Monitoring behaviourally relevant spatio-temporal activity patterns in prefrontal networks using in vivo wide-field microendoscopy

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Ensembles in the medial prefrontal cortex inhibit responding to rewards. How such ensembles are formed during associative learning will be studied in freely moving rats, using microendoscopy and targeted molecular interference.

Decision making is a basic mental process for the control and execution of behaviour. Its impairment may result in impulsive and compulsive actions, both key features in many psychopathologies including addiction and eating disorders. Whether or not a response will be executed is critically determined by the medial prefrontal cortex (mPFC). This control function is accomplished by the interplay of mPFC subregions, in particular between the prelimbic (PL) and infralimbic (IL) areas as shown by classical lesion and stimulation methods. An unresolved question is how distinct neuronal populations within the mPFC contribute to specific task execution.

In other words, do PL and IL-specific neuronal ensembles exist that produce distinguishable spatio-temporal activity patterns? If so, how are these activities related to each other, and finally, do these patterns encode behavioural output such as enacting or inhibiting a learned response? After demonstrating that cue-specific ensembles exist in the IL via activity-dependent chemogenetic ablation of those neurons, we will now address these questions by using single photon, wide-field microendoscopy to record calcium signals in freely behaving rats. Fluorescence will be generated by Ca2+ indicator proteins that are expressed in genetically defined populations of neurons. Upon successful completion we will have gained a better understanding how neuronal ensembles, depending on their specific location within the mPFC, contribute to behavior and ultimately also to behavioral pathologies.
Meinhardt MW, Hansson AC*, Perreau-Lenz S, Bauder C, Harper C, Heilig M, Drescher KU, Spanagel R*, WH Sommer (2013) Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence. J Neurosci 33:2794-2806.

Tapocik J, Solomon M, Flanigan M, Meinhardt M, Barbier E, Schank J, Schwandt M, Sommer MH§, Heilig M§ (2013) Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence Pharmacogenomics J 13:286-296.§equal contribution

Körber C*, Horstmann H, Sätzler K, Kuner T (2012) Endocytic structures and synaptic vesicle recycling at a central synapse in awake rats. Traffic 13:1601-1611.

Hermann D, Weber-Fahr W, Sartorius A, Hoerst M, Frischknecht U, Tunc-Skarka N, Perreau-Lenz S, Hansson AC*, Krumm B, Kiefer F, Spanagel R*, Mann K, Ende G, Sommer WH (2012) Translational magnetic resonance spectroscopy reveals excessive central gluta- mate levels during alcohol withdrawal in humans and rats. Biol Psychiatry 71:1015-1021.

Nanguneri S, Flottmann B, Horstmann H, Heilemann M, Kuner T (2012) Three-dimensional, tomographic super-resolution fluorescence imaging of serially sectioned thick samples. PloS one 7:e38098.

Abraham NM, Egger V, Shimshek DR, Renden R, Fukunaga. I, Sprengel R*, Seeburg PH, Klug- mann M, Margrie TW, Schaefer AT, Kuner T (2010) Synaptic inhibition in the olfactory bulb accelerates odor discrimination in mice. Neuron 65:399-411.

Sommer WH, Rimondini R, Hansson AC*, Hipskind PA, Gehlert DR, Barr CS, Heilig M (2008) Upregulation of Voluntary Alcohol Intake, Behavioral Sensitivity to Stress, and Amygdala Crhr1 Expression Following a History of Dependence. Biol Psychiatry 63:139-145.

Kuner T, Li Y, Gee KR, Bonewald LF, Augustine GJ (2008) Photolysis of a caged peptide reveals rapid action of N-ethylmaleimide sensitive factor before neurotransmitter release. Proc Natl Acad Sci U S A 108:347-352.

Björk K ,Rimondini R, Hansson AC*, Terasmaa A, Hyytiä P, Heilig M, Sommer WH (2008) Modu- lation of voluntary ethanol consumption by beta-arrestin 2. FASEB J 22:2552-2560.

Dübel J, Haverkamp S, Schleich W, Augustine, GJ, Feng G, Kuner T , Euler T (2006) Two-pho- ton imaging reveals somato-dendritic chloride gradient in retinal ON-type bipolar cells ex- pressing the biosensor Clomeleon. Neuron 49:81-94.

Wimmer VC, Nevian T, Kuner T (2004) Targeted in vivo expression of proteins in the calyx of Held. Pflugers Arch 449:319-333.

Kuner T & Augustine GJ (2000) A genetically encoded ratiometric indicator for chloride: capturing chloride transients in hippocampal neurons. Neuron 27:447-459.

* Principal investigators of other projects within the CRC