Stress and addiction neurobiology - Dr. Golub

Addiction is a complex disorder that can drastically affect cognitive and emotional development in adolescence and lead to long term behavioral impairments. Addiction risk and vulnerability, as well as the impact of substance consume on developing brain are not sufficiently understood so far.  Our outpatient addiction center for children and adolescents combines clinical and basic research methods in order to study neurobiological mechanisms of addiction and develop new state- of-the-art diagnostic and treatment options for our patients.

Projects

Molecular/ (epi-)genetic biomarkers of addiction

There are indications that several physiological and neuroendocrine systems are affected by drug addiction and might play an important role in the disorder’s pathogenesis. Supporting the view of psychiatric disorders as systemic diseases, with molecular alterations in both the brain and peripheral tissues, we investigate peripheral molecular and epigenetic targets in patients with addiction disorders and their family members. Our goal is a better understanding of the transgenerational transmission of addiction behavior, in addition to providing valuable risk biomarkers, as well as predicting the treatment response.

 

Prenatal factors in the development of child and adolescent psychiatric disorders

We focus on in–utero effects, such as prenatal trauma, maternal depression or fetal noxious exposure that may influence brain and behavioral development of a child. We investigate alterations in the stress system, attentional and cognitive processes that occur following these environmental exposures. In particular, we show epigenetic mechanisms responsible for cognitive and attention related effects of fetal alcohol exposure; changes in the expression and methylation patterns of the hypothalamic–pituitary–adrenal axis (HPA)-axis genes in children of the mothers that suffered from depression during their pregnancy. Taken together, our work emphasizes the importance of the prenatal period for the child’s development and helps to understand factors and mechanisms that lead to the development of psychiatric disorders in later life.

 

Early clinical markers of addiction vulnerability

We apply clinical and diagnostic instruments to study risk factors for adolescent drug addiction, prediction of addiction vulnerability and treatment response, with a focus on the early life and family related environment, as well comorbid psychiatric disorders.

 

Stress and addiction

One particular research interest of our group concerns the relation of drug addiction and stress. Addiction progresses through stages of intoxication, withdrawal and anticipation, each representing different neurobiological mechanisms that are involved in the transition from recreational to compulsive drug use. Both down regulation of the reward system and the up regulation of the stress system function have been described in the course of addiction disorders. Understanding individual differences in the stress systems’ function through measurements of basal, reactive and cumulative cortisol levels may explain resilience or vulnerability to substance-related disorders and heterogeneous responses to treatment. Furthermore, we try to understand biological processes underlying high comorbidity of substance-related addiction and stress-related disorders, such as depression, posttraumatic stress disorder and anxiety.

 

Developing and implementing new therapeutic methods for addiction treatment in youth

The efficacy of currently available treatment options for addiction disorders is still unacceptably low. Therefore, we adapt, apply and evaluate new therapeutic programs for the treatment of substance-related addiction, such as the Matrix model, a complex therapeutic program for treating substance-related disorders developed in the USA. As part of the therapeutic program, we work closely with parents to educate them about their child’s condition, as well as to analyze dysfunctional communication patterns. This way we aim to reduce anger and blame within the parent-child interaction and help parents understand that drug abuse usually derives from underlying (emotional) problems that need to be addressed in the course of treatment.

 

Publications:

