Our main interest is structural plasticity in relation to stress and disease. In addition to apoptosis, we focus on the regulation of adult neurogenesis and its relevance for depression and dementia.
Even though we do have an interest in neurogenesis in other brain areas, particular in the cortex and during early development, our primary focus is the hippocampus since it is not only affected in both these disease conditions but is also very sensitive to stress hormone action and implicated in learning and memory. The hippocampus is furthermore unique as it contains stem cells that continue to generate new neurons in adult animals, including humans,
a process called "adult neurogenesis"
Key interest is the functional relevance of adult neurogenesis for brain function. We are also interested in whether blockade of stress effects on neurogenesis can be beneficial in terms of e.g. the recovery from depression. We hypothesize that e.g. stress-induced reductions in the number of newborn neurons will interfere with the role of the hippocampus e.g. in cognition and in negative feedback of the HPA-axis, and we study how such deficits are ameliorated by means of antidepressant treatments.
Group leader
Paul Lucassen
Confocal image of newborn neurons (in red) in the adult hippocampus, (mature neurons in green) imaged in 3 dimensions X, Y and Z. Image by Vivi Heine
Since early life stress effects on neurogenesis are much more pronounced when given earlier in life, and early life stress represents a risk factor for depression, we examine the consequences of early life events for structural plasticity and neurogenesis changes in the adult brain and the consequences for cognition.
Inability of the brain to structurally and functionally "adapt" to altered circumstances is not limited to depression but may also accompany brain diseases like dementia and Alzheimer’s disease. A second interest is therefore whether an
inability to increase adult neurogenesis in response to primary neuronal damage, could potentially
contribute to the cognitive deficits in dementia ?
Conversely, are the alterations in cell cycle protein
expression as observed in the Alzheimer hippocampus relevant
for the cognitive deficits in this disorder ?
Within an EU funded framework (NEURAD; http://www.neurad-alzheimer.de) we work on the possible contribution of adult neurogenesis and cell cycle related changes to the onset and temporal development of Alzheimer pathology. In addition to comparative analyses of human brain tissue, functional consequences of the cell cycle changes for long-term potentiation and learning and memory are being addressed in transgenic mouse models based on amyloid and tau changes and combinations thereof.
Confocal image of 2 immunocytochemically
stained newborn cells (red) in the adult (green) dentate gyrus (A)
and a higher magnification showing a newborn (red label) cell that developed
into a glia cell (blue). Image by Vivi Heine
To answer these question, various techniques have been implemented, or are applied in close collaboration, including stereological analysis of the different stages of neurogenesis and apoptosis, quantitative neuroanatomy, confocal microscopic imaging, microarray analysis of microdissected brain regions using laserdissection microscopy, transgenic mouse models, RIA, molecular (siRNA), electrophysiological (LTP) and behavioral (rotarod, water maze, object recognition task) readouts.
A) Doublecortin (DCX) immunostaining of immature neurons in the adult
hippocampal dentate gyrus. DCX positive somata are located in the
subgranular zone at the border between the granular cell layer (gcl) and
the hilus (h) with extensions (arrowheads) passing through the gcl and
running into the molecular layer (ml)
B) Graph depicting quantification of BrdU- and DCX-positive cell numbers
in the hippocampus of rats treated with vehicle (veh), corticosterone
(cort) or corticosterone plus the GR antagonist mifepristone (RC), and
with mifepristone alone (RO). The significant reduction in both BrdU- (21
day old cells) and DCX-positive cellnumbers after 21 days of
corticosterone treatment is normalized by mifepristone treatment for the
last 4 days, whereas the drug alone has no effect (Mayer et al., JNE
2006) Similar results are obtained after chronic stress (Oomen et al.,
EJN, 2007)
C+D) Details of the different individual morphological patterns of
DCX-positive cells
Carlos Fitzsimons
We are grateful to our sponsors
Krugers HJ, Oomen CA, Gumbs M, Li M, Velzing EH, Joels M, Lucassen PJ. (2011)
Maternal deprivation and dendritic complexity in the basolateral amygdala.
Neuropharmacology. 2011 Sep 29. [Epub ahead of print]
Wang Q, Joels M, Swaab DF, Lucassen PJ (2011)
Hippocampal GR expression is increased in elderly depressed females
Neuropharmacology. 2011 Sep 19. [Epub ahead of print]
Xiao AW, He J, Wang Q, Luo Y, Sun Y, Zhou YP, Guan Y, Lucassen PJ, Dai JP. (2011)
The origin and development of plaques and phosphorylated tau are associated
axonopathy in Alzheimer's disease.
