Locus Coeruleus Norepinephrine Drives Stress-Induced Increases in Basolateral Amygdala Firing and Impairs Extinction Learning

J Neurosci. 2020 Jan 22;40(4):907-916. doi: 10.1523/JNEUROSCI.1092-19.2019. Epub 2019 Dec 4.

Abstract

Stress impairs extinction learning, and these deficits depend, in part, on stress-induced norepinephrine (NE) release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered soon after fear conditioning. Here, we explored whether locus coeruleus (LC)-NE regulates stress-induced changes in spike firing in the BLA and consequent extinction learning impairments. Rats were implanted with recording arrays in the BLA and, after recovery from surgery, underwent a standard auditory fear conditioning procedure. Fear conditioning produced an immediate and dramatic increase in the spontaneous firing of BLA neurons that persisted (and in some units, increased further) up to an hour after conditioning. This stress-induced increase in BLA firing was prevented by systemic administration of propranolol. Conditioning with a weaker footshock caused smaller increases in BLA firing rate, but this could be augmented by chemogenetic activation of the LC. Conditioned freezing in response to a tone paired with a weak footshock was immune to the IED, but chemogenetic activation of the LC before the weak conditioning protocol increased conditioned freezing behavior and induced an IED; this effect was blocked with intra-BLA infusions of propranolol. These data suggest that stress-induced activation of the LC increases BLA spike firing and causes impairments in extinction learning. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with stress- and trauma-related disorders.SIGNIFICANCE STATEMENT Patients with post-traumatic stress disorder (PTSD) show heightened amygdala activity; elevated levels of stress hormones, including norepinephrine; and are resistant to the extinction of fear memories. Here, we show that stress increases basolateral amygdala (BLA) spike firing. This could be attenuated by systemic propranolol and mimicked by chemogenetic activation of the locus coeruleus (LC), the source of forebrain norepinephrine (NE). Finally, we show that LC-NE activation is sufficient to produce extinction deficits, and this is blocked by intra-BLA propranolol. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with PTSD and related disorders.

Keywords: amygdala; extinction; fear conditioning; locus coeruleus; norepinephrine; stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Basolateral Nuclear Complex / drug effects
  • Basolateral Nuclear Complex / physiology*
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology*
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Learning / drug effects
  • Learning / physiology*
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Propranolol / pharmacology
  • Rats

Substances

  • Adrenergic beta-Antagonists
  • Propranolol