Skip to main content

Advertisement

SpringerLink
Log in

Infusion of growth hormone into the hippocampus induces molecular and behavioral responses in mice

  • Research Article
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

An Erratum to this article was published on 26 September 2014

Abstract

Growth hormone (GH) has been implicated in a variety of brain functions, including neural development, cognition, and neuroprotection. The biological effects of GH are known to rely on the binding of GH to the GH receptor (GHR), yet the resulting signals in the brain remain poorly understood. The present study investigated the effects of hippocampal infusions of recombinant GH and a GHR antagonist on the expression of immediate early genes (IEGs) and behavioral responses in mice. The infusions induced differential expression of Arc, Nr4a1, and Npas4 mRNAs among the IEGs. The infusions also elicited differential behavioral responses, such as varied levels of spontaneous locomotion, self-grooming, and frequency of access to the corner fields in the open-field test. Polynomial regression analyses and canonical discriminant analyses between gene expression and behavioral changes demonstrated that the expression level of Arc mRNA was strongly correlated with locomotor activity level (r = 0.71 and 0.92 on days 8 and 10, respectively) and that the correlation was completely discriminable between drugs (error rate = 0 %). This analysis also revealed that a decrease in Npas4 mRNA was negatively correlated with the number of corner accesses (r = −0.63) and that this correlation was partially discriminable between drugs (error rate = 16.67 %). Taken together, these results suggest that the GH–GHR complex modulates Arc and Npas4 signaling, which affects spontaneous locomotor and exploratory behaviors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

Arc :

Activity-regulated cytoskeletal-associated protein

CNS:

Central nervous system

Fos :

FBJ osteosarcoma oncogene

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GH:

Growth hormone

GHR:

Growth hormone receptor

IEGs:

Immediate early genes

Npas4 :

Neuronal PAS domain protein

Nr4a1:

Nuclear receptor subfamily 4, group A, member 1

qRT-PCR:

Quantitative real-time polymerase chain reaction

rGH:

Human GH recombinant

TLE:

Temporal lobe epilepsy

References

  • Akiyama K, Ishikawa M, Saito A (2008) mRNA expression of activity-regulated cytoskeleton-associated protein (arc) in the amygdala-kindled rats. Brain Res 1189:236–246

    Article  PubMed  CAS  Google Scholar 

  • Becker AJ, Chen J, Zien A, Sochivko D, Normann S, Schramm J et al (2003) Correlated stage- and subfield-associated hippocampal gene expression patterns in experimental and human temporal lobe epilepsy. Eur J Neurosci 18:2792–2802

    Article  PubMed  Google Scholar 

  • Beranek L, Hajdu I, Gardi J, Taishi P, Obál Fn Jr, Krueger JM (1999) Central administration of the somatostatin analog octreotide induces captopril-insensitive sleep responses. Am J Physiol 277:R1297–R1304

    PubMed  CAS  Google Scholar 

  • Bozzi Y, Dunleavy M, Henshall DC (2011) Cell signaling underlying epileptic behavior. Front Behav Neurosci 5:45

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Castro JE, Varea E, Márquez C, Cordero MI, Poirier G, Sandi C (2010) Role of the amygdala in antidepressant effects on hippocampal cell proliferation and survival and on depression-like behavior in the rat. PLoS One 5:e8618

    Article  PubMed  PubMed Central  Google Scholar 

  • Deijen JB, de Boer H, Blok GJ, van der Veen EA (1996) Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendocrinology 21:313–322

    Article  PubMed  CAS  Google Scholar 

  • Donahue CP, Kosik KS, Shors TJ (2006) Growth hormone is produced within the hippocampus where it responds to age, sex, and stress. Proc Natl Acad Sci USA 103:6031–6036

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ekinci O, Titus JB, Rodopman AA, Berkem M, Trevathan E (2009) Depression and anxiety in children and adolescents with epilepsy: prevalence, risk factors, and treatment. Epilepsy Behav 14:8–18

    Article  PubMed  Google Scholar 

  • Elliott RC, Miles MF, Lowenstein DH (2003) Overlapping microarray profiles of dentate gyrus gene expression during development- and epilepsy-associated neurogenesis and axon outgrowth. J Neurosci 23:2218–2227

    PubMed  CAS  Google Scholar 

  • Escorihuela RM, Fernández-Teruel A, Gil L, Aguilar R, Tobeña A, Driscoll P (1999) Inbred Roman high- and low-avoidance rats: differences in anxiety, novelty-seeking, and shuttlebox behaviors. Physiol Behav 67:19–26