Neurosci Bull. 2011 Oct;27(5):287-99.
Korosi A, Naninck EF, Oomen CA, Schouten M, Krugers H, Fitzsimons C, Lucassen PJ. (2011)
Early-life stress mediated modulation of adult neurogenesis and behavior
Behav Brain Res. 2011 Jul 28. [Epub ahead of print]
A. Korosi, E. Naninck, C.A. Oomen, M. Schouten, H. Krugers, C. Fitzsimons, PJ. Lucassen (2011)
Early-life stress mediated modulation of adult neurogenesis and behavior
Behav Brain Res 2011, in press.
Arianna Novati; Henriëtte J Hulshof; Jaap Koolhaas, Paul J. Lucassen, Peter Meerlo (2011)
Chronic sleep restriction decreases hippocampal volume in adolescent rats,
without altering glucocorticoid levels or adult neurogenesis.
Neuroscience. 2011 Sep 8;190:145-55.
P.J. Lucassen Structural plasticity in relation to stress and depression (models)
European Neuropsychopharmacology, in press, 2011
Paula van Tijn, Willem Kamphuis, MW Marlatt, Elly M. Hol, Paul J. Lucasssen (2011)
Presenilin mouse and zebrafish models for dementia: Focus on neurogenesis.
Progress in Neurobiology, Volume 93, Issue 2, February 2011, Pages 149-164
Robert Eendebak, Paul J. Lucassen and Carlos P. Fitzsimons (2011)
Nuclear Receptors and microRNAs: Who regulates the regulators?
FEBS letters, volume 585, issue 5, 2011, pp. 717 - 722.
Van Bokhoven, P., Oomen C.A., Hoogendijk, W.J.G., Smit, A.B., Lucassen P.J.* and Spijker, S. (2011)
* (shared last authors)
Reduction in hippocampal neurogenesis after social defeat is long-lasting
and responsive to late antidepressant treatment.
Eur J Neurosci. 2011 Apr 14. doi: 10.1111/j.1460-9568.2011.07668.
Oomen CA, Soeters H, Audureau N, Vermunt L, van Hasselt FN, Manders EM, Joëls M,
Krugers H, Lucassen PJ. (2011)
Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats
Psychopharmacology (Berl). 2011 Mar;214(1):249-60
Elodie Bruel-Jungerman, Paul J. Lucassen and Fiona Francis (2011)
Cholinergic influences on cortical development and adult neurogenesis
Behavioral Brain research, 2011 Jan 25.
Naninck EF, Lucassen PJ, Bakker J. (2011)
Sex differences in adolescent depression: do sex hormones determine vulnerability ?
J Neuroendocrinol. 2011 May;23(5):383-92
PDF
Marijke A.M. Lemmens, Annerieke S.R. Sierksma, Bart P.F. Rutten, Frank Dennissen,
Harry W.M. Steinbusch, Paul J. Lucassen* and Christoph Schmitz* (shared last authors) (2011)
Age-related changes of neuron numbers in the frontal cortex of a transgenic mouse model
of Alzheimer’s disease, Brain Structure and Function, in press, 2011.
Michael W Marlatt, Ingrid Philippens, Erik Manders, Boldizsár Czéh, Marian Joels,
Harm Krugers, Paul J Lucassen (2011)
Distinct structural plasticity in the hippocampus and amygdala of the middle-aged common marmoset (Callithrix jacchus)
Experimental Neurology, Vol 230, Issue 2, August 2011, Pages 291-301
PDF
Harm J Krugers, Paul J Lucassen, Henk Karst and Marian Joëls (2010)
Chronic stress, hippocampal structure and synaptic function: relevance of (anti)glucocorticoids.
Frontiers in Synaptic Neuroscience. Juli 2010 doi: 10.3389/fnsyn.2010.00024
NA Datson, C Speksnijder, JL Mayer, PJ Steenbergen, ER de Kloet, M Joëls, PJ Lucassen. The transcriptional response to chronic unpredictable stress is highly divergent between the hippocampal subregions DG and CA1. Hippocampus, 2010 PDF
CA Oomen, H Soeters, N Audureau, L Vermunt, F van Hasselt, M Joëls, PJ Lucassen and H Krugers (2010)
Reduced neurogenesis and altered cellular morphology after early maternal deprivation
is paralleled by impaired water maze aquisition but increases in fear memory in the adult male rat
Journal of Neuroscience 2010; 30, 6635-6645.
