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Growth hormone in the brain: Focus on cognitive function
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 227
Keyword [en]
Growth hormone, central nervous system, cognition, morphine, gamma-hydroxybutyrate, diabetes, Barnes maze, Morris water maze, mice, rats
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-317305ISBN: 978-91-554-9854-2 (print)OAI: oai:DiVA.org:uu-317305DiVA: diva2:1082142
Public defence
2017-05-05, B42, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council, 9459Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2017-04-12 Created: 2017-03-15 Last updated: 2017-04-21
List of papers
1. The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments
Open this publication in new window or tab >>The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments
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2012 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 523, no 1, 82-86 p.Article in journal (Refereed) Published
Abstract [en]

Previous studies have indicated that both growth hormone (GH) deficiency and diabetes are conditions associated with impairments in learning and memory processes. In this study, we investigated the effect of streptozotocin-induced diabetes on spatial learning in mice using the Barnes maze (BM). The expression of the GH receptor (GHR) gene transcript in areas of the brain associated with learning and memory were examined. The results indicated that the GHR gene transcript is up-regulated in the prefrontal cortex (PFC) of diabetic mice compared to controls. In addition, there was a significant correlation between the expression of GHR mRNA and performance in the BM during the acquisition phase in diabetic but not control mice. These results suggest that diabetes induces an imbalance in the GH/IGF-1 system leading to altered activity in the PFC and associated cognitive deficiencies.

Keyword
Barnes maze (BM), Cognition, Diabetes, Growth hormone receptor (GHR), Mice, Streptozotocin (STZ)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-181862 (URN)10.1016/j.neulet.2012.06.050 (DOI)000307619600017 ()
Available from: 2012-10-01 Created: 2012-10-01 Last updated: 2017-03-15Bibliographically approved
2. Growth hormone reverses streptozotocin-induced cognitive impairments in male mice
Open this publication in new window or tab >>Growth hormone reverses streptozotocin-induced cognitive impairments in male mice
2013 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 238, 273-278 p.Article in journal (Refereed) Published
Abstract [en]

In recent decades, growth hormone (GH) replacement therapy in human subjects deficient in the hormone has resulted in a number of beneficial effects on cognitive performance. Studies in hypophysectomised rats report similar effects of GH treatment on learning and memory tasks. The purpose of this study was to investigate the ability of GM to reverse learning impairments in mice with streptozotocin (STZ)-induced diabetes. Diabetic and control mice were given recombinant human GM (rhGH) 0.1 IU/kg/day for ten consecutive days. In the latter phase of the treatment the cognitive abilities of the mice were tested using the Barnes maze (BM). A profound hormonal effect was seen when analysing the search patterns used by the animals in the maze. rhGH treatment significantly counteracted the cognitive disabilities expressed as lack of direct search strategies on the last day in the BM. In addition, the number of primary errors made by diabetic mice during the acquisition phase was reduced by rhGH treatment, although the primary escape latency was unchanged in these animals when compared to saline-treated diabetic animals. These results suggest that specific cognitive impairments induced by STZ, i.e. the disabilities seen in strategic behaviour, could be reversed by exogenous hormone treatment. Our findings highlight the influence of GH on brain function and in particular on cognitive behaviour related to learning and memory.

Keyword
Barnes maze (BM), Growth hormone (GH), Cognition, Search strategies, Mice, Streptozotocin (STZ)
National Category
Natural Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-195347 (URN)10.1016/j.bbr.2012.10.036 (DOI)000314138800035 ()
Available from: 2013-02-26 Created: 2013-02-25 Last updated: 2017-03-15Bibliographically approved
3. The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration
Open this publication in new window or tab >>The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration
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2017 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 646, 15-20 p.Article in journal (Refereed) Published
Abstract [en]

In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.

Keyword
Growth hormone, gamma-hydroxybuturate, insulin-like growth factor-1, central nervous system, frontal cortex, cognition
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-317299 (URN)10.1016/j.neulet.2017.02.053 (DOI)000401679600003 ()28249788 (PubMedID)
Funder
Swedish Research Council, 9459Carl Tryggers foundation
Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2017-06-19Bibliographically approved
4. Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
Open this publication in new window or tab >>Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The use of opioid analgesics to treat non-cancer pain has increased over the years.  Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory were evaluated using the Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system were analyzed using quantitative PCR (qPCR) and the levels of IGF-1 in plasma were examined with ELISA. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.

Keyword
Morphine, Morris water maze, mini-osmotic pumps, memory, insulin-like growth factor-1, N-metyl-D-aspartate
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-317302 (URN)
Funder
Swedish Research Council, 9459Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2017-03-15

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