IMIM - Institut Hospital del Mar d'Investigacions Mèdiques IMIM - Institut Hospital del Mar d'Investigacions Mèdiques

Mecanismos celulares en conducta fisiológica y patológica

The HIGHMEMORY Project: Investigating how the brain encode and store incidental associations

Funded with a ERC Starting Grant from the European Research Council

Animals and humans adapt to changes in the environment through the encoding and storage of previous experiences. Although associative learning involving a reinforcer has been the major focus in the field of cognition, other forms of learning are gaining popularity as they are likely more relevant and frequent in human daily choices. Indeed, associations between non-reinforcing stimuli represent the most evolutionarily advanced way to increase the chances of predicting future events and adapting individuals' behavior. Animals are also able to form these higher-order conditioning processes, but more research is needed to understand how the brain encode and store these complex cognitive processes.

The HighMemory project proposes to study the role of hippocampo-cortical circuits in higher-order conditioning processes in mouse models. These processes explain why individuals are very often repulsed or attracted by stimuli (persons, places, sounds), which do not have intrinsic repellent or appealing value and were never explicitly paired with negative or positive outcomes. A possible explanation of these "ungrounded" aversions or repulsions is that these stimuli were incidentally associated with other cues directly reinforced. This is called higher-order conditioning or mediated learning (ML). However, with increased number of incidental associations, the subjects acquire more information, allowing the separation between the real saliences of two different stimuli. Therefore, with the increase of training, ML evolves into what researchers define as "reality testing" (RT). Importantly, these behavioral processes involve the hippocampus, are characterized by defined and accessible phases and involve several brain regions, making them perfect models to study the tight regulation of behavior by hippocampo-cortical projections. By using cutting edge genetic (viral and chemogenetic techniques), Ca2+ imaging and mouse behavioral (sensory preconditioning) approaches, the aim of HighMemory is to dissect and characterize, at macro- (brain regions), meso- (cell sub-types) and micro-scale (activity changes), the causal involvement of hippocampo-cortical projections in higher-order cognitive processes, from the formation of ML, the transition to RT and the expression of these distinct mental states. Notably, we hope that HighMemory will provide important information to better understand and tackle the physiology of complex cognitive processes and mental disorders such as psychotic-like states.

The BECALM Project: Involvement of cannabinoid receptors in the pathophysiology of Alzheimer disease

Funded by the Retos Call 2018 from the Agencia estatal de Investigación (AEI).

Alzheimer's disease (AD) is a neurodegenerative process characterized by molecular alterations, such as the presence of senile plaques, and behavioral deficits like cognitive impairments. AD has been also associated with numerous alterations of brain bioenergetic processes including alterations in astroglial metabolism and mitochondrial functions.  However, the precise mechanisms of these dysfunctions and its impact in the pathophysiology of AD remain unknown.

Type-1 cannabinoid (CB1) receptors, one of the main components of the endocannabinoid system (ECS), control different intercellular processes such as cell metabolism or synaptic plasticity. Importantly, they have been linked to the pathophysiology of AD. Indeed, alterations of different components of the ECS have been described both in AD animal models and in human patients. Moreover, in vitro and in vivo pharmacological activation of CB1 receptors displayed efficacy in reducing the neurotoxic effects of amyloid-B peptide and to counteract the cognitive impairment found in AD mouse models. Although accumulating evidence point to a role of CB1 receptors in the AD pathophysiology, further research is needed to decipher the specific mechanisms linking ECS and AD.

CB1 receptors are functionally present in different cell-types (neurons and astrocytes) both in the plasmatic and mitochondrial membranes. Indeed, cannabinoids acting at mitochondrial CB1 receptors (mtCB1) affect brain mitochondrial respiration and control behavioral processes. However, whether cell-type- or mtCB1-dependent mechanisms can participate in a pathological condition such as AD has been not explored yet. Thus, in this project, I hypothesized that CB1R-dependent cell-type specific bioenergetic processes participate in AD.

Overall, the BECALM project is highly relevant to better understand how the ECS in general, and CB1 receptors in particular, might be considered a potential therapeutic target against AD for several reasons; 1. It represents a thorough investigation in animal models of the impact and importance of bioenergetics processes on the development of molecular and behavioral AD phenotypes. The focus on individual and gender variability will help to identify specific bioenergetic alterations underlying possible differences in the vulnerability towards cannabinoid-induced improvements on molecular or behavioral deficits; 2. This proposal will bring potential translational observations by using mouse models; 3. By targeting specific brain regions and cell-types, this project aims to provide a thorough functional mapping of CB1 receptors and bioenergetics involvement in AD at macro- (brain regions), meso- (cell types) and micro-scale (subcellular localization). In conclusion, by exploring novel and promising scientific paths, this project will substantially contribute towards the comprehension of the mechanistic basis of AD.


Arnau Busquets(ELIMINAR)

93 3160390

Dr. Aiguader, 88, 2ª Planta
08003 Barcelona

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