DZ Christensen, T Schneider-Axmann, PJ Lucassen, TA Bayer, O Wirths (2010) Accumulation of intraneuronal beta-amyloid correlates with ApoE4 genotype. Acta Neuropathol. 119(5):555-6, 2010.
Michael W. Marlatt and Paul J. Lucassen. Neurogenesis and Dementia:
Biology and Pathophysiology of Mice and Men.
Current Alzheimer's disease, 7(2), p. 113-125, 2010
Michael W. Marlatt, Paul J. Lucassen, Henriette van Praag.
Side by side comparison of effects of running and antidepressants on neurogenesis in mice
Brain Research Jun, 1341: 93-9, 2010.
PJ Lucassen, MW Stumpel, Q Wang, E Aronica.
Decreased numbers of progenitor cells but no response to antidepressant
drugs in the hippocampus of elderly depressed patients.
Neuropharmacology, 58 940-949, 2010
Oliver Wirths, Tobias Bethge, Andrea Marcello, Anja Harmeier, Sadeem Jawahr, Paul J. Lucassen,
Gerd Multhaup, David Brody, Thomas Esparza, Martin Ingelsson,
Hannu Kalimo, Lars Lannfelt and Thomas A. Bayer.
Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases.
Journal Neural Transmission 117 : p85-96, 2010
PJ Lucassen, P Meerlo, AS Naylor, AM van Dam, AG Dayer, E Fuchs, CA Oomen, B Czeh.
Regulation of neurogenesis by stress, sleep, exercise and inflammation; implications for depression
and antidepressant action. European NeuroPsychoPharmacology, Vol 20, Issue 1, 2010, 1-17.
K Boer, PJ Lucassen, WGM Spliet, C van Rijen, E Vreugdenhil, D Troost, F Jansen, E Aronica.
Doublecortin like (DCL) expression in focal cortical dysplasia and cortical tubers
of tuberous sclerosis complex, Epilepsia 50; 12, p 2629-2637, 2009.
M Marlatt, JM Hoozemans, R Veerhuis and PJ Lucassen (2009)
Alzheimer's disease and adult neurogenesis: are endogenous stem cells part of the solution?
Editorial for US Neurology, Vol 5, issue 1, p12-14, 2009
PJ Lucassen, W. Scheper and EJ van Someren. Adult neurogenesis and the unfolded protein response;
new cellular and molecular avenues in sleep research. Editorial for Sleep Medicine Reviews 13: 183-186, 2009.
Marian Joëls, Harmen J. Krugers, Paul J. Lucassen and Henk Karst (2009)
Corticosteroid effects on cellular physiology of limbic cells. Brain Research, 129; 91-100.
Karin Boekhoorn en Paul J. Lucassen. Nieuwe neuronen in volwassen hersenen (in Dutch).
Tijdschrift voor neuropsychiatrie en Gedragsneurologie, Juni 2009; p. 119 - 123.
PJ Lucassen, O Bosch, E Jousma, SA Krömer, R Andrews, JR Seckl and ID Neumann (2009)
Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low anxiety :
possible key role of lack of induction of placental 11B-hydroxysteroid dehydrogenase type 2.
Eur. J. Neurosci., 29; 97-103, 2009
Charlotte A. Oomen, Carlos E.N. Girardi, Rudy Cahyadi, Eva C. Verbeek,
Harm Krugers, Marian Joëls and Paul J. Lucassen (2009)
Opposite effects of early maternal deprivation on neurogenesis in male versus female rats.
PLOS One, 3(11): e3675-88.
M.J.A. Joosen, E. Jousma, T.M. van den Boom, W.C. Kuijpers, A.B. Smit, P.J. Lucassen and H.P.M. van Helden (2009)
Long-term cognitive deficits accompanied by reduced neurogenesis after soman poisoning
Neurotoxicology 30; 72-80, 2009
Goran Simic, Mihovil Mladinov, Natasa Jovanov-Milosevic, Atiqul Islam, Alen Pajtak, Jadranka Sertic,
Paul J. Lucassen, Patrick R. Hof, Bozo Kruslin (2008)
Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular
atrophy
Acta Neuropathol, 115(3):313-26, 2008.
