GABAergic mechanisms regulated by miR-33 encode state-dependent fear.
Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar. Restricted access to such memories can present a risk for psychiatric disorders and hamper their treatment. To better understand the mechanisms underlying state-dependent fear, we used a mouse model of contextual fear conditioning. We found that heightened activity of hippocampal extrasynaptic GABAA receptors, believed to impair fear and memory, actually enabled their state-dependent encoding and retrieval. This effect required protein kinase C-βII and was influenced by miR-33, a microRNA that regulates several GABA-related proteins. In the extended hippocampal circuit, extrasynaptic GABAA receptors promoted subcortical, but impaired cortical, activation during memory encoding of context fear. Moreover, suppression of retrosplenial cortical activity, which normally impairs retrieval, had an enhancing effect on the retrieval of state-dependent fear. These mechanisms can serve as treatment targets for managing access to state-dependent memories of stressful experiences.
Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Vladimir
V
Jovasevic
Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Kevin A
KA
Corcoran
Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Katherine
K
Leaderbrand
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Naoki
N
Yamawaki
Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Anita L
AL
Guedea
Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Helen J
HJ
Chen
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Gordon M G
GM
Shepherd
Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Jelena
J
Radulovic
D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects / Q000502:physiology* / Q000523:psychology; D018755:GABA Agonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D009924:Organ Culture Techniques; D011963:Receptors, GABA-A / Q000378:metabolism*
D018755:GABA Agonists; D007555:Isoxazoles; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D011963:Receptors, GABA-A; C015542:gaboxadol