Neuropharmacology Research Group (Head: N. Singewald)

 

Staff

 


Scientists:
- Ebner Karl
- Murphy Conor
- Sah Anupam
- Sartori Simone
- Singewald Nicolas

 
 PhD-Students:
- Fontebasso Veronica
- Fritz Eva Maria
- Keil Thomas
- Rooney Sinead 
Technical/Research associates:
- Bauer Peter 
- Kharitonova Maria
 
Alumni:
- Schmuckermair Claudia (click here)
- Whittle Nigel (click here)

 

Neurobiology underlying psychopathology and psychotherapeutic drug action as rational approach in target-based drug development

Treatment resistance in pathological anxiety and comorbid depression

 

 

 

Neurobiology underlying psychopathology and psychotherapeutic drug action as rational approach in target-based drug development

A growing number of psychiatric disorders that afflict humans are emotional disorders, e.g. depression and anxiety disorders including phobias, panic, post-traumatic stress disorder, obsessive compulsion disorder, and generalized anxiety. Many of these disorders are stress-related and represent one of the greatest preventive and therapeutic challenges for the 21st century.

Our main research interests focus on neurobiological mechanisms important in these disorders, as well as in illness recovery by existing and new therapeutic approaches. We are using an array of neuropharmacological, molecular and behavioural methods (see key methods) to track affected neural circuits, altered neuronal activation, gene expression patterns and neurochemistry important in the expression and/or attenuation of fear, anxiety- and depression-related behaviour. An important principle of this work is to use specific psychopathological animal models of enhanced fear, anxiety and depression (genetic models: S1 model, HAB rats and mice, Flinders sensitive line, dietary models: Mg2+ deficiency, Zn2+ deficiency, tryptophan deficiency), and more recently investigate also samples of humans affected by these disorders. Current projects focus on the role of ion channels (LTCC), classical transmitters and neuropeptides such as substance P, galanin, NPY and NPS in stress, anxiety and depression and testing of their usefulness as target systems of antidepressant/anxiolytic treatment. Furthermore, we are investigating the role of adult neurogenesis, non-coding RNA´s, epigenetic mechanisms, neuroimmunology and dopamine-signaling in the different psychopathological animal models mentioned above.

 

Neurobiological mechanisms in impaired fear extinction

Effective long-term treatment for fear and anxiety-related disorders is a continuing challenge. One emerging treatment strategy is combining exposure-based cognitive behavioural therapy (CBT) with cognitive enhancers. We have recently identified several approaches for long-term rescue of impaired fear inhibition. Specifically, we provide evidence that histone deacetylase (HDAC) inhibitors and facilitating dopaminergic signalling act as  cognitive enhancing strategies to rescue aberrant fear extinction consolidation in S1 (129S1/SvImJ) mice (Whittle, Maurer et al, 2016). On the basis of these results we are trying to gain detailed and causal insight into which DA receptors and brain region(s) mediate the normalisation of impaired fear extinction by using pharmacological, optogenetic and chemogenetic approaches.

Our laboratory has recently shown that microRNA (mir-144) that is involved in rescue of impaired extinction (Murphy et al, 2016). We are currently establishing whether microRNAs can be used as bio-markers/novel therapeutic targets for the treatment of anxiety disorders. In addition, we aim to improve the tolerability of exposure based therapy by combining the therapeutic actions of non-sedative anxiolytic drugs which do not impair extinction learning and appropriate cognitive enhancers.We have recently identified the utility of the non-sedative anxiolytic Neuropeptide S for this purpose and have shown that augmenting Neuropeptide S with D-Cycloserine prevents the return of fear in extinction-impaired rodents (Sartori et al, 2016).

Finally, we have started to identify potential epigenetic biomarkers in blood cells that can be associated with the sensitivity to and the extent of the therapeutic effect of exposure therapy in anxiety disorder patients. These highly translational questions will be addressed within the SFB-44 and the SPIN consortium together with international collaborators. Revealing mechanisms via which rescue of impaired fear extinction can be achieved in a better tolerated, persistent and context-independent manner is expected to foster the rational development of novel cognitive enhancers which may be used as augmenting CBT adjuncts to treat anxiety disorders more effectively. 

 

Drug development for anxiety disorders

As mentioned above, there is great demand for drugs with anxiolytic and fear extinction facilitating properties (Singewald et al, 2015) and that the potential non-sedative neuropeptide S may represent an interesting drug target in that respect (Sartori et al, 2016). However, small, non-peptidergic NPS receptor (NPSR) agonists which may ultimately be applied to patients suffering from specific anxiety disorders are not available. In the search for these NPSR agonists, using cell-based Ca2+ mobilization assay, we have identified several candidates by virtual screening of suitable compounds. We are currently testing whether these candidates can attenuate the adversity of exposure therapy.

Another line of drug development concerns the development of acute anxiolytic drugs with novel mechanism of action with a more desirable side-effect profile than the existing benzodiazepines. Promising candidates include Neurokinin-1 receptor antagonists (see Krautscheid et al, 2014).