Michael W. Marlatt, Paul J. Lucassen, George Perry, Mark A. Smith and Xiongwei Zhu (2008)
Alzheimer's Disease: Cerebrovascular Dysfunction, Oxidative stress, and Advanced Clinical Therapies.
Journal of Alzheimer's Disease vol 15, 199-210, 2008.
PJ Lucassen, EC Verbeek, CA Oomen (2008)
Wat doen die nieuwe hersencellen daar ?
Neurogenese en celdood in volwassen hersenen (In Dutch)
Online journal BLIND! issue 15, online per april 2008 at www.ziedaar.nl
Alyssa Thompson, Karin Boekhoorn, Anne-Marie Van Dam, and Paul J Lucassen (2008)
Changes in adult neurogenesis in neurodegenerative diseases; cause or consequence?
Genes, Brain and Behaviour, 7 (Suppl. 1), 28-42, 2008.
Karin Boekhoorn, Angela Sarabdjitsingh, Hendrik Kommerie, Karin de Punder,
Theo Schouten, Paul J. Lucassen and Erno Vreugdenhil (2008)
Doublecortin (DCX) and doublecortin-like (DCL) are differentially expressed in the early but not late
stages of murine neocortical development.
Journal of Comparative Neurology, 507(4):1639-1652, 2008.
HJ Krugers, S van der Linden, E van Olst, DN Alfarez, S Maslam, PJ Lucassen, M Joëls (2007)
Dissociation between apoptosis, neurogenesis and synaptic potentiation in the dentate gyrus of adrenalectomized rats.
Synapse 61; 221-230, 2007.
E Vreugdenhil, SM Kolk, K Boekhoorn, C Fitzsimons, M Schaaf,
T Schouten, A Sarabdjitsingh, R Sibug and PJ Lucassen (2007)
Doublecortin-Like, a Microtubule Associated Protein Expressed in Radial Glia is Crucial for Neuronal Precursor Division and Radial Process Stability. Eur J Neurosci, Vol. 25, pp. 635–648, 2007.
AH Veenema, ER de Kloet, MC de Wilde, AJ Roelofs, M Kawata, B Buwalda, I Neumann, JM Koolhaas, PJ Lucassen.
(2007)
Differential effects of stress on adult hippocampal cell proliferation in low and high aggressive mice,
J. Neuroendocrinol., 19(7); 489-98, 2007.
K Sennvik*, K Boekhoorn*, R Lasrado*, D Terwel, S Verhaeghe, H Korr,
C Schmitz, T Tomiyama, H Mori, H Krugers, M Joels, H Dawson, GJA Ramakers, PJ Lucassen and F Van Leuven. (2007)
Tau-4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/knockout mice.
FASEB J. 2007;21(9):2149-61.
B Czeh and PJ Lucassen (2007)
What causes the hippocampal volume decrease in depression? :
Are neurogenesis, glial changes and apoptosis implicated?
Eur. Arch. Gen Psy. & Clin. Neurosci., 257 (5): 250-60, 2007.
M Joëls, H Karst, HJ Krugers and PJ Lucassen (2007)
Chronic stress: Implications for neuron morphology, function and neurogenesis
Front Neuroendocrinol.
2007; 28(2-3):72-96
HG Kuhn, C Cooper-Kuhn, K Boekhoorn and PJ Lucassen (2007)
Changes in neurogenesis in dementia and Alzheimer mouse models: are they functionally relevant?
Eur. Arch. Gen Psy. & Clin. Neurosci., 57(5): 281-9, 2007.
PDF
Charlotte A. Oomen, Joseph L. Mayer, E. Ron de Kloet, Marian Joels and Paul J.Lucassen. (2007)
Brief treatment with the glucocorticoid receptor antagonist mifepristone
normalizes the reduction in neurogenesis after chronic stress.
European Journal of Neuroscience, 26, 3395-3401.
R.W.H. Verwer,A.A. Sluiter, R.A. Balesar, J.C. Baayen, D.P. Noske,
C.M.F. Dirven, J. Wouda, A.M. van Dam, P.J. Lucassen, D.F. Swaab. (2007)
Mature astrocytes in the adult human neocortex express the early neuronal marker doublecortin.