    Article  PubMed  CAS  Google Scholar 

  • Ettinger AB, Weisbrot DM, Krupp LB, Coyle PK, Jandorf L, Devinsky O (1998) Fatigue and depression in epilepsy. J Epilepsy 11:105–109

    Article  Google Scholar 

  • Fattore L, Piras G, Corda MG, Giorgi O (2009) The Roman high- and low-avoidance rat lines differ in the acquisition, maintenance, extinction, and reinstatement of intravenous cocaine self-administration. Neuropsychopharmacology 34:1091–1101

    Article  PubMed  CAS  Google Scholar 

  • Flood WD, Moyer RW, Tsykin A, Sutherland GR, Koblar SA (2004) Nxf and Fbxo33: novel seizure-responsive genes in mice. Eur J Neurosci 20:1819–1826

    Article  PubMed  Google Scholar 

  • Glauser TA (2004) Effects of antiepileptic medications on psychiatric and behavioral comorbidities in children and adolescents with epilepsy. Epilepsy Behav 5:S25–S32

    Article  PubMed  Google Scholar 

  • Goosens KA, Maren S (2001) Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats. Learn Mem 8:148–155

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gorter JA, van Vliet EA, Aronica E, Breit T, Rauwerda H, Lopes da Silva FH et al (2006) Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J Neurosci 26:11083–11110

    Article  PubMed  CAS  Google Scholar 

  • Hale MW, Hay-Schmidt A, Mikkelsen JD, Poulsen B, Shekhar A, Lowry CA (2008) Exposure to an open-field arena increases c-Fos expression in a distributed anxiety-related system projecting to the basolateral amygdaloid complex. Neuroscience 155:659–672

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Harvey S, Hull K (2003) Neural growth hormone: an update. J Mol Neurosci 20:1–13

    Article  PubMed  CAS  Google Scholar 

  • Hawk JD, Abel T (2011) The role of NR4A transcription factors in memory formation. Brain Res Bull 85:21–29

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Herrington J, Carter-Su C (2001) Signaling pathways activated by the growth hormone receptor. Trends Endocrinol Metab 12:252–257

    Article  PubMed  CAS  Google Scholar 

  • Hevroni D, Rattner A, Bundman M, Lederfein D, Gabarah A, Mangelus M et al (1998) Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms. J Mol Neurosci 10:75–98

    Article  PubMed  CAS  Google Scholar 

  • Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ (2007) Predictors of pharmacoresistant epilepsy. Epilepsy Res 75:192–196

    Article  PubMed  CAS  Google Scholar 

  • Hodge C, Liao J, Stofega M, Guan K, Carter-Su C, Schwartz J (1998) Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. J Biol Chem 273:31327–31336

    Article  PubMed  CAS  Google Scholar 

  • Homberg JR, van den Akker M, Raasø HS, Wardeh G, Binnekade R, Schoffelmeer AN et al (2002) Enhanced motivation to self-administer cocaine is predicted by self-grooming behavior and relates to dopamine release in the rat medial prefrontal cortex and amygdala. Eur J Neurosci 15:1542–1550

    Article  PubMed  Google Scholar 

  • Kato K, Masa T, Tawara Y, Kobayashi K, Oka T, Okabe A et al (2001) Dendritic aberrations in the hippocampal granular layer and the amygdalohippocampal area following kindled-seizures. Brain Res 901:281–295

    Article  PubMed  CAS  Google Scholar 

  • Kato K, Suzuki M, Kanno H, Sekino S, Kusakabe K, Okada T et al (2009) Distinct role of growth hormone on epilepsy progression in a model of temporal lobe epilepsy. J Neurochem 110:509–519

    Article  PubMed  CAS  Google Scholar 

  • Lamberts SW, Verleun T, Hofland L, Del Pozo E (1987) A comparison between the effects of SMS 201–995, bromocriptine and a combination of both drugs on hormone release by the cultured pituitary tumour cells of acromegalic patients. Clin Endocrinol (Oxf) 27:11–23

    Article  CAS  Google Scholar 

  • Laron Z (2009) Growth hormone and insulin-like growth factor I: effects on the brain. In: Arnold A et al (eds) Hormones, brain and behavior. Academic Press, San Diego, pp 2449–2470

    Chapter  Google Scholar 

  • Lukasiuk K, Kontula L, Pitkänen A (2003) cDNA profiling of epileptogenesis in the rat brain. Eur J Neurosci 17:271–279

