The endocannabinoid system is the target of the main psychoactive component of the plant Cannabis sativa, the Δ⁹‐tetrahydrocannabinol (THC). This system is composed by the cannabinoid receptors, the ...endogenous ligands, and the enzymes involved in their metabolic processes, which works both centrally and peripherally to regulate a plethora of physiological functions. This review aims at explaining how the site‐specific actions of the endocannabinoid system impact on memory and feeding behavior through the cannabinoid receptors 1 (CB₁R). Centrally, CB₁R is widely distributed in many brain regions, different cell types (e.g. neuronal or glial cells) and intracellular compartments (e.g. mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB₁R according to their cell‐type localization (e.g. glutamatergic or GABAergic neurons). Thus, understanding the cellular and subcellular function of CB₁R will provide new insights and aid the design of new compounds in cannabinoid‐based medicine. Also watch the Video Abstract.
Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not ...consider the insular cortex (IC) to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor (GR) agonist RU 28362 (3 or 10 ng in 0.5 μl) infused bilaterally into the IC of male Sprague-Dawley rats immediately after one-trial inhibitory avoidance training dose-dependently enhanced 48 h retention performance. Moreover, training on the inhibitory avoidance task increased neuronal activity of the IC, as assessed by an increased number of cells expressing immunoreactivity for phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). However, systemic administration of a memory-enhancing dose of corticosterone (1 mg/kg) after inhibitory avoidance training rapidly reduced the number of pERK1/2-positive cells in the IC, suggesting that glucocorticoid administration reduces overall neuronal activity of the IC. To investigate which components of the inhibitory avoidance training experience were influenced by the intra-IC glucocorticoid administration, in the last experiment rats were trained on a modified inhibitory avoidance task in which context exposure and footshock training occur on two sequential days. RU 28362 administration into the IC enhanced later retention when infused immediately after either the context or footshock training. Thus, these findings indicate that the IC mediates glucocorticoid effects on the consolidation of memory of different components of inhibitory avoidance training and suggest that the IC might be an important element of the rodent brain network involved in emotional regulation of learning and memory.
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces ...amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB
) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB
receptors. Genetic exclusion of CB
receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB
receptors signal through intra-mitochondrial Gα
protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB
receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.
Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote ...food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.
A cannabinoid link between mitochondria and memory Hebert-Chatelain, Etienne; Desprez, Tifany; Serrat, Roman ...
Biochimica et biophysica acta. Bioenergetics,
August 2016, 2016-08-00, Volume:
1857
Journal Article
Rodent models for sleep restriction have good face validity when examining food intake and related regulatory metabolic hormones. However, in contrast to epidemiological studies in which sleep ...restriction is associated with body weight gain, sleep-restricted rats show a decrease in body weight. This difference with the human situation might be caused by the alternation between periods of sleep restriction and sleep allowance that often occur in real life. Therefore, we assessed the metabolic consequences of a chronic sleep restriction protocol that modeled working weeks with restricted sleep time alternated by weekends with sleep allowance. We hypothesized that this protocol could lead to body weight gain. Male Wistar rats were divided into three groups: sleep restriction (SR), forced activity control (FA), and home cage control (HC). SR rats were subjected to chronic sleep restriction by keeping them awake for 20 h per day in slowly rotating drums. To model the human condition, rats were subjected to a 4-wk protocol, with each week consisting of a 5-day period of sleep restriction followed by a 2-day period of sleep allowance. During the first experimental week, SR caused a clear attenuation of growth. In subsequent weeks, two important processes occurred: 1) a remarkable increase in food intake during SR days, 2) an increase in weight gain during the weekends of sleep allowance, even though food intake during those days was comparable to controls. In conclusion, our data revealed that the alternation between periods of sleep restriction and sleep allowance leads to complex changes in food intake and body weight, that prevent the weight loss normally seen in continuous sleep-restricted rats. Therefore, this "week-weekend" protocol may be a better model to study the metabolic consequences of restricted sleep.
Le récepteur aux cannabinoïdes de type 1 (CB1) est un récepteur couplé aux protéines G, abondamment exprimé dans le cerveau et régulant plusieurs processus physiologiques. Cependant, les mécanismes ...cellulaires par lesquels les CB1 régulent ces processus n’ont été que peu analysés. Bien que les CB1 localisés dans les membranes plasmiques sont connus pour induire la transduction de signal; une partie de ces récepteurs sont aussi fonctionnels au niveau des mitochondries (mtCB1), où leur stimulation réduit la respiration mitochondriale. L’objectif de cette thèse fut d’évaluer l’impact de l’activation des récepteurs mtCB1 du cerveau sur les effets connus des cannabinoïdes. Afin de distinguer la fonction des mtCB1 de celle des autres populations de récepteurs, nous avons développé des outils basés sur la signalisation induite par les mtCB1. Dans les mitochondries isolées de cerveau, l’activation des protéines Gαi/o, dépendante des mtCB1 diminue l’activité de l’adénylyl cyclase soluble (sAC). L'inhibition locale de l’activité de sAC prévient l’amnésie, la catalepsie et partiellement l’hypolocomotion induite par les cannabinoïdes. De plus, nous avons généré une protéine fonctionnelle mutante CB1 (DN22-CB1) dépourvue des 22 premiers acides aminés des CB1 ainsi que de sa localisation mitochondriale. Contrairement aux CB1, l'activation des DN22-CB1 n’affecte pas l'activité mitochondriale. Enfin, l’expression des DN22-CB1 dans l’hippocampe bloque à la fois la diminution de la transmission synaptique et l’amnésie induites par les cannabinoïdes. Ces travaux démontrent l’implication des mtCB1 dans certains effets des cannabinoïdes et le rôle clé des processus bioénergétiques contrôlant les fonctions cérébrales.
Type-1 cannabinoid receptor CB1 is a G protein-coupled receptor (GPCR), widely expressed in the brain, which regulates numerous physiological processes. However, the cellular mechanisms of CB1-mediated control of these functions are poorly understood. Although CB1 are known to signal at the plasma membrane, a portion of these receptors are also present in mitochondria (mtCB1), where mtCB1 activation decreases mitochondrial activity. The goal of this thesis was to dissect the impact of brain mtCB1 signaling in known behavioral effects induced by cannabinoids. To distinguish the functions of mtCB1 from other receptor pools, we developed tools based on the characterization of the intra-mitochondrial molecular cascade induced by mtCB1 receptors. In isolated brain mitochondria, we found that intra-mitochondrial decrease of soluble-adenylyl cyclase (sAC) activity links mtCB1- dependent activation of Gαi/o proteins to decrease cellular respiration. Local brain inhibition of sAC activity blocks cannabinoid-induced amnesia, catalepsy and contributes to the hypolocomotor effect of cannabinoids. In addition, we generated a functional mutant CB1 protein (DN22-CB1) lacking the first 22 amino acid of CB1 and its mitochondrial localization. Differently from CB1, activation of DN22-CB1 does not affect mitochondrial activity. Hippocampal in vivo expression of DN22-CB1 abolished both cannabinoid-induced impairment of synaptic transmission and amnesia in mice. Together, these studies couple mitochondrial activity to behavioral performances. The involvement of mtCB1 in the effects of cannabinoids on memory and motor control highlights the key role of bioenergetic processes as regulators of brain functions.
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