Amygdala transcriptome and cellular mechanisms underlying stress-enhanced fear learning in a rat model of posttraumatic stress disorder.
Severe stress or trauma can cause permanent changes in brain circuitry, leading to dysregulation of fear responses and the development of posttraumatic stress disorder (PTSD). To date, little is known about the molecular mechanisms underlying stress-induced long-term plasticity in fear circuits. We addressed this question by using global gene expression profiling in an animal model of PTSD, stress-enhanced fear learning (SEFL). A total of 15 footshocks were used to induce SEFL and the volatile anesthetic isoflurane was used to suppress the behavioral effects of stress. Gene expression in lateral/basolateral amygdala was measured using microarrays at 3 weeks after the exposure to different combinations of shock and isoflurane. Shock produced robust effects on amygdalar transcriptome and isoflurane blocked or reversed many of the stress-induced changes. We used a modular approach to molecular profiles of shock and isoflurane and built a network of regulated genes, functional categories, and cell types that represent a mechanistic foundation of perturbation-induced plasticity in the amygdala. This analysis partitioned perturbation-induced changes in gene expression into neuron- and astrocyte-specific changes, highlighting a previously underappreciated role of astroglia in amygdalar plasticity. Many neuron-enriched genes were highly correlated with astrocyte-enriched genes, suggesting coordinated transcriptional responses to environmental challenges in these cell types. Several individual genes were validated using RT-PCR and behavioral pharmacology. This study is the first to propose specific cellular and molecular mechanisms underlying SEFL, an animal model of PTSD, and to nominate novel molecular and cellular targets with potential for therapeutic intervention in PTSD, including glycine and neuropeptide systems, chromatin remodeling, and gliotransmission.
Waggoner Center for Alcohol and Addiction Research and the College of Pharmacy, University of Texas, 1 University Station, Austin, TX, USA.
Igor
I
Ponomarev
Vinuta
V
Rau
Edmond I
EI
Eger
R Adron
RA
Harris
Michael S
MS
Fanselow
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D005239:Fear / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics; D009483:Neuropsychological Tests; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D020318:Rats, Long-Evans; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000503:physiopathology; D013315:Stress, Psychological / Q000235:genetics* / Q000503:physiopathology
D018685:Anesthetics, Inhalation; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D007530:Isoflurane