37
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Fetal brain 11β-hydroxysteroid dehydrogenase type 2 selectively determines programming of adult depressive-like behaviors and cognitive function, but not anxiety behaviors in male mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Highlights

          • Aberrant exposures to glucocorticoids during fetal life programme the risk of psychiatric disease in offspring.

          • Placental 11β-HSD2 protects the fetus from maternal glucocorticoids.

          • This study investigates the role of 11β-HSD2 in the fetal brain.

          • Deletion of 11β-HSD2 in the fetal brain causes depressive-like and cognitive dysfunction in adults.

          • Thus fetal brain 11β-HSD2 protects against programming of adult brain function.

          Summary

          Stress or elevated glucocorticoids during sensitive windows of fetal development increase the risk of neuropsychiatric disorders in adult rodents and humans, a phenomenon known as glucocorticoid programming. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of glucocorticoids in the placenta, controls access of maternal glucocorticoids to the fetal compartment, placing it in a key position to modulate glucocorticoid programming of behavior. However, the importance of the high expression of 11β-HSD2 within the midgestational fetal brain is unknown. To examine this, a brain-specific knockout of 11β-HSD2 (HSD2BKO) was generated and compared to wild-type littermates. HSD2BKO have markedly diminished fetal brain 11β-HSD2, but intact fetal body and placental 11β-HSD2 and normal fetal and placental growth. Despite normal fetal plasma corticosterone, HSD2BKO exhibit elevated fetal brain corticosterone levels at midgestation. As adults, HSD2BKO show depressive-like behavior and have cognitive impairments. However, unlike complete feto-placental deficiency, HSD2BKO show no anxiety-like behavioral deficits. The clear mechanistic separation of the programmed components of depression and cognition from anxiety implies distinct mechanisms of pathogenesis, affording potential opportunities for stratified interventions.

          Related collections

          Most cited references53

          • Record: found
          • Abstract: found
          • Article: not found

          Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety.

          The glucocorticoid receptor (Gr, encoded by the gene Grl1) controls transcription of target genes both directly by interaction with DNA regulatory elements and indirectly by cross-talk with other transcription factors. In response to various stimuli, including stress, glucocorticoids coordinate metabolic, endocrine, immune and nervous system responses and ensure an adequate profile of transcription. In the brain, Gr has been proposed to modulate emotional behaviour, cognitive functions and addictive states. Previously, these aspects were not studied in the absence of functional Gr because inactivation of Grl1 in mice causes lethality at birth (F.T., C.K. and G.S., unpublished data). Therefore, we generated tissue-specific mutations of this gene using the Cre/loxP -recombination system. This allowed us to generate viable adult mice with loss of Gr function in selected tissues. Loss of Gr function in the nervous system impairs hypothalamus-pituitary-adrenal (HPA)-axis regulation, resulting in increased glucocorticoid (GC) levels that lead to symptoms reminiscent of those observed in Cushing syndrome. Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour because mutant animals show an impaired behavioural response to stress and display reduced anxiety.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The tail suspension test: a new method for screening antidepressants in mice.

            A novel test procedure for antidepressants was designed in which a mouse is suspended by the tail from a lever, the movements of the animal being recorded. The total duration of the test (6 min) can be divided into periods of agitation and immobility. Several psychotropic drugs were studied: amphetamine, amitriptyline, atropine, desipramine, mianserin, nomifensine and viloxazine. Antidepressant drugs decrease the duration of immobility, as do psychostimulants and atropine. If coupled with measurement of locomotor activity in different conditions, the test can separate the locomotor stimulant doses from antidepressant doses. Diazepam increases the duration of immobility. The main advantages of this procedure are the use of a simple, objective test situation, the concordance of the results with the validated "behavioral despair" test from Porsolt and the sensitivity to a wide range of drug doses.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              When is the hippocampus involved in recognition memory?

              The role of the hippocampus in recognition memory is controversial. Recognition memory judgments may be made using different types of information, including object familiarity, an object's spatial location, or when an object was encountered. Experiment 1 examined the role of the hippocampus in recognition memory tasks that required the animals to use these different types of mnemonic information. Rats with bilateral cytotoxic lesions in the hippocampus or perirhinal or prefrontal cortex were tested on a battery of spontaneous object recognition tasks requiring the animals to make recognition memory judgments using familiarity (novel object preference); object-place information (object-in-place memory), or recency information (temporal order memory). Experiment 2 examined whether, when using different types of recognition memory information, the hippocampus interacts with either the perirhinal or prefrontal cortex. Thus, groups of rats were prepared with a unilateral cytotoxic lesion in the hippocampus combined with a lesion in either the contralateral perirhinal or prefrontal cortex. Rats were then tested in a series of object recognition memory tasks. Experiment 1 revealed that the hippocampus was crucial for object location, object-in-place, and recency recognition memory, but not for the novel object preference task. Experiment 2 revealed that object-in-place and recency recognition memory performance depended on a functional interaction between the hippocampus and either the perirhinal or medial prefrontal cortices. Thus, the hippocampus plays a role in recognition memory when such memory involves remembering that a particular stimulus occurred in a particular place or when the memory contains a temporal or object recency component.
                Bookmark

                Author and article information

                Contributors
                Journal
                Psychoneuroendocrinology
                Psychoneuroendocrinology
                Psychoneuroendocrinology
                Pergamon Press
                0306-4530
                1873-3360
                1 September 2015
                September 2015
                : 59
                : 59-70
                Affiliations
                [a ]UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom
                [b ]Centre for Cognitive and Neural Systems, University of Edinburgh, EH8 9JZ, United Kingdom
                [c ]School of Anatomy, Physiology & Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
                Author notes
                [* ]Corresponding author at: Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. Tel.: +44 131 242 6737. megan.holmes@ 123456ed.ac.uk
                Article
                S0306-4530(15)00183-3
                10.1016/j.psyneuen.2015.05.003
                4510145
                26036451
                8286e49e-2a87-4ade-8eab-7b2826a1e1df
                Crown Copyright © Published by Elsevier Ltd. All rights reserved.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 26 January 2015
                : 8 May 2015
                : 8 May 2015
                Categories
                Article

                Endocrinology & Diabetes
                glucocorticoids,developmental programming,affective behaviors,brain 11β-hsd2

                Comments

                Comment on this article