Restoration of hippocampal growth hormone reverses stress-induced hippocampal impairment

Though growth hormone (GH) is synthesized by hippocampal neurons, where its expression is influenced by stress exposure, its function is poorly characterized. Here, we show that a regimen of chronic stress that impairs hippocampal function in rats also leads to a profound decrease in hippocampal GH levels. Restoration of hippocampal GH in the dorsal hippocampus via viral-mediated gene transfer completely reversed stress-related impairment of two hippocampus-dependent behavioral tasks, auditory trace fear conditioning, and contextual fear conditioning, without affecting hippocampal function in unstressed control rats. GH overexpression reversed stress-induced decrements in both fear acquisition and long-term fear memory. These results suggest that loss of hippocampal GH contributes to hippocampal dysfunction following prolonged stress and demonstrate that restoring hippocampal GH levels following stress can promote stress resilience.

[1]  T. Baram,et al.  Rapid Loss of Dendritic Spines after Stress Involves Derangement of Spine Dynamics by Corticotropin-Releasing Hormone , 2008, The Journal of Neuroscience.

[2]  T. Shors,et al.  The hippocampus is necessary for enhancements and impairments of learning following stress , 2007, Nature Neuroscience.

[3]  S. Chattarji,et al.  Stress Leads to Contrasting Effects on the Levels of Brain Derived Neurotrophic Factor in the Hippocampus and Amygdala , 2012, PloS one.

[4]  Peter H. Seeburg,et al.  Nucleotide sequence and amplification in bacteria of structural gene for rat growth hormone , 1977, Nature.

[5]  F. Nyberg,et al.  Growth hormone and its receptors in the central nervous system--location and functional significance. , 1996, Hormone research.

[6]  Kenneth S Kosik,et al.  Transcriptional profiling reveals regulated genes in the hippocampus during memory formation , 2002, Hippocampus.

[7]  Greg D. Gale,et al.  Hippocampus and contextual fear conditioning: Recent controversies and advances , 2001, Hippocampus.

[8]  K. Lattal,et al.  Double Dissociation of Amygdala and Hippocampal Contributions to Trace and Delay Fear Conditioning , 2011, PloS one.

[9]  F. Lim,et al.  Generation of High‐Titer Defective HSV‐1 Vectors , 2013, Current protocols in neuroscience.

[10]  Carolyn M. Mazure,et al.  Does stress cause psychiatric illness , 1995 .

[11]  L. Grover,et al.  Growth hormone enhances excitatory synaptic transmission in area CA1 of rat hippocampus. , 2006, Journal of neurophysiology.

[12]  Christian Büchel,et al.  Dissociable Roles for the Hippocampus and the Amygdala in Human Cued versus Context Fear Conditioning , 2008, The Journal of Neuroscience.

[13]  Bruce S. McEwen,et al.  Allostasis and Allostatic Load , 2007 .

[14]  A. Bartke,et al.  Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice , 2005, Neurobiology of Aging.

[15]  R. Neve,et al.  Generation of high-titer defective HSV-1 vectors. , 2001, Current protocols in neuroscience.

[16]  B. McEwen,et al.  Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors , 1995, Neuroscience.

[17]  Tracey J. Shors,et al.  Sex Differences and Opposite Effects of Stress on Dendritic Spine Density in the Male Versus Female Hippocampus , 2001, The Journal of Neuroscience.

[18]  D. M. Lyons,et al.  The neurobiology of the stress-resistant brain , 2011, Stress.

[19]  S. Chattarji,et al.  Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Y. Endo,et al.  A long-term stress exposure impairs maze learning performance in rats , 1999, Neuroscience Letters.

[21]  Martin Picard,et al.  A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development , 2011, Development and Psychopathology.

[22]  Jens C. Pruessner,et al.  City living and urban upbringing affect neural social stress processing in humans , 2011, Nature.

[23]  A. Schatzberg,et al.  Cortisol activity and cognitive changes in psychotic major depression. , 2001, The American journal of psychiatry.

