Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1.

Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo.

The cannabinoid receptor type 1 (CB1) is abundantly expressed in the central nervous system where it negatively controls the release of several neurotransmitters. CB1 activity plays a crucial role in learning and memory and in synaptic plasticity. In the present study, the role of CB1 was investigated in three different hippocampus-dependent memory tasks and in in vivo hippocampal synaptic plasticity in knockout (CB1-ko) and wildtype mice. There was no difference in short-term and long-term social and object recognition memory between CB1-ko and wildtype mice. In contrast, in background contextual fear conditioning CB1-ko mice showed enhanced freezing levels in the conditioning context and increased generalised contextual fear after a high-intensity conditioning foot shock of 1.5 mA, but not after 0.7 mA. In in vivo field potential recordings in the dentate gyrus, CB1-ko mice displayed a decreased paired-pulse facilitation of the populations spikes, suggesting an altered inhibitory synaptic drive onto hippocampal granule cells. Furthermore, CB1-ko mice displayed significantly higher levels of in vivo long-term potentiation (LTP) in the dentate gyrus. In conclusion, CB1 deficiency leads to enhanced contextual fear memory and altered synaptic plasticity in the hippocampus, supporting the key role of endocannabinoid signalling in learning and memory, in particular following highly aversive encounters.

Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice.

The transient receptor potential vanilloid type 1 channel (TRPV1) (formerly called vanilloid receptor VR1) is known for its key role of functions in sensory nerves such as perception of inflammatory and thermal pain. Much less is known about the physiological significance of the TRPV1 expression in the brain. Here we demonstrate that TRPV1 knock-out mice (TRPV1-KO) show less anxiety-related behavior in the light-dark test and in the elevated plus maze than their wild-type littermates with no differences in locomotion. Furthermore, TRPV1-KO mice showed less freezing to a tone after auditory fear conditioning and stress sensitization. This reduction of conditioned and sensitized fear could not be explained by alterations in nociception. Also, tone perception per se was unaffected, as revealed by determination of auditory thresholds through auditory brainstem responses and distortion-product otoacoustic emissions. TRPV1-KO showed also less contextual fear if assessed 1 d or 1 month after strong conditioning protocols. These impairments in hippocampus-dependent learning were mirrored by a decrease in long-term potentiation in the Schaffer collateral-commissural pathway to CA1 hippocampal neurons. Our data provide first evidence for fear-promoting effects of TRPV1 with respect to both innate and conditioned fear and for a decisive role of this receptor in synaptic plasticity.