Cellular and Sub-cellular targets of cannabinoids in the brain: Form signaling to behavior and beyond.
During the past 15 years my research has focused on the role of the ECS and in particular the CB1 receptor in the regulation of several physiological and behavioral outcomes.
At beginning of my carrer I contributed to highlight the role of neuronal CB1 signalling as a key determinant of the ECS action on energy balance regulation. I showed that CB1R exerts a bimodal control of feeding behavior and, by regulating energy expenditure and sympathetic nervous system activity, it mediates also periphery/brain axes of communication that are altered in pathological conditions such as obesity and metabolic disorders. The differences observed between the role of endogenous versus exogenous CB1 agonists, as well as between agonists versus antagonists in most of my studies suggest that this receptor may have different pharmacological properties according to the cell type-specific signalling involved.
Thus, the first concept rising from these observations is that a high degree of heterogeneity exists for CB1 mediated actions in different neuronal circuits in esponse to endogenous and exogenous ligands, which support the idea that selective CB1 signalling might be specific to brain region/cell population/subcellular compartement involved. Following this line of research, I focused my attention on the basal ganlia, which represent the most abundant brain CB1 receptor pools. I contributed to show that CB1 activation can modulate several cellular processes which goes beyond regulation of neurotransmitter release. These include several intra-cellular signaling pathways involved in maintaning cellular homeostasis, e.g. kinases pathways, autophagy, neurosteroids, bioenergetics and many more processes. Moreover, we found that, based on the specific brain regions/cell types/subcellular compartements involved, CB1 signaling orchestrates many neurophysiological readouts that eventuallly lead to behavioral alterations, ranging from feeding to motor, cognitive and pain related processes. These processes are well know targets of cannabinoid-based medicine, as well as side effects often associated with recreational use of this drug, two phenomena that are exponentially rising wordwide.
Thus the study of biochemical, molecular and neurophysiological adaptations underlying such heterogeneity in CB1 signaling will represent the subject of my future studies. The expected results of this future work might provide novel insight into physiological processes regulated by the ECS, as well as newer and more selective therapeutical targets for motor, pain and addiction related diseases. Furthermore, given the high abundance of CB1 receptor and endocannabinoid signaling in the mammalian brain, understanding the neurophsyiological and behavioral regulation by this neuromodulatory system has been and will always be an important way to understand brain fuctionning.
Soria-Gomez E, Pagano Zottola AC, Mariani Y, Desprez T, Barresi M, Bonilla-Del Río I, Muguruza C, Le Bon-Jego M, Julio-Kalajzić F, Flynn R, Terral G, Fernández-Moncada I, Robin LM, Oliveira da Cruz JF, Corinti S, Amer YO, Goncalves J, Varilh M, Cannich A, Redon B, Zhao Z, Lesté-Lasserre T, Vincent P, Tolentino-Cortes T, Busquets-García A, Puente N, Bains JS, Hebert-Chatelain E, Barreda-Gómez G, Chaouloff F, Lohman AW, Callado LF, Grandes P, Baufreton J, Marsicano G*, Bellocchio L*. Subcellular specificity of cannabinoid effects in striatonigral circuits. Neuron. 2021 May 5;109(9):1513-1526.e11.
Blázquez C, Ruiz-Calvo A, Bajo-Grañeras R, Baufreton JM, Resel E, Varilh M, Pagano Zottola AC, Mariani Y, Cannich A, Rodríguez-Navarro JA, Marsicano G, Galve-Roperh I, Bellocchio L*, Guzmán M*. Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination. Elife. 2020 Aug 10;9:e56811.
Ruiz-Calvo A, Maroto IB, Bajo-Grañeras R, Chiarlone A, Gaudioso Á, Ferrero JJ, Resel E, Sánchez-Prieto J, Rodríguez-Navarro JA, Marsicano G, Galve-Roperh I, Bellocchio L*, Guzmán M*. Pathway-Specific Control of Striatal Neuron Vulnerability by Corticostriatal Cannabinoid CB1 Receptors. Cereb Cortex. 2018 Jan 1;28(1):307-322.
Hebert-Chatelain E*, Desprez T*, Serrat R*, Bellocchio L*, Soria-Gomez E, Busquets-Garcia A, Pagano Zottola AC, Delamarre A, Cannich A, Vincent P, Varilh M, Robin LM, Terral G, García-Fernández MD, Colavita M, Mazier W, Drago F, Puente N, Reguero L, Elezgarai I, Dupuy JW, Cota D, Lopez-Rodriguez ML, Barreda-Gómez G, Massa F, Grandes P, Bénard G, Marsicano G. A cannabinoid link between mitochondria and memory. Nature. 2016 Nov 24;539(7630):555-559.
Bellocchio L, Ruiz-Calvo A, Chiarlone A, Cabanas M, Resel E, Cazalets JR, Blázquez C, Cho YH, Galve-Roperh I, Guzmán M. Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK. J Neurosci. 2016 Oct 12;36(41):10611-10624.
Chiarlone A*, Bellocchio L*, Blázquez C, Resel E, Soria-Gómez E, Cannich A, Ferrero JJ, Sagredo O, Benito C, Romero J, Sánchez-Prieto J, Lutz B, Fernández-Ruiz J, Galve-Roperh I, Guzmán M. A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8257-62.
Soria-Gómez E*, Bellocchio L*, Reguero L, Lepousez G, Martin C, Bendahmane M, Ruehle S, Remmers F, Desprez T, Matias I, Wiesner T, Cannich A, Nissant A, Wadleigh A, Pape HC, Chiarlone AP, Quarta C, Verrier D, Vincent P, Massa F, Lutz B, Guzmán M, Gurden H, Ferreira G, Lledo PM, Grandes P, Marsicano G. The endocannabinoid system controls food intake via olfactory processes. Nat Neurosci. 2014 Mar;17(3):407-15.
Bellocchio L*, Soria-Gómez E*, Quarta C, Metna-Laurent M, Cardinal P, Binder E, Cannich A, Delamarre A, Häring M, Martín-Fontecha M, Vega D, Leste-Lasserre T, Bartsch D, Monory K, Lutz B, Chaouloff F, Pagotto U, Guzman M, Cota D, Marsicano G. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB1 receptor blockade. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4786-91.
Quarta C*, Bellocchio L*, Mancini G, Mazza R, Cervino C, Braulke LJ, Fekete C, Latorre R, Nanni C, Bucci M, Clemens LE, Heldmaier G, Watanabe M, Leste-Lassere T, Maitre M, Tedesco L, Fanelli F, Reuss S, Klaus S, Srivastava RK, Monory K, Valerio A, Grandis A, De Giorgio R, Pasquali R, Nisoli E, Cota D, Lutz B, Marsicano G, Pagotto U. CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metab. 2010 Apr 7;11(4):273-85.
Bellocchio L*, Lafenêtre P*, Cannich A, Cota D, Puente N, Grandes P, Chaouloff F, Piazza PV, Marsicano G. Bimodal control of stimulated food intake by the endocannabinoid system. Nat Neurosci. 2010 Mar;13(3):281-3. doi: 10.1038/nn.2494. Epub 2010 Feb 7.