[24]  C. Sandi,et al.  Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training , 2003, The European journal of neuroscience.

[25]  T. Shors,et al.  Growth hormone is produced within the hippocampus where it responds to age, sex, and stress. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[26]  James L. McGaugh,et al.  Stress and glucocorticoids impair retrieval of long-term spatial memory , 1998, Nature.

[27]  E. Kandel,et al.  A Molecular Circuit Composed of CPEB-1 and c-Jun Controls Growth Hormone-Mediated Synaptic Plasticity in the Mouse Hippocampus , 2008, The Journal of Neuroscience.

[28]  C Weiss,et al.  Stress-induced facilitation of classical conditioning. , 1992, Science.

[29]  John F. Disterhoft,et al.  Increased Excitability of Aged Rabbit CA1 Neurons after Trace Eyeblink Conditioning , 2000, The Journal of Neuroscience.

[30]  P. Gass,et al.  Reduced cell proliferation in the dentate gyrusis not correlated with the development of learned helplessness , 2003, Biological Psychiatry.

[31]  F. Martin,et al.  Functional glucocorticoid inducible enhancer activity in the 5′-flanking sequences of the rat growth hormone gene , 1991, The Journal of Steroid Biochemistry and Molecular Biology.

[32]  Peter R Killeen,et al.  Chronic stress impairs spatial memory and motivation for reward without disrupting motor ability and motivation to explore. , 2006, Behavioral neuroscience.

[33]  F. Sarubbo,et al.  Cognitive improvement by acute growth hormone is mediated by NMDA and AMPA receptors and MEK pathway , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[34]  K. Goosens.  Hippocampal regulation of aversive memories , 2011, Current Opinion in Neurobiology.

[35]  Angela L. Lee,et al.  Restructuring the neuronal stress response with anti-glucocorticoid gene delivery , 2004, Nature Neuroscience.

[36]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[37]  Hongkui Zeng,et al.  Differential Control of Learning and Anxiety along the Dorsoventral Axis of the Dentate Gyrus , 2013, Neuron.

[38]  J F Disterhoft,et al.  Transient changes in excitability of rabbit CA3 neurons with a time course appropriate to support memory consolidation. , 1996, Journal of neurophysiology.

[39]  B. McEwen.  Protective and damaging effects of stress mediators. , 1998, The New England journal of medicine.

[40]  E. Shimizu,et al.  Genetic enhancement of learning and memory in mice , 1999, Nature.

[41]  L. Squire,et al.  Working memory, long-term memory, and medial temporal lobe function. , 2011, Learning & memory.

[42]  Adam M. Campbell,et al.  The Temporal Dynamics Model of Emotional Memory Processing: A Synthesis on the Neurobiological Basis of Stress-Induced Amnesia, Flashbulb and Traumatic Memories, and the Yerkes-Dodson Law , 2007, Neural plasticity.

[43]  F. Nyberg,et al.  Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-d-aspartate receptor subunits gene transcripts in male rats , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Adams,et al.  Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats , 2012, Neurobiology of Aging.

[45]  Tracey J. Shors,et al.  Memory traces of trace memories: neurogenesis, synaptogenesis and awareness , 2004, Trends in Neurosciences.

[46]  S. Chattarji,et al.  Chronic Stress Induces Contrasting Patterns of Dendritic Remodeling in Hippocampal and Amygdaloid Neurons , 2002, The Journal of Neuroscience.

[47]  Bruce S. McEwen,et al.  Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons , 1992, Brain Research.

[48]  K. Luan Phan,et al.  The contextual brain: implications for fear conditioning, extinction and psychopathology , 2013, Nature Reviews Neuroscience.

[49]  Tracey J. Shors,et al.  Acute Stress Rapidly and Persistently Enhances Memory Formation in the Male Rat , 2001, Neurobiology of Learning and Memory.

[50]  A. Turnley,et al.  Growth hormone signaling and hippocampal neurogenesis: Insights from genetic models , 2008, Hippocampus.