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@PHDTHESIS{AmbradGiovannetti:162223,
      author       = {Ambrad Giovannetti, Eleonora},
      title        = {{H}ippocampal network and inhibitory neuron dysfunction in
                      age and disease},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      reportid     = {DZNE-2021-01292},
      pages        = {158 pages, 21 figures},
      year         = {2021},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2021},
      abstract     = {Aging 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.},
      cin          = {AG Fuhrmann},
      cid          = {I:(DE-2719)1011004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      experiment   = {EXP:(DE-2719)LMF-20190308},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:5-64273},
      url          = {https://pub.dzne.de/record/162223},
}