Brain, 130, 3321-3335.
JL Mayer, L Klumpers, S Maslam, ER de Kloet, M Joëls and PJ Lucassen. (2006)
Brief treatment with the glucocorticoid receptor antagonist mifeprestone
normalizes the corticosterone-induced reduction of adult hippocampal neurogenesis.
Journal of Neuroendocrinology 2006; 18; 629–631.
Boekhoorn K Terwel D, Biemans B, Borghgraef P, Krugers H, Wiegert O,
Ramakers GJ, Joels M, Van Leuven F and Lucassen PJ. (2006)
Improved LTP and memory in tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy.
J Neurosci 2006; 26(13):3514-3523.
Boekhoorn K, Joels M and Lucassen PJ. (2006)
Increased proliferation reflects glial and vascular-associated changes,
but not neurogenesis in the presenile Alzheimer hippocampus.
Neurobiol. Disease, 2006; 24(1):1-14.
PJ Lucassen, VM Heine, E van der Beek, VM Wiegant, R De Kloet, M Joels, E Fuchs, DF Swaab and B Czeh (2006)
Stress, depression and hippocampal apoptosis.
CNS and Neurological Disorders - Drug Targets, vol. 5, no 5, pp 531-546, 2006.
Heine VM, Zareno J, Maslam S, Joels M, Lucassen PJ (2005)
Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression.
Eur J Neurosci. 2005 ;21(5):1304-14
DF Swaab, A Bao and PJ Lucassen (2005)
The stress system in the human brain in depression and neurodegeneration.
Aging Research Reviews, Vol 4; p 141-194, 2005.
PJ Lucassen, CP Fitzsimons, E Vreugdenhil, P Hu, CA Oomen, Y Revsin, M Joëls and E R De Kloet
Regulation of structural plasticity and neurogenesis during stress and diabetes;
protective effects of glucocorticoid receptor antagonists.
In: HORMONES IN NEURODEGENERATION, NEUROPROTECTION AND NEUROGENESIS
(A. Gravanis and C Mellon, Editors),
Wiley Blackwell Publishers, UK, 2010. In press.
PJ Lucassen, P Meerlo, AM van Dam, A. Dayer, A. Naylor, B Czeh and CA Oomen.
Do depression, stress, inflammation and sleep alter hippocampal apoptosis and neurogenesis?
In: Understanding Depression: a translational approach
(Eds: Carmine M. Pariante, Randolph Nesse, David Nutt, Lewis Wolpert).
Oxford University Press, 2009, p.139-156.
Lucassen PJ, Swaab DF. Hypothalamo-pituitary-adrenal axis, stress and depression
In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 3. Springer, Heidelberg, 2009. pp 1892-1895.
Swaab DF, Lucassen PJ. Neuroendocrinology. In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 4. Springer, Heidelberg, 2009. pp 2631-2635.
Swaab DF, Lucassen PJ.
Hypothalamo-neurohypophysial system. In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 3. Springer, Heidelberg, 2009. pp 1888-1892.
Bao AM, Lucassen PJ, Swaab DF.
Neuroendocrinology of Psychiatric Disorders. In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 4. Springer, Heidelberg, 2009. pp 2641-2645.
Lucassen PJ, Boekhoorn K, Francis F.
Cortical development - disorders. In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 1. Springer, Heidelberg, 2009. pp 894-896.
Lucassen PJ, Swaab DF.
Endocrine disorders of development and growth. In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 2. Springer, Heidelberg, 2009. pp 1103-1106.
Swaab DF, Lucassen PJ.
Neuroendocrinology of tumours. In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 4. Springer, Heidelberg, 2009. pp 2645-2648.
DF Swaab and PJ Lucassen.
Neuroendocrinology of eating disorders. In: Binder, Hirokawa, Windhorst (eds).
Encyclopedia of Neuroscience, Vol. 4. Springer, Heidelberg, 2009. pp 2635-2637.
Lucassen P.J., Oomen C.A., van Dam A.-M., and Czéh B. (2008)
Regulation of hippocampal neurogenesis by systemic factors including stress, glucocorticoids, sleep, and inflammation.
In Adult neurogenesis (ed. F.H. Gage, G. Kempermann, and H. Song), pp. 363-395.
Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
All portrait pictures by Els Velzing This page was last updated on 22 october 2011
