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.

Background: Fear and other anxiety linked emotions are evolutionary conserved across the species that aids survival by increasing awareness and enable rapid responses to possible hazards. Excessive fear and anxiety, on the other hand, are hallmarks of variety of disabling anxiety disorders like PTSD (Post Traumatic Stress Disorder) or phobias that affect millions of people throughout the world. Understanding the neural circuits underlying processing of fear memory, its extinction and how they drive behaviour open the new perspectives to form novel groups of drugs supporting treatment of those emotional disorders. In our lab, a fear inhibition is studied through a procedure in which a previously fear conditioned organism is exposed to a fear-eliciting cue in the absence of any aversive event. This procedure results in a decline in conditioned fear responses that is attributed to a process called fear extinction. In this paradigm, we study time-dependent changes in circuits involved memory processing by manipulating neuronal activity in regions of higher activity during extinction learning. In this model of study, we have discovered that medial septal nucleus (MS) and nucleus reuniens (RE) have elevated activity during fear memory extinction processing. Moreover, inactivation of RE neurons strongly enhance attenuation of fear that was acquired 24 hours before (recent) and robustly prevents the extinction of distant (remote/30 days-old) one. Downregulating of MS nucleus also results in impairment of remote fear extinction memory processing. Abovementioned observations and anatomical connections of RE and MS lead me to hypothesize, that particularly RE-MS circuit is necessary for an animal to extinguish fear memory and function of this connection is changing with time. Taken together my planned experiments will have a great impact of understanding neurobiological mechanisms underlying time-dependent extinction of fear, especially that research community nowadays pays more attention to how time affects processing the traumatic experiences.

Background: Development of drug addiction involves functional alterations within brain areas controlling reward-driven behaviour and memory processes. In this context, remodelling of the glutamatergic synapses has gained a lot of attention (Hanse et al, 2013; Lüscher et al, 2011; Wolf, 2016). Still the molecular processes which contribute to the remodelling of the synapses and circuits in addicted individuals are poorly understood. Our aim in this project is to test the hypothesis that regulation of activity of CA1 pyramidal neurons by Arc/Arg3.1 protein controls addiction-related behaviours. Arc/Arg3.1 protein is rapidly upregulated by strong synaptic activity and critically contributes to weakening glutamatergic synapses by promoting AMPA receptor endocytosis (Plath et al, 2006; Tzingounis and Nicoll, 2006). The hypothesis is also based on our observations showing that Arc knockout mice (Arc KO) are impaired in alcohol seeking during relapse induced by alcohol-associated cues, while alcohol consumption and seeking in wild-type animals affects expression of Arc protein in the area CA1 of the hippocampus. To verify the hypothesis we plan to realize the following tasks: Task 1. To test the role of Arc/Arg3.1 in CA1 in regulation of addiction-related behaviours. Task 2. To test the role of Arc/Arg3.1 in regulation of alcohol-induced plasticity of CA1 neurons. Task 3. To test the dynamics of CA1 neurons during alcohol consumption and seeking.

Finnished grants