Understanding the neuronal circuitry underlying Memory and Anxiety: the roles of GABA and CCK

Our brain processes information in a network of nerve cells. The communication between these nerve cells (neurons) occurs via specialized structures called synapses. When an electrical signal (action potential) travels along the neuron and reaches the synapse then a messenger substance is released from the synapse. This messenger substance is received by a receptor protein in the membrane of the adjacent nerve cell. In general nerve cells can be grouped into ?Yes-neurons?, which activate other neurons via their messenger substance and communicate information between different brain regions, and ?No-neurons?, which inactivate the ?Yes-cells? and thus regulate the flow of information. Dysfunction of subclasses of ?No-neurons? leads to pathological information-processing in psychiatric disorders. Recent studies have indicated that one particular sub-type of the ?No-neurons?, the so called CCK+ interneurons might be very important for controlling the flow of information related to the formation of memories and the regulation of mood and anxiety. We want to directly test the function of these particular ?No-neurons? in memory formation and fear/anxiety. To this end we are developing new methods that allow us to functionally remove specific nerve cells and messenger substances in model systems to test their behavioural relevance - similar to an electrician who goes through the components of a circuit board to identify a problem. Understanding how ?Yes neurons? and ?No-neurons? interact to generate memories and emotions will help to understand what is going wrong in memory and anxiety disorders and may lead to the development of new therapeutic strategies to treat such diseases.

Memory deficits as well as anxiety/mood disorders have a very high prevalence, cause substantial personal distress and represent a significant economic burden for society. Understanding the neuronal circuits underlying these pathologies is a prerequisite for new therapeutic strategies. However, progress in the field of circuit analysis has been slow due to the lack of methods with sufficient resolution. Using newly developed molecular tools we want to directly test the involvement of cholecystokinin (CCK)-expressing GABAergic interneurons in learning and memory and mood regulation. In the hippocampus, a structure critical for learning, recent studies indicate that CCK+ interneurons play a key role in orchestrating the encoding of spatial information by individual principal cells. Apart from GABA CCK+ interneurons also release the neuropeptide CCK, which strongly enhances memory performance after intra-hippocampal application, whereas CCK antagonists or knockout of CCK (or its receptor) impair memory performance. In addition, CCK-interneurons in the hippocampus and basolateral amygdala have been implicated in the regulation of emotion: They form a hub for inputs from neurotransmitters such as serotonin and neuromodulatory lipids such as endocannabinoids that control mood. Furthermore, CCK+ interneurons act through GABAA receptor types, which form the target of the most commonly used anxiolytics. Whereas injections of CCK, evoke fear and anxiety, CCK antagonists are strongly anxiolytic and reduce panic attacks in patients.
The molecular techniques for high resolution in vivo circuit dissection that we have developed and will develop for this proposal put us into a unique position to directly test the hypothesis that CCK-interneurons play key roles in memory and emotion. To analyse their role in memory we will 1, functionally remove them from the hippocampus by cell-type-selective block of synaptic output with tetanus toxin and 2, independently perturb their GABAergic and CCKergic out-put by cell-type-selective knock down to dissect the neurotransmitter functions. We will investigate CCK-interneurons in anxiety by 3, targeting these cells in the basolateral amygdala. These perturbations will be analysed at the cellular (in vitro electrophysiology), network (local field potential recordings) and behavioural (memory and anxiety tests) level.