Dataset Information

Topographical Visualization of the Reciprocal Projection between the Medial Septum and the Hippocampus in the 5XFAD Mouse Model of Alzheimer's Disease.

ABSTRACT: It is widely known that the degeneration of neural circuits is prominent in the brains of Alzheimer's disease (AD) patients. The reciprocal connectivity of the medial septum (MS) and hippocampus, which constitutes the septo-hippocampo-septal (SHS) loop, is known to be associated with learning and memory. Despite the importance of the reciprocal projections between the MS and hippocampus in AD, the alteration of bidirectional connectivity between two structures has not yet been investigated at the mesoscale level. In this study, we adopted AD animal model, five familial AD mutations (5XFAD) mice, and anterograde and retrograde tracers, BDA and DiI, respectively, to visualize the pathology-related changes in topographical connectivity of the SHS loop in the 5XFAD brain. By comparing 4.5-month-old and 14-month-old 5XFAD mice, we successfully identified key circuit components of the SHS loop altered in 5XFAD brains. Remarkably, the SHS loop began to degenerate in 4.5-month-old 5XFAD mice before the onset of neuronal loss. The impairment of connectivity between the MS and hippocampus was accelerated in 14-month-old 5XFAD mice. These results demonstrate, for the first time, topographical evidence for the degradation of the interconnection between the MS and hippocampus at the mesoscale level in a mouse model of AD. Our results provide structural and functional insights into the interconnectivity of the MS and hippocampus, which will inform the use and development of various therapeutic approaches that target neural circuits for the treatment of AD.

SUBMITTER: Kim S

PROVIDER: S-EPMC6721212 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Topographical Visualization of the Reciprocal Projection between the Medial Septum and the Hippocampus in the 5XFAD Mouse Model of Alzheimer's Disease.

Kim Sujin S Nam Yunkwon Y Jeong Yu-On YO Park Hyun Ha HH Lee Seong-Kyung SK Shin Soo Jung SJ Jung Haram H Kim Byeong-Hyeon BH Hong Sang Bum SB Park Yong Ho YH Kim Jihee J Yu Jaemin J Yoo Doo-Han DH Park Sun-Hyun SH Jeon Seong Gak SG Moon Minho M

International journal of molecular sciences 20190816 16

It is widely known that the degeneration of neural circuits is prominent in the brains of Alzheimer's disease (AD) patients. The reciprocal connectivity of the medial septum (MS) and hippocampus, which constitutes the septo-hippocampo-septal (SHS) loop, is known to be associated with learning and memory. Despite the importance of the reciprocal projections between the MS and hippocampus in AD, the alteration of bidirectional connectivity between two structures has not yet been investigated at th ...[more]

PMID: 31426329

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Project description:The medial septum (MS) plays an essential role in rhythmogenesis in the hippocampus (HIPP); theta-rhythmic bursts of MS neurons are believed to drive theta oscillations in rats' HIPP. The MS theta pacemaker hypothesis has solid foundation but the MS-hippocampal interactions during different behavioral states are poorly understood. The MS and the HIPP have reciprocal connections and it is not clear in particular what role, if any, the strong HIPP to MS projection plays in theta generation. To study the functional interactions between MS and HIPP during different behavioral states, this study investigated the relationship between MS single-unit activity and HIPP field potential oscillations during theta states of active waking and REM sleep and non-theta states of slow wave sleep (SWS) and quiet waking (QW), i.e., sleep-wake states that comprise the full behavioral repertoire of undisturbed, freely moving rats. We used non-parametric Granger causality (GC) to decompose the MS-HIPP synchrony into its directional components, MS?HIPP and HIPP?MS, and to examine the causal interactions between them within the theta frequency band. We found a significant unidirectional MS?HIPP influence in non-theta states which switches to bidirectional theta drive during theta states with MS?HIPP and HIPP?MS GC being of equal magnitude. In non-theta states, unidirectional MS?HIPP influence was accompanied by significant MS-HIPP coherence, but no signs of theta oscillations in the HIPP. In theta states of active waking and REM sleep, sharp theta coherence and strong theta power in both structures was associated with a rise in HIPP?MS to the level of the MS?HIPP drive. Thus, striking differences between waking and REM sleep theta states and non-theta states of SWS and QW were primarily observed in activation of theta influence carried by the descending HIPP?MS pathway associated with more regular rhythmic bursts in the MS and sharper MS?HIPP GC spectra without a significant increase in MS?HIPP GC magnitude. The results of this study suggest an essential role of descending HIPP to MS projections in theta generation.

Project description:BackgroundLow-grade, chronic inflammation in the central nervous system characterized by glial reactivity is one of the major hallmarks for aging-related neurodegenerative diseases like