000162223 001__ 162223
000162223 005__ 20250411105458.0
000162223 0247_ $$2URN$$aurn:nbn:de:hbz:5-64273
000162223 037__ $$aDZNE-2021-01292
000162223 041__ $$aEnglish
000162223 1001_ $$0P:(DE-2719)2811489$$aAmbrad Giovannetti, Eleonora$$b0$$eFirst author$$udzne
000162223 245__ $$aHippocampal network and inhibitory neuron dysfunction in age and disease
000162223 260__ $$c2021
000162223 300__ $$a158 pages, 21 figures
000162223 3367_ $$2DataCite$$aOutput Types/Dissertation
000162223 3367_ $$2ORCID$$aDISSERTATION
000162223 3367_ $$2BibTeX$$aPHDTHESIS
000162223 3367_ $$02$$2EndNote$$aThesis
000162223 3367_ $$0PUB:(DE-HGF)11$$2PUB:(DE-HGF)$$aDissertation / PhD Thesis$$bphd$$mphd$$s1744361599_16420
000162223 3367_ $$2DRIVER$$adoctoralThesis
000162223 502__ $$aDissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, 2021$$bDissertation$$cRheinische Friedrich-Wilhelms-Universität Bonn$$d2021$$o2021-06-17
000162223 520__ $$aAging and Alzheimer' s disease (AD) are two highly intertwined pathological processes. Indeed, one of the highest risk factors for developing AD is age. Mechanistically, it has been suggested that remodeling of inhibitory neuron function causes the disruption of the homeostatic excitatory/inhibitory balance that is at the basis for effective information processing in the central nervous system. In the hippocampus proper and medial entorhinal cortex (MEC), a plethora of inhibitory neurons is tailored to orchestrate input/output conversion in excitatory neurons, thereby supporting hippocampal-dependent cognitive processes, like episodic memory and navigation. Furthermore, altered inhibitory function is a major contributor to aberrant oscillatory activity recorded by means of electroencephalograms and local field potentials (LFP) in the hippocampal system of both aged and AD brains. Hence, therapeutic approaches devoted to the restoration of inhibitory tone, with the aim of normalizing oscillatory correlates of cognitive processes, have emerged as a strategy to counteract the deleterious effects of aging and AD. In particular, theta and gamma oscillations have been the preferred target of investigation and manipulation. None the less, more evidence is required to understand how age and AD impact oscillatory activity in the hippocampus and MEC, and whether inhibitory neurons driven rhythmogenesis is a viable strategy to alleviate the cognitive burden associated with both conditions.Here, I probed the hippocampal network of aged PV-Cre:: WT mice and their APPswe/PS 1 dE9 (PV-Cre::APP/PSl) transgenic littermates, used as model of familial AD. To do so, I employed LFP recordings, and LFP recordings coupled with optogenetic stimulation of local parvalbumin-positive (PV+) interneurons in the CAI compartment of the hippocampus of awake, freely moving animals. I showed that theta oscillations linearly decrease with age in PV-Cre::WT animals, but not in PV-Cre::APP/PSI mice, which is indicative of inhibitory neuron dysfunction. Interestingly, theta-gamma coupling measured as a modulation index (MI) in the stratum lacunosum moleculare (SLM) was reduced in PV-Cre::APP/PSI animals, showing that feedback communication between the hippocampus and the MEC is altered. Besides, I detected an age-dependent linear increase in the MI of PV -Cre:: WT animals, but not in.PV-Cre::APP/PSI animals, indicating that age-related network remodeling differs between healthy and AD conditions. Next, I investigated the effects of optogenetically stimulating hippocampal py+ neurons of aged PV-Cre::WT and PV-Cre::APP/PS 1 mice during memory tasks probing recognition-, working- and spatial memory. Here, optogenetic stimulation of PV+ intemeurons in aged PV-Cre::WT and PV-Cre::APP/PSl animals was sufficient to rescue cognitive deficits of APP/PSl animals, but not WT animals, in a spatial memory task. Furthermore, I showed that somatostatin-positive (SOM+) long-range inhibitory projections between the hippocampus and the MEC, a poorly described neuronal population, are impaired in SST-Cre::APP/PSI mice. This was concomitant with a reduction of local SOM-immunoreactivity in the MEC. Potentially, the structural and functional alterations of local and long-range projecting SOM+ neurons underlie the alterations of theta-gamma coupling observed in APP/PS 1 animals.The results presented in this thesis thus contribute to the existing knowledge about oscillatory aberrations in health and disease. In addition, these results provide new perspectives on the mechanisms that cause network dysfunction and cognitive deficits in healthy and AD-like conditions.
000162223 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
000162223 693__ $$0EXP:(DE-2719)LMF-20190308$$5EXP:(DE-2719)LMF-20190308$$eLight Microscope Facility (CRFS-LMF) / Bonn$$x0
000162223 8564_ $$uhttps://hdl.handle.net/20.500.11811/9375
000162223 8564_ $$uhttps://pub.dzne.de/record/162223/files/DZNE-2021-01292_Restricted.pdf
000162223 8564_ $$uhttps://pub.dzne.de/record/162223/files/DZNE-2021-01292_Restricted.pdf?subformat=pdfa$$xpdfa
000162223 909CO $$ooai:pub.dzne.de:162223$$pVDB
000162223 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2811489$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000162223 9131_ $$0G:(DE-HGF)POF4-352$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vDisease Mechanisms$$x0
000162223 9141_ $$y2021
000162223 9201_ $$0I:(DE-2719)1011004$$kAG Fuhrmann$$lNeuroimmunology and Imaging$$x0
000162223 980__ $$aphd
000162223 980__ $$aVDB
000162223 980__ $$aI:(DE-2719)1011004
000162223 980__ $$aUNRESTRICTED