response rates for CBT for anxiety disorders: Need for standardized criteria. Clin Psychol Rev 42:72-82.

Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129-151.

Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, Hobfoll SE, Koenen KC, Neylan TC, Hyman SE (2015) Post-traumatic stress disorder. Nat Rev Dis Primers 1:15057.