Hippocampal Growth Hormone: Modulation by Estrogen and Stress

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The hippocampus, a telencephalic brain structure, functions in cognition and stress regulation. Growth hormone (GH)-binding sites and insulin-like growth factor (IGF) receptors have been found in the hippocampus and other brain centers. A previous study of gene transcriptional profiling unexpectedly found increased GH expression in the hippocampus of male rats who had acquired a hippocampus-dependent learning task, but very low or undetectable GH expression in naïve rats or rats exposed to other types of training.1

These findings prompted Donahue at al to characterize hippocampal GH expression with respect to age, sex and an acutely stressful experience. Using real-time PCR, GH mRNA levels were similar between male and female juvenile (prepubertal) Sprague-Dawley rats, but more than doubled in adult males, and more than tripled in adult female rats. Female levels were almost double that of males. On closer examination, GH mRNA levels in the adult females were dependent upon the stage of the estrus cycle, with maximal levels during proestrus (ovulation and high estrogen concentrations), intermediate levels during estrus, and lowest levels (comparable to adult males) during diestrus. In contrast, mRNA for GH receptor and IGF-I were lowest during proestrus, but higher in males, and in females during estrus and diestrus. Thus, it seems that estrogen inhibited hippocampal expression of GH receptor and IGF-I, with subsequent induction of GH expression. To prove the effects of estrogen, ovariectomized female rats were treated with either estradiol or vehicle. The GH mRNA and protein in the ovariectomized rats were similar to that of male rats, but increased with estradiol treatment. Estradiol treatment reduced hippocampal GH receptor and IGF-I mRNAs in the ovariectomized females. Finally, in vitro incubation of one-week-old primary neurons with estradiol tripled GH mRNA levels, confirming a direct effect of estrogen on GH expression by neurons.

The authors also explored a possible functional correlate of the sexually dimorphic expression of hippocampal GH. Prior studies of rats exposed to an acutely stressful event found that the experience improved learning in males but impaired learning in females. Thus, Donahue and colleagues exposed rats to 30 brief, intermittent tail shocks (1 per minute, lasting 1 second) while in a dark sound-attenuating restraining tube. Upon completion, rats were returned to their cages and then sacrificed 24 hours later. In males, stress doubled hippocampal GH mRNA without changing IGF-I mRNA levels. In females, however, stress during diestrus tripled GH mRNA levels and reduced IGF-I mRNA by about 3-fold; stress during estrus or proestrus did not significantly alter GH mRNA levels.

The authors concluded that hippocampal GH expression is modulated by age, estrogen, exposure to a stressful experience, and from their previous study, learning hippocampal-dependent memory tasks.1 They postulated that GH acts to induce neuronal growth, which leads to learning and memory. Supporting this hypothesis, in parallel to the GH levels found in this study, hippocampal dendritic spines and new neuronal growth are greater in adult females than males, especially during proestrus, are changed by stressful experiences differently in males than females, and increase with learning.

Donahue CP, Kosik KS, Shors TJ. Growth hormone is produced within the hippocampus where it responds to age, sex, and stress.Proc Natl Acad Sci U S A. 2006;103:6031–3036.

Editor’s Comment

The GH/IGF axis is increasingly appreciated as important for brain functions outside the hypothalamus-pituitary unit. For further discussion of the effects of age, sex and stressful stimuli on hippocampal function, which exceeds the scope of this review, I refer the reader to paper on the subject.2-4 The role of IGF-I in learning and memory was previously reviewed in GGH.5 This paper supports a role of hippocampal GH in learning. Another recent paper demonstrated hippocampal binding of circulating ghrelin, with formation of dendritic spine synapses, generation of long-term potentiation and improvements in spatial learning and memory. Targeted disruption of the ghrelin gene led to fewer spine synapses and impaired performance on behavioral memory testing, with correction of both deficits by the administration of ghrelin.6

Adda Grimberg , MD

References - (linked to Pubmed Links)

  1. Donahue CP, Jensen RV, Ochiishi T, et al. Hippocampus. 2002;12:821 – 833.
  2. Driscoll I, Sutherland RJ. Rev Neurosci. 2005;16:87 – 121.
  3. Shors TJ. Annu Rev Psychol. 2006;57:55 – 85.
  4. McCarthy MM, Konkle AT. Front Neuroendocrinol. 2005;26:85 – 102.
  5. Growth Genet Horm.2004;20:15.
  6. Diano S, Farr SA, Benoit SC, et al. Nat Neurosci 2006;9:381 – 388.

 

 

 


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