title: Disrupted Prediction Error Links Excessive Amygdala Activation to Excessive Fear.
abstract: Basolateral amygdala (BLA) is critical for fear learning, and its heightened activation is widely thought to underpin a variety of anxiety disorders. Here we used chemogenetic techniques in rats to study the consequences of heightened BLA activation for fear learning and memory, and to specifically identify a mechanism linking increased activity of BLA glutamatergic neurons to aberrant fear. We expressed the excitatory hM3Dq DREADD in rat BLA glutamatergic neurons and showed that CNO acted selectively to increase their activity, depolarizing these neurons and increasing their firing rates. This chemogenetic excitation of BLA glutamatergic neurons had no effect on the acquisition of simple fear learning, regardless of whether this learning led to a weak or strong fear memory. However, in an associative blocking task, chemogenetic excitation of BLA glutamatergic neurons yielded significant learning to a blocked conditioned stimulus, which otherwise should not have been learned about. Moreover, in an overexpectation task, chemogenetic manipulation of BLA glutamatergic neurons prevented use of negative prediction error to reduce fear learning, leading to significant impairments in fear inhibition. These effects were not attributable to the chemogenetic manipulation enhancing arousal, increasing asymptotic levels of fear learning or fear memory consolidation. Instead, chemogenetic excitation of BLA glutamatergic neurons disrupted use of prediction error to regulate fear learning.
  
  
  CONCLUSIONS
  Several neuropsychiatric disorders are characterized by heightened activation of the amygdala. This heightened activation has been hypothesized to underlie increased emotional reactivity, fear over generalization, and deficits in fear inhibition. Yet the mechanisms linking heightened amygdala activation to heightened emotional learning are elusive. Here we combined chemogenetic excitation of rat basolateral amygdala glutamatergic neurons with a variety of behavioral approaches to show that, although simple fear learning is unaffected, the use of prediction error to regulate this learning is profoundly disrupted, leading to formation of inappropriate fear associations and impaired fear inhibition.
authors.affiliation: School of Psychology, University of New South Wales Australia, Sydney, New South Wales 2052, Australia, and.
authors.forename: Auntora
authors.initials: A
authors.lastname: Sengupta
authors.affiliation: Discipline of Pharmacology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Bryony
authors.identifier: http://orcid.org/0000-0002-4973-0771
authors.initials: B
authors.lastname: Winters
authors.affiliation: Discipline of Pharmacology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Bagley
authors.affiliation: School of Psychology, University of New South Wales Australia, Sydney, New South Wales 2052, Australia, and g.mcnally@unsw.edu.au.
authors.forename: Gavan P
authors.initials: GP
authors.lastname: McNally
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000679:Amygdala / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D004597:Electroshock / Q000009:adverse effects; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D043587:Receptor, Muscarinic M3; D011955:Receptors, Drug; D018698:Glutamic Acid; D003024:Clozapine; C079149:clozapine N-oxide
keywords: DREADD; amygdala; anxiety; extinction; fear conditioning; prediction error