    Article  PubMed  Google Scholar 

  • Lyons MR, West AE (2011) Mechanisms of specificity in neuronal activity-regulated gene transcription. Prog Neurobiol 94:259–295

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Nedivi E, Hevroni D, Naot D, Israeli D, Citri Y (1993) Numerous candidate plasticity-related genes revealed by differential cDNA cloning. Nature 363:718–722

    Article  PubMed  CAS  Google Scholar 

  • Nyberg F (2000) Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance. Front Neuroendocrinol 21:330–348

    Article  PubMed  CAS  Google Scholar 

  • Okuno H (2011) Regulation and function of immediate-early genes in the brain: beyond neuronal activity markers. Neurosci Res 69:175–186

    Article  PubMed  CAS  Google Scholar 

  • Perini GI, Tosin C, Carraro C, Bernasconi G, Canevini MP, Canger R et al (1996) Interictal mood and personality disorders in temporal lobe epilepsy and juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 61:601–605

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Plath NL, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C et al (2006) Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52:437–444

    Article  PubMed  CAS  Google Scholar 

  • Ploski JE, Monsey MS, Nguyen T, DiLeone RJ, Schafe GE (2011) The Neuronal PAS Domain Protein 4 (Npas4) is required for new and reactivated fear memories. PLoS One 6:e23760

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ramamoorthi K, Fropf R, Belfort GM, Fitzmaurice HL, McKinney RM, Neve RL, Otto T, Lin Y (2011) Npas4 regulates a transcriptional program in CA3 required for contextual memory formation. Science 334:1669–1675

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ramsey MM, Weiner JL, Moore TP, Carter CS, Sonntag WE (2004) Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience 129:119–127

    Article  PubMed  CAS  Google Scholar 

  • Stanfield JP (1960) The blood supply of the human pituitary gland. J Anat 94:257–273

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tang Y, Lu A, Aronow BJ, Wagner KR, Sharp FR (2002) Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia. Eur J Neurosci 15:1937–1952

    Article  PubMed  Google Scholar 

  • Tournier BB, Steimer T, Millet P, Moulin-Sallanon M, Vallet P, Ibaaemorrhageal (2013) Innately low D2 receptor availability is associated with high novelty-seeking and enhanced behavioural sensitization to amphetamine. Int J Neuropsychopharmacol 16(8):1819–1834

    Article  PubMed  CAS  Google Scholar 

  • van Dam PS, Aleman A, de Vries WR, Deijen JB, van der Veen EA, de Haan EHF, Koppeschaar HPF (2000) Growth hormone, insulin-like growth factor I and cognitive function in adults. Growth Horm IGF Res Suppl B:S69–S73

  • Vazquez B, Devinsky O (2003) Epilepsy and anxiety. Epilepsy Behav 4:S20–S25

    Article  PubMed  Google Scholar 

  • Witter MP, Amaral DG (2004) Hippocampal formation. In: Paxinos G (ed) The rat nervous system, 3rd edn. Academic Press Inc., San Diego, pp 635–704

    Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Kyoto Sangyo University Research Grants (E1106), the Ministry of Education, Culture, Sports, Science and Technology (17580260), and Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST). The funding source had no role in study design/concept, data collection/analysis/interpretation, and manuscript preparation/submission. We appreciate Dr. Takeo Yoshikawa and Dr. Kazuyuki Yamada, Brain Science Institute, RIKEN, for their discussions regarding the manuscript, and Dr. Yoshiaki Nakayama and Dr. Akira Kurosaka for generously allowing us to use their dark-light box.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan

    Paitoon Srimontri, Haruna Hirota & Keiko Kato

  2. Kobe City Meat Safety Inspection Office, 7-1-20, Karumo-dori, Nagata-ku, Kobe, Japan

    Hiroki Kanno

  3. Laboratory for Molecular Membrane Neuroscience, Brain Science Institute, RIKEN, Wako, Saitama, 351-0198, Japan

    Toshiya Okada

  4. Department of Structural and Functional Biosciences for Animals, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Osaka, 598-8531, Japan

    Yoshio Hirabayashi

Authors
  1. Paitoon Srimontri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haruna Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroki Kanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiya Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshio Hirabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keiko Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keiko Kato.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 3839 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Srimontri, P., Hirota, H., Kanno, H. et al. Infusion of growth hormone into the hippocampus induces molecular and behavioral responses in mice. Exp Brain Res 232, 2957–2966 (2014). https://doi.org/10.1007/s00221-014-3977-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-014-3977-y

Keywords

Search

Navigation