Behavioural Brain Research 142 (2003) 69–79
Reduced attention in mice overproducing
M.M. van Gaalen
, M. Stenzel-Poore
, F. Holsboer
, T. Steckler
Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, D-80804 Munich, Germany
Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR, USA
Received 9 September 2002; received in revised form 7 November 2002; accepted 7 November 2002
Data from several studies suggest that unrestrained secretion of corticotropin-releasing hormone in the CNS produces several signs and
symptoms of depression. Recent evidence indicates that blockade of the CRH receptor 1 reduced depression scores in depressed patients.
One of the symptoms that occur is depression is impairment in attentional processes. Whether these impairments are due to alterations
in the CRH system are so far unknown. In order to investigate whether overproduction of CRH alters attentional process, transgenic
mice overproducing CRH were tested on an operant ﬁve choice serial reaction time task, a task which taxes sustained and divided
Mutants showed impaired autoshaping. During initial discrimination learning, transgenics performed below wildtype level, but with
extended training with long stimulus durations, transgenic animals reached similar accuracy levels as wildtype mice. When animals
were tested at shortest stimulus duration (0.5 s), a mild but signiﬁcant impairment in accurate responding emerged in transgenics. This
was accompanied by longer correct response latencies, while incorrect latencies did not differ between groups, suggesting attentional
impairment in CRH transgenics.
Because these animals have been reported to also show increased anxiety-related behaviour, animals were treated with the anxiolytic
benzodiazepine diazepam. Diazepam failed to affect accuracy, but transgenic mice showed a stronger behavioural disinhibition. This
suggests that the attentional impairment seen in CRH overexpressors is independent of alterations in anxiety-like behaviour.
These ﬁndings may have implications for understanding the pathophysiology of psychiatric disorders such as depression, where it
has been suggested that an overactivity of the CRH system accounts for a variety of symptoms, including hyper-arousal and attentional
© 2002 Elsevier Science B.V. All rights reserved.
Keywords: Attention; Corticotropin-releasing hormone; CRH; Overexpressor; Transgenic; Mouse
Corticotropin-releasing hormone (CRH) is a potent me-
diator of the stress response [10,17,34], anxiety-related be-
Abbreviations: CRH, corticotropin-releasing hormone; CRHR1, corti-
cotropin-releasing hormone receptor-subtype 1; ICV, intracerebroventric-
Corresponding author. Present address: Department of Medical Phar-
macology, VUmc, Research Institute Neurosciences VU, Van der Boe-
chorststraat 7, 1081 BT Amsterdam, The Netherlands.
E-mail addresses: email@example.com (M.M. van Gaalen),
firstname.lastname@example.org (T. Steckler).
Present address: Johnson & Johnson Pharmaceutical Research and De-
velopment, Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30,
B-2340 Beerse, Belgium. Fax: +32-14-60-61-21.
haviour [43,46] and arousal . It is believed that CRH
plays a crucial role in a range of psychiatric disorder, such
as depression and other affective disorders. Patients suffer-
ing from major depression show alterations in cognitive im-
pairments such as attentional deﬁcits [23,27,37,51]. Whether
disruption of attentional processes are due to alterations in
CRH activity is unknown.
CRH-containing neurones are present throughout the neo-
cortex, but particular high densities are found in the pre-
frontal cortex . Of the two CRH receptors identiﬁed
in the brain, the CRHR1 is highly abundant in brain ar-
eas which have been suggested to play a role in atten-
tion, such as frontal cortical areas, the superior colliculi, the
cholinergic basal forebrain and brainstem nuclei [2,6]. High
degrees of co-localisation of choline-acetyltransferase and
0166-4328/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved.