Marloes Henckens

RESEARCH

The research of our lab aims at understanding how stress exposure can lastingly affect brain function. Using animals models that allow for controlled study of the mechanistic underpinnings of stress-related psychopathology, we aim to elucidate how stress influence brain function at the molecular (investigating the epigenetic mechanisms and local gene expression) and neural circuit level (by means of neuronal activation markers, rodent MRI, viral tracing and optogenetics), while warranting translational value. Particular focus is put on the inter-individual differences in the neural correlates of stress responsivity and subsequent coping, by behavioral identification of stress resilient vs. susceptible subjects. The neural mechanisms underlying natural stress resilience may contain unique information for new treatment options for those suffering from stress-related mental disease. 

Our research focuses along 3 main research lines:

1) Stress-induced imbalance in neural network function

Recent advances in the field of neuroscience made clear that proper stress recovery requires a complex interplay of functional brain networks, which' dysfunction or imbalance may ultimately result in stress-related disorders such as major depression or post-traumatic stress disorder (PTSD). In the healthy brain, neural resources are rapidly reallocated in response to acute stress/trauma exposure to prioritize emotional processing by the so-called salience network over the cognitive control network. During subsequent stress recovery, this reallocation is reversed (Hermans et al., 2014). Using rodent functional neuroimaging, analyses of neuronal activity markers, as well as transgenic animal models, we are currently testing the hypothesis that PTSD may result from a chronic imbalance in neural network function (either present at baseline, occurring in response to trauma, or during recovery) in which salience processing continuously overrules cognitive function. Moreover, we are looking into the activity and connectivity of the renowned default mode network, which is also suggested to be upregulated in response to acute stress and dysregulated in stress-related mental disease (Henckens et al., 2015).

Own data demonstrating the existence of a default mode network in the mouse brain using resting-state fMRI.  


Additional reading:

  • Henckens MJ, van der Marel K, van der Toorn A, Pillai AG, Fernández G, Dijkhuizen RM, Joëls M (2015). Stress-induced alterations in large-scale functional networks of the rodent brain. NeuroImage 105: 312-22. 
  • Hermans EJ, Henckens MJ, Joëls M, Fernández G (2014). Dynamic adaptation of large-scale brain networks in response to acute stressors. Trends Neurosci 37(6): 304-14.


2) Epigenetic signature of trauma susceptibility

The mechanistic underpinnings of altered neuronal activity (as identified by research line 1) are further studied by focusing on the epigenetic mechanisms underlying gene expression differences. By making use of the recently developed transgenic FosTRAP and ArcTRAP mouse lines (Guenthner et al., 2013) - in which we can fluorescently label all Fos- or Arc-expressing neurons (i.e., those active) - we can isolate neurons that are active at any given time-point (e.g., before, during or after trauma). The activated neuronal populations can then be characterized by isolating the fluorescently labeled cells using fluorescence-activated cell sorting (FACS) allowing for the analysis of their molecular footprint. 

Additional reading:

  • Dirven BCJ, Homberg JR, Kozicz T, Henckens MJAG (2017). Epigenetic programming of the neuroendocrine stress response by adult life stress. J Mol Endocrinol 59(1): R11-31.


3) Memory engram for trauma

 Intrusive memories of the trauma, such as flashbacks or recurrent nightmares, are among the most devastating symptoms of PTSD. Over-generalization of the traumatic memory has been suggested to underline these intrusive memories triggered by indiscriminate factors. Memory generalization has been related to deficits in hippocampus-mediated pattern separation, the process by which memories are stored as unique representations resistant to confusion. However, other research challenges this view and proposes that the abnormal memory trace in PTSD is caused by altered systems' memory processing instead. Aberrant amygdala activation in response to the trauma has been suggested to lead to altered configurations of neural activity and thereby qualitatively impact the formation of emotional memory representations. Using the FosTRAP and ArcTRAP mice in combination with brain clearing techniques (iDISCO+) and immunohistochemistry we are investigating these theories. Moreover, we are looking into the contribution of specific stress hormones (i.e., corticosterone and noradrenaline) to the process of memory generalization.   

 Own data showing fluorescent labeling of active neurons (in red) in the ArcTRAP mice. a) Mouse brain slice in which neurons active during trauma encoding are labeled in red and those active during trauma recall in green (anti c-Fos staining). b) Zoomed in picture on the mouse hippocampus of the slice in section a; c) Entire mouse brain hemisphere made transparent using iDISCO+.  



Recent publications:

  • Schipper P, Henckens MJAG, Lopresto D, Kozicz T, Homberg JR (2017). Acute inescapable stress alleviates fear extinction recall deficits caused by serotonin transporter abolishment. Behav Brain Res [Epub ahead of print]
  • Dirven BCJ, Homberg JR, Kozicz T, Henckens MJAG (2017). Epigenetic programming of the neuroendocrine stress response by adult life stress. J Mol Endocrinol 59(1): R11-31.
  • van Bodegom M, Homberg JR, Henckens MJAG (2017). Modulation of the hypothalamus-pituitary-adrenal axis by early life stress exposure. Front Cell Neurosci 11: 87.
  • Henckens MJ, Printz Y, Shamgar U, Dine J, Lebow M, Drori Y, Kuehne C, Kolarz A, Eder M, Deussing JM. Justice NJ, Yizhar O, Chen A (2017). CRF receptor type 2 neurons in the posterior bed nucleus of the stria terminalis critically contribute to stress recovery. Mol Psychiatry 22(12): 1691-1700.  
  • Schipper P, Henckens MJAG, Borghans B, Hiemstra M, Kozicz T, Homberg JR (2017). Prior fear conditioning does not impede enhanced active avoidance in serotonin transporter knockout rats. Behav Brain Res 326: 77-86. 
  • Henckens MJ, Deussing JM, Chen A (2016). Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. Nat Rev Neurosci 17(10): 636-51.
  • Henckens MJ, Klumpers F, Everaerd D, Kooijman SC, van Wingen GA, Fernández G (2016). Interindividual differences in stress sensitivity: basal and stress-induced cortisol levels differentially predict neural vigilance processing under stress. Soc Cogn Affect Neurosci 11(4): 663-73.
  • Schipper P, Lopresto D, Reintjes RJ, Joosten J, Henckens MJ, Kozicz T, Homberg JR (2015). Improved stress control in serotonin transporter knockout rats: Involvement of the prefrontal cortex and dorsal raphe nucleus. ACS Chem Neurosci 6(7): 1143-50. 
  • Hermans EJ, Henckens MJ, Joëls M, Fernández G (2015). Toward a mechanistic understanding of interindividual differences in cognitive changes after stress: reply to van den Bos. Trends Neurosci 38(7): 403-4.
  • Henckens MJ, van der Marel K, van der Toorn A, Pillai AG, Fernández G, Dijkhuizen RM, Joëls M (2015). Stress-induced alterations in large-scale functional networks of the rodent brain. NeuroImage 105: 312-22. 
  • Pillai AG, Henckens MJ, Fernández G, Joëls M (2014). Delayed effects of corticosterone on slow afterhyperpolarization potentials in mouse hippocampal versus prefrontal pyramidal neurons. PLoS One 9(6): e99208. 
  • Hermans EJ, Henckens MJ, Joëls M, Fernández G (2014). Dynamic adaptation of large-scale brain networks in response to acute stressors. Trends Neurosci 37(6): 304-14.      

    Find a list of all publications here.