Handling and novel object recognition modulate fear response and endocannabinoid signaling in nucleus basalis magnocellularis

[EN] Storage of aversive memories is of utmost importance for survival, allowing animals to avoid upcoming similar stimuli. However, without reinforcement, the learned avoidance response gradually decreases over time. Although the molecular mechanisms controlling this extinction process are not well known, there is evidence that the endocannabinoid system plays a key role through CB1 receptor-mediated modulation of cholinergic signaling. In this study, we measured fear extinction throughout 7 months using naive rats, assessed in passive avoidance (PA) test in a non-reinforced manner. Then, we evaluated the effect of gentle handling and non-aversive novel object recognition test (NORT) on the extinction and expression of fear memories by measuring passive avoidance responses. Neurochemical correlates were analyzed by functional autoradiography for cannabinoid, cholinergic, and dopaminergic receptors. Despite results showing a gradual decrease of passive avoidance response, it did not fully disappear even after 7 months, indicating the robustness of this process. Meanwhile, in rats that received gentle handling or performed NORT after receiving the PA aversive stimulus, extinction occurred within a week. In contrast, gentle handling performed before receiving the aversive stimulus exacerbated fear expression and triggered escape response in PA. The neurochemical analysis showed increased cannabinoid and cholinergic activity in the nucleus basalis magnocellularis (NBM) in rats that had performed only PA, as opposed to rats that received gentle handling before PA. Additionally, a correlation between CB1 mediated-signaling in the NBM and freezing in PA was found, suggesting that the endocannabinoid system might be responsible for modulating fear response induced by aversive memories.Basque Government IT975-16 to the "Neurochemistry and Neurodegeneration" consolidated research group; Instituto de Salud Carlos III, Grant/Award Number: PI20/0015

Lisofosfolipidoen eta Alzheimer gaixotasunaren arteko erlazioa: etorkizuneko itu farmakologikoaren bila

Lipidoak funtzio energetikoaz eta egitura-funtzioez gain deskribatu diren beste funtzioei esker garrantzitsuak bilakatzen ari dira. Funtzio neurotransmisorea edota neuromoduladorea aurkeztu duten lipidoen artean, lisofosfolipidoak aurkitu ditzakegu. Lisofosfolipidoak lipido molekula txiki bioaktiboak, karbonodun kate bakarra eta buru polar bat edukitzeagatik bereizten direnak dira. Lisofosfolipidoen artean, azido lisofosfatidikoa eta esfingosina 1-fosfatoaren egitura eta sistemen funtzioak izan dira hobeto deskribatu direnak. Lisofosfolipidoak zelulaz kanpoko bitartekari aritzen dira berentzat espezifikoak diren G proteinei loturiko hartzaileak aktibatuz. Molekula horien seinaleztapenaren bidez zenbait prozesu neurokimiko modulatzen dira, adibidez, neuromodulazioa eta neuroinflamazioa. Gainera, ikasketarekin eta oroimenarekin erlazioa erakutsi dute. Horren haritik, orain arte ondoen deskribatutako lisofosfolipidoen sistemak, azido lisofosfatidikoa eta esfingosina l-fosfatoa, hain zuzen ere, asaldatuta daude Alzheimer gaixotasunean eta gaixotasun honetako zenbait animalia-eredutan. Aldaketa horien zentzua oraindik ez dago finkatuta, baina haien eragina beste neurotransmisio-sistemen edota bestelako funtzio biologikoen modulazioaren bidez gerta daitezke. Beraz, lipido hauek etorkizun handiko itu farmakologikoak izan daitezke Alzheimer gaixotasunean agertzen diren sintoma neuropatologikoak eta neuropsikiatrikoak arintzeko. Hortaz, merkatuan dauden lipidoen seinaleztapena itutzat duten eta beste neuroendekapenezko gaixotasunak tratatzeko erabilgarriak diren farmakoak baliagarriak izan litezke Alzheimer gaixotasuna tratatzeko, aukera emanez horrela Alzheimer gaixotasuna tratatzeko dagoen hutsune farmakologikoa betetzeko.; In addition to energy and structural functions, lipids are becoming important thanks to the other functions described. Some lipids have been shown to exhibit neurotransmitter or neuromodulatory function, including lysophospholipids. Lysophospholipids are small bioactive lipid molecules that are distinguished only by having a single carbon chain and a single polar head. The lysophosphatidic acid and sphingosine l-phosphate structure and system functions are best described among those with neurotransmitter function. Lysophospholipids act as extracellular mediators that activate receptor-specific G proteins that are specific to them. The signaling of these molecules modulate certain neurochemical processes, including neuromodulation and neuroinflammation. They have also presented the relationship with learning and memory. In this respect, the best described lysophospholipid systems, lysophosphatidic acid and sphingosine 1-phosphate, are indeed disturbed in Alzheimer’s disease and in some animal models of this disease. The meaning of these changes is not yet established, but their effect may be related to the modulation of other neurotransmission systems or other biological functions. These lipids are therefore supposed to be the promising pharmacological targets to alleviate the neuropathological and neuropsychiatric symptoms that appear in Alzheimer’s disease. Therefore, marketed drugs that have lipid signaling as a pharmacological target and that are useful to treat other neurodegenerative diseases could be also helpful to treat the Alzheimer’s disease, and with this it might be possible to fill the pharmacological gap in the treatment of Alzheimer’s disease so far

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.This study was supported by Ministerio de Economía, Innovación y Competitividad (MINECO), Spain #RTI2018-099282-B-I00B to A.O., #SAF2017-84060-R to R.M.; Generalitat de Catalunya, Spain (2017SGR-669 to R.M.); Ministerio de Ciencia e Innovación (SAF2016-78508-R; AEI/MINEICO/FEDER, UE) to VC. Basque Government IT1454-22 to the 'Neurochemistry and Neurodegeneration' consolidated research group to R R-P. Instituto de Salud Carlos III (PI20/00153, co-funded by the European Union [ERDF 'A way to make Europe']) to R R-P. ICREA (Institució Catalana de Recerca i Estudis Avançats, Spain) Academia to A.O. and R.M. Grant 'Unidad de Excelencia María de Maeztu', funded by the MINECO (#MDM-2014-0370); IPEP MdM 2017 to A.O. and E.E. FEDER, European Commission funding is also acknowledged