title: Cannabinoid CB1 receptors in distinct circuits of the extended amygdala determine fear responsiveness to unpredictable threat.
abstract: The brain circuits underlying behavioral fear have been extensively studied over the last decades. Although the vast majority of experimental studies assess fear as a transient state of apprehension in response to a discrete threat, such phasic states of fear can shift to a sustained anxious apprehension, particularly in face of diffuse cues with unpredictable environmental contingencies. Unpredictability, in turn, is considered an important variable contributing to anxiety disorders. The networks of the extended amygdala have been suggested keys to the control of phasic and sustained states of fear, although the underlying synaptic pathways and mechanisms remain poorly understood. Here, we show that the endocannabinoid system acting in synaptic circuits of the extended amygdala can explain the fear response profile during exposure to unpredictable threat. Using fear training with predictable or unpredictable cues in mice, combined with local and cell-type-specific deficiency and rescue of cannabinoid type 1 (CB1) receptors, we found that presynaptic CB1 receptors on distinct amygdala projections to bed nucleus of the stria terminalis (BNST) are both necessary and sufficient for the shift from phasic to sustained fear in response to an unpredictable threat. These results thereby identify the causal role of a defined protein in a distinct brain pathway for the temporal development of a sustained state of anxious apprehension during unpredictability of environmental influences, reminiscent of anxiety symptoms in humans.
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: M D
authors.initials: MD
authors.lastname: Lange
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Daldrup
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Remmers
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Szkudlarek
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Lesting
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Guggenhuber
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ruehle
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Jüngling
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Seidenbecher
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany.
authors.forename: H C
authors.initials: HC
authors.lastname: Pape
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000209:etiology; D001008:Anxiety Disorders / Q000209:etiology / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology; D003463:Cues; D063388:Endocannabinoids / Q000378:metabolism; D005239:Fear / Q000502:physiology*; D008297:Male; D051379:Mice; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism* / Q000502:physiology; D013216:Reflex, Startle / Q000502:physiology; D012686:Septal Nuclei / Q000502:physiology
chemical_list: D002186:Cannabinoids; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1