 

 

Treatment resistance in pathological anxiety and comorbid depression
 

Treatment-resistant mood disorders pose a great socioeconomic and life-threatening burden on public health system, as they are associated with greater morbidity as well as more suicide attempts. One of the biggest risk factors for treatment resistance is having a comorbid condition such as anxiety or substance abuse reducing considerably the chances of remission from either anxiety or depression. Studies have shown that more than 70% of individuals with depressive disorders also have anxiety symptoms and 40-70% simultaneously met criteria for at least one type of anxiety disorder. This comorbidity issue, potential ways to achieve long-term remission from comorbid anxiety/depressive disorders, as well as the relevant underlying neurobiology are clearly understudied so far.

Reflecting an important group of treatment resistant patients, we have identified a mouse model displaying enhanced innate anxiety and comorbid depression that does not respond to a range of SSRIs, the established first line treatment. Using this model, we have shown that high frequency stimulation of the nucleus accumbens induced an anxiolytic- and antidepressant-like effect along with normalization of aberrant neuronal brain activity in specific brain regions (Schmuckermair et al, 2013). Aberrant activity within the hippocampus seems to be associated with the time-course of recurring depression and its normalization might be considered as a biomarker for successful remission (Sah et al, 2012). Our data also provide evidence that drugs counteracting pathological anxiety in this model interact with adult hippocampal neurogenesis, supporting the birth of new neurons as a promising target (Sah et al, 2012). We found that the enhanced anxiety/depression is also associated with alterations in the neuroinflammatory system. We are currently investigating these promising approaches as well as other new possibilities to encompass not only improvement but also sustained and complete remission from pathological anxiety and comorbid depression.

 

 

 

                   Selected publications:
Murphy, C. P. et al. MicroRNA-Mediated Rescue of Fear Extinction Memory by miR-144-3p in Extinction-Impaired Mice. Biological psychiatry, doi:10.1016/j.biopsych.2016.12.021 (2016). PDF
 
Whittle, N. et al. Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction. Transl Psychiatry 6, e974, doi:10.1038/tp.2016.231 (2016). PDF
 
Fitzgerald, PJ. et al. Durable fear memories require PSD-95. Mol Psychiatry Jul;20(7):913. doi: 10.1038/mp.2015.44 (2015) PDF
 
Haaker, J. et al. Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear. Proceedings of the National Academy of Sciences of the United States of America 110, E2428-2436, doi:10.1073/pnas.1303061110 (2013). PDF
 
Whittle, N et al. Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model. Neuropharmacology. Jan;64:414-23. doi: 10.1016/j.neuropharm.2012.06.001(2013) PDF
 
Schmuckermair, C. et al. Behavioral and neurobiological effects of deep brain stimulation in a mouse model of high anxiety- and depression-like behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38, 1234-1244, doi:10.1038/npp.2013.21 (2013). PDF
 
Sah, A. et al. Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior. Transl Psychiatry 2, e171, doi:10.1038/tp.2012.94 (2012). PDF 

 

 

Reviews:
Ebner, K. & Singewald, N. Individual differences in stress susceptibility and stress inhibitory mechanisms. Curr Opin Behav Sci, Vol.14 p. 54-64 (2017). PDF
 
Singewald, N., Schmuckermair, C., Whittle, N., Holmes, A. & Ressler, K. J. Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacology & therapeutics 149, 150-190, doi:10.1016/j.pharmthera.2014.12.004 (2015). PDF
 
Whittle, N. & Singewald, N. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand? Biochemical Society transactions 42, 569-581, doi:10.1042/bst20130233 (2014). PDF
 
Holmes, A. & Singewald, N. Individual differences in recovery from traumatic fear. Trends in neurosciences 36, 23-31, doi:10.1016/j.tins.2012.11.003 (2013). PDF
 
Sartori, S. B., Landgraf, R. & Singewald, N. The clinical implications of mouse models of enhanced anxiety. Future neurology 6, 531-571, doi:10.2217/fnl.11.34 (2011). PDF


 

Key Techniques
  • RT-qPCR
  • In-situ-hybridisation (fluorescent, radioactive)
  • Immunohistochemistry
  • Chromatin immunoprecipitation (ChiP)
  • Luciferase assays
  • Cell-based-Ca2+-mobilisation assays
  • Receptor binding assays
  • Drug testing
  • Radioimmunoassay
  • Radioenzymatic assay
  • HPLC
  • Behavioural test batteries
  • Establishing model organism
  • Deep brain stimulation
  • Microdialysis
  • Microinjections/viral injections
  • Ultrasonic vocalisation detection
  • catfish
  • Telemetric Cardiac monitoring
  • Neurospheres, neuronal cell culture

 

Techniques currrently established

  • Optogenetics
  • DREADD
  • CRISPR/Cas
  • in-vivo electrophysiology (LFPs, tetrodes, EEG/EMG)





go up