Ongoing grants
Narodowe Centrum Nauki (PL) SONATA grant, 2023/51/D/NZ4/02942; 2 000 000 PLN
Background: Alcohol use disorder (AUD) is a progressive and debilitating psychiatric condition characterized by pathological alcohol craving and a persistent motivation to consume alcohol. While AUD stands as one of the leading causes of premature death worldwide, the available pharmacological interventions for controlling alcohol misuse are limited. To propose a new therapeutic approach for combating AUD, a better understanding of the neurobiology of the disease is crucial. Increasing evidence indicates that abnormal activity in the glutamatergic synapses correlates with the development of drug addiction. Arc is one of the fundamental proteins contributing to the function and plasticity of glutamatergic synapses. The causal role of Arc in the AUD is just beginning to be elucidated. We have demonstrated that mice lacking Arc in the central nucleus of the amygdala exhibit increased alcohol seeking triggered by cues predicting alcohol availability, and, in humans, a polymorphism in the ARC gene (rs10097505; G> A) emerged as a predictor of the frequency of alcohol consumption. Additionally, ARC gene methylation correlates with both alcohol consumption and amygdala volume in the IMAGEN cohort of young people using alcohol. Importantly, the smaller volume of the amygdala has been correlated with a risk of heavy alcohol drinking in young adults. These results support our hypothesis that Arc plays a regulatory role in both the structural and functional development of the amygdala and contributes to the susceptibility to the AUD-prone phenotype.
In the current project, we will investigate the influence of Arc on amygdala development using transgenic mice and genetically modified viral vectors, and applying advanced techniques such as iDISCO with light-sheet microscopy, ex vivo electrophysiology, and face block scanning three-dimensional electron microscopy. We will also examine the effect of developmental Arc in amygdala on the AUD phenotype. In particular, we will explore the role of Arc in cortical amygdala (CoA) on the manifestation of the AUD phenotype and structural and functional features of the COA neurons. As the past decade has witnessed remarkable advances in understanding the role of Arc in hippocampal development and synaptic functions, our project aims to illuminate the contribution of Arc to the amygdala development and the structure and function of amygdala neurons. This study will provide novel insights into the mechanisms of the AUD, thereby broadening perspectives and facilitating the search for effective therapeutic interventions.
Narodowe Centrum Nauki (PL) MAESTRO grant: 2020/38/A/NZ4/00483, 4400 000 PLN;
Background: Hippocampus is a part of our brain system for spatial navigation and memory, as well as one of the most investigated regions of the brain. However, recent experiments showed that our understanding of its the function is incomplete and can be challenged. In particular, data from Bannerman and collaborators indicate that hippocampus is required for spatial choice, i.e. choice that uses spatial information to suppress inappropriate behaviours, rather than spatial memory. In agreement with these findings our experiments show that inactivation of hippocampus impairs spatial choice in close-to-ecologic conditions, but it has no impact on memory. Moreover, we observed that cellular and behavioural mechanisms that support spatial choice in old mice differ from those observed in young animals. Motivated by these observations we will investigate neuronal networks that support spatial choice, and, in particular, the role of the hippocampus in these networks. To this end we plan to accomplish three tasks: identify brain networks activated during spatial choice training; analyse activity of hippocampal neurons during spatial choice and analyse brain networks during spatial choice in the aged brain.
Overall, our study will describe neuronal networks that suppress incorrect spatial choices in close-to-ecologic conditions. We will implement novel technologies to visualise the networks and present their characteristics with single cell resolution both ex vivo and in a behaving animal. Our study will significantly extend understanding of the hippocampus as a hub brain region for spatial choice. Moreover, our experiments will extend our understanding of dCA1 function in the aged brain and we will possibly propose new strategies to support healthy cognitive aging. This project will be a significant technological advancement. In collaboration with dr. Xiaoke Chen (Stanford University) and Alessio Attardo (Max Plank Institute of Psychiatry), we will introduce in the lab cutting-edge technologies that allow for whole-brain imaging ex vivo and in vivo imaging of the hippocampus of the living mouse. These techniques will allow us to ask many further questions related to brain functions that are not accessible with traditional microscopy.
Narodowe Centrum Nauki (PL) & DFG (GE), OPUS LAP 2022/47/I/NZ4/03012, 2 549 840 PLN + € 580 425
Background: Compulsive alcohol seeking and choice of alcohol-predicting contexts - that often result in relapse to alcohol consumption - are hallmarks of alcohol use disorders (AUD). While the neuronal networks driving these pathological behaviors are poorly understood, those supporting navigation towards rewards are likely to be important. Goal-oriented navigation in mammals relies on the use of internal representations of space produced in the dorsal hippocampus. Consistently, recent work has shown that activity of the dorsal hippocampus is driving spatial memory related to cocaine. It is thus natural to suppose that neuronal networks involving the dorsal hippocampus, also play a fundamental role in maladaptive alcohol seeking. Yet, studying these networks in laboratory animals has been prevented by many technical limitations: impossibility to track activity of a large number of neurons of live subjects, poor behavioral stratification of individuals, as well as lack of tools to precisely control the activity of specific brain circuits.
Here, we propose to combine: wide field head mounted microscopes to image neuronal activity of hundreds of pyramidal neurons in the dorsal CA1 area (dCA1) of mice; genetic and chemogenetic tools to label and manipulate neuronal networks with cell-type and projection specificity; a novel behavioral task and apparatus (E-maze) to investigate the dCA1 representations during spatial planning, decision, navigation and consumption of alcohol; as well as a well-established animal model of AUD. These methods will enable us to study whether dCA1 coding during alcohol seeking predicts the emergence of AUD-like behavioral phenotypes.
Specifically, we propose to tackle the following three questions: Q1. How do spatial representations in dCA1 change with alcohol sensitization? Q2. Can changes in dCA1 activity patterns predict the appearance of compulsive alcohol seeking? Q3. What is the function of specific dCA1 projections in the regulation of alcohol seeking?
In addition to the social importance of studying the neuronal basis of psychiatric disorders, the strength of this proposal lies in the combination of the complementary expertise of Attardo and Radwanska laboratories to investigate the influence of chronic alcohol consumption on behavior and neuronal network activity, all in freely-moving mice self-administering alcohol. This synergy will enable us to produce rich, longitudinal and multidimensional datasets, which will make it possible to link the activity of specific brain pathways to the propensity to develop alcohol addiction. Our project shall provide a mechanistic explanation for individual variance in vulnerability to compulsive alcohol seeking.
Finnished grants