David Robbe

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

Do endocannabinoids (eCBs) participate in long-term synaptic plasticity in the brain? Using pharmacological approaches and genetically altered mice, we show that stimulation of prelimbic cortex afferents at naturally occurring frequencies causes a long-term depression of nucleus accumbens glutamatergic synapses mediated by eCB release and presynaptic CB1 receptors. Translation of glutamate synaptic transmission into eCB retrograde signaling involved metabotropic glutamate receptors and postsynaptic intracellular Ca2+ stores. These findings unveil the role of the eCB system in activity-dependent long-term synaptic plasticity and identify a mechanism by which marijuana can alter synaptic functions in the endogenous brain reward system.

Cannabinoids reveal importance of spike timing coordination in hippocampal function

Cannabinoids impair hippocampus-dependent memory in both humans and animals, but the network mechanisms responsible for this effect are unknown. Here we show that the cannabinoids Δ9-tetrahydrocannabinol and CP55940 decreased the power of theta, gamma and ripple oscillations in the hippocampus of head-restrained and freely moving rats. These effects were blocked by a CB1 antagonist. The decrease in theta power correlated with memory impairment in a hippocampus-dependent task. By simultaneously recording from large populations of single units, we found that CP55940 severely disrupted the temporal coordination of cell assemblies in short time windows (<100 ms) yet only marginally affected population firing rates of pyramidal cells and interneurons. The decreased power of local field potential oscillations correlated with reduced temporal synchrony but not with firing rate changes. We hypothesize that reduced spike timing coordination and the associated impairment of physiological oscillations are responsible for cannabinoid-induced memory deficits.

A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity.

Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Δ9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.

Hippocampal place cell assemblies are speed-controlled oscillators

The phase of spikes of hippocampal pyramidal cells relative to the local field θ oscillation shifts forward (“phase precession”) over a full θ cycle as the animal crosses the cells receptive field (“place field”). The linear relationship between the phase of the spikes and the travel distance within the place field is independent of the animals running speed. This invariance of the phase–distance relationship is likely to be important for coordinated activity of hippocampal cells and space coding, yet the mechanism responsible for it is not known. Here we show that at faster running speeds place cells are active for fewer θ cycles but oscillate at a higher frequency and emit more spikes per cycle. As a result, the phase shift of spikes from cycle to cycle (i.e., temporal precession slope) is faster, yet spatial-phase precession stays unchanged. Interneurons can also show transient-phase precession and contribute to the formation of coherently precessing assemblies. We hypothesize that the speed-correlated acceleration of place cell assembly oscillation is responsible for the phase–distance invariance of hippocampal place cells.

Presynaptic Homeostatic Plasticity Rescues Long-Term Depression after Chronic Δ9-Tetrahydrocannabinol Exposure

Alterations of long-term synaptic plasticity have been proposed to participate in the development of addiction. To preserve synaptic functions, homeostatic processes must be engaged after exposure to abused drugs. At the mouse cortico-accumbens synapses, a single in vivo injection of Δ9-tetrahydrocannabinol (THC) suppresses endocannabinoid-mediated long-term depression. Using biochemical and electrophysiological approaches, we now report that 1 week of repeated in vivo THC treatment reduces the coupling efficiency of cannabinoid CB1 receptors (CB1Rs) to Gi/o transduction proteins, as well as CB1R-mediated inhibition of excitatory synaptic transmission at the excitatory synapses between the prefrontal cortex and the nucleus accumbens (NAc). Nonetheless, we found that cortico-accumbens synapses unexpectedly express normal long-term depression because of a reversible switch in its underlying mechanisms. The present data show that, in THC-treated mice, long-term depression is expressed because a presynaptic mGluR2/3 (metabotropic glutamate receptor 2/3)-dependent mechanism replaces the impaired endocannabinoid system. Thus, in the NAc, a novel form of presynaptic homeostasis rescues synaptic plasticity from THC-induced deficits.

Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony

Activation of type 1 cannabinoid receptors (CB1R) decreases GABA and glutamate release in cortical and subcortical regions, with complex outcomes on cortical network activity. To date there have been few attempts to disentangle the region- and cell-specific mechanisms underlying the effects of cannabinoids on cortical network activity in vivo. Here we addressed this issue by combining in vivo electrophysiological recordings with local and systemic pharmacological manipulations in conditional mutant mice lacking CB1R expression in different neuronal populations. First we report that cannabinoids induce hypersynchronous thalamocortical oscillations while decreasing the amplitude of faster cortical oscillations. Then we demonstrate that CB1R at striatonigral synapses (basal ganglia direct pathway) mediate the thalamocortical hypersynchrony, whereas activation of CB1R expressed in cortical glutamatergic neurons decreases cortical synchrony. Finally we show that activation of CB1 expressed in cortical glutamatergic neurons limits the cannabinoid-induced thalamocortical hypersynchrony. By reporting that CB1R activations in cortical and subcortical regions have contrasting effects on cortical synchrony, our study bridges the gap between cellular and in vivo network effects of cannabinoids. Incidentally, the thalamocortical hypersynchrony we report suggests a potential mechanism to explain the sensory “high” experienced during recreational consumption of marijuana.

The striatum multiplexes contextual and kinematic information to constrain motor habits execution

The striatum is required for the acquisition of procedural memories, but its contribution to motor control once learning has occurred is unclear. We created a task in which rats learned a difficult motor sequence characterized by fine-tuned changes in running speed adjusted to spatial and temporal constraints. After training and extensive practice, we found that the behavior was habitual, yet tetrode recordings in the dorsolateral striatum (DLS) revealed continuous integrative representations of running speed, position and time. These representations were weak in naive rats that were hand-guided to perform the same sequence and developed slowly after learning. Finally, DLS inactivation in well-trained animals preserved the structure of the sequence while increasing its trial-by-trial variability. We conclude that, after learning, the DLS continuously integrates task-relevant information to constrain the execution of motor habits. Our results provide a straightforward mechanism by which the basal ganglia may contribute to habit formation and motor control.

Response outcomes gate the impact of expectations on perceptual decisions

Perceptual decisions are not only determined by current sensory information but are also influenced by expectations based on recent experiences. Can the impact of these expectations be flexibly modulated based on the outcome of previous decisions? We trained rats in several two-alternative forced choice auditory tasks, where the probability to repeat the previous stimulus category was varied in blocks of trials. All rats capitalized on the serial correlations of the stimulus sequence by consistently exploiting a transition bias: a tendency to repeat or alternate their previous response using an internal trial-by-trial estimate of the sequence repeating probability. Surprisingly, this bias was null in trials immediately following an error. The internal estimate however was not reset and it became effective again causing a bias after the next correct response. This ability to rapidly activate and inactivate the bias was captured by a non-linear generative model of rat behavior, whereby a reward-driven modulatory signal gated the use of the latent estimate of the environment statistics on the current decision. These results demonstrate that, based on the outcome of previous choices, rats flexibly modulate how expectations influence their current decisions.