  1. Frey S, Eichler A, Stonawski V, Kriebel J, Wahl S, Gallati S, Goecke TW, Fasching PA, Beckmann MW, Kratz O, Moll GH, Heinrich H, Kornhuber J*, Golub Y*. Prenatal alcohol exposure is associated with adverse cognitive effects and distinct whole-genome DNA methylation patterns in primary school children. Accepted Frontiers in Genetics.
  2. Golub Y, Panaseth K, Grimm J, Raabe E, Goecke TW , Fasching P, Beckmann MW, Kornhuber J, Kratz O, Heinrich H, Moll GH, Eichler A. Saliva and Hair cortisol as biomarkers of internalising symptoms in 6-8 year old children. Accepted developmental psychobiology.
  3. Stonawski V, Frey S, Golub Y, Moll GH, Heinrich H, Eichler A. [Epigenetic modifications in children associated with maternal emotional stress during pregnancy]. Z Kinder Jugendpsychiatr Psychother. 2017 Mar 3:1-13.
  4. Golub Y, Canneva F, Funke R, Frey S, Distler J, von Hörsten S, Freitag CM, Kratz O, Moll GH, Solati J. Effects of in-utero environment and maternal behaviour on neuroendocrine and behavioural alterations in a mouse model of prenatal trauma.  Dev Neurobiol. 2016;76(11):1254-1265. 
  5. Funke R, Eichler A, Distler J, Golub Y, Kratz O, Moll, GH. (in press) Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression. Stress and Health. 2016
  6. Canneva F, Golub Y, Distler J, Dobner J, Meyer S, von Hörsten S. DPP4-deficient congenic rats display blunted stress, improved fear extinction and increased central NPY. Psychoneuroendocrinology. 2015; 53: 195-206.
  7. Solati J, Kleehaupt E, Kratz O, Moll GH, Golub Y. Inverse effects of lipopolysaccharides on anxiety in pregnant mice and their offspring. Physiol Behav. 2015; 139:369-74.
  8. Schöpf I, Easton AC, Solati J, Golub Y, Kornhuber J, Giese KP, Müller CP.αCaMKII autophosphorylation mediates neuronal activation in the hippocampal dentate gyrus after alcohol and cocaine in mice. Neurosci Lett. 2015; 30; 591:65-8
  9. Solati J, Hajikhani R, Golub Y. Activation of GABAA receptors in the medial prefrontal cortex produces an anxiolytic-like response. Acta Neuropsychiatr. 2013; 25(4):221-6.
  10. Easton AC, Lucchesi W, Lourdusamy A, Lenz B, Solati J, Golub Y, Lewczuk P, Fernandes C, Desrivieres S, Dawirs RR, Moll GH, Kornhuber J, Frank J, Hoffmann P, Soyka M, Kiefer F; GESGA Consortium, Schumann G, Peter Giese K, Müller CP, Treutlein J, Cichon S, Ridinger M, Mattheisen P, Herms S, Wodarz N, Zill P, Maier W, Mössner R, Gaebel W, Dahmen N, Scherbaum N, Schmäl C, Steffens M, Lucae S, Ising M, Müller-Myhsok B, Nöthen MM, Mann K, Rietschel M. αCaMKII autophosphorylation controls the establishment of alcohol drinking behavior. Neuropsychopharmacology. 2013; 38(9):1636-47.
  11. Easton AC, Lourdusamy A, Havranek M, Mizuno K, Solati J, Golub Y, Clarke TK, Vallada H, Laranjeira R, Desrivières S, Moll GH, Mössner R, Kornhuber J, Schumann G, Giese KP, Fernandes C, Quednow BB, Müller CP. αCaMKII controls the establishment of cocaine's reinforcing effects in mice and humans. Transl Psychiatry. 2014;7;4:e457.
  12. Solati J, Hajikhani R, Golub Y. Activation of GABAA receptors in the medial prefrontal cortex produces an anxiolytic-like response. Acta Neuropsychiatr. 2013 Aug;25(4):221-6.
  13. Sauerhoefer E, Pamplona FA, Bedenk B, Moll GH, Dawirs RR, von Hörsten S, Wotjak CT, Golub Y. Generalized contextual fear and avoidance after fear incubation depend on associative rather than non-associative memory components. Behavioural Brain Rsearch 2012, 30; 233(2):483-493.
  14. Herrmann L, Ionescu I, Henes K, Golub Y, Wang N, Buell DR, Holsboer F, Wotjak CT,  Schmidt U. Neuropeptide S (NPS) and Fluoxetine Counteract Trauma Stress-Induced Long-Term Reduction of Hippocampal Synaptic Protein Expression. PLoSONE 2012, 7(8); e42603.
  15. Golub Y, Kaltwasser SF, Mauch CP, Herrmann L, Schmidt U, Holsboer F, Czisch M, Wotjak CT. Reduced hippocampus volume in the mouse model of Posttraumatic Stress Disorder. Journal of Psychiatric Research, 2011; May;45(5):650-9. 
  16. Dahlhoff M, Siegmund A, Golub Y, Wolf E, Holsboer F, Wotjak CT. AKT/GSK-3beta/beta-catenin signalling within hippocampus and amygdala reflects genetically determined differences in posttraumatic stress disorder like symptoms. Neuroscience. 2010; 169(3):1216-26.
  17. Golub Y, Mauch CP, Dahlhoff M, Wotjak CT. Consequences of extinction training on associative and non-associative fear in a mouse model of Posttraumatic Stress Disorder (PTSD). Behav Brain Res. 2009; 28;205(2):544-9.
  18. Golub Y, Berg D, Calne D, Pfeiffer R, Uitti R, Stoessl J, Wszolek Z, Farrer M, Mueller J, Gasser T, Fuchs J. Genetic factors influencing age at onset in LRRK2 linked Parkinson disease. Parkinsonism Relat Disord. 2009; 15(7):539-41. 
  19. Fuchs J, Tichopad A, Golub Y, Munz M, Schweitzer K, Wolf B, Berg D, Mueller J and Gasser T. a-synuclein expression in blood and brain depends on genetic variability. FASEB J. 2008; 22(5):1327-34.

 

Contact:

Dr. Yulia Golub
Tel. 0351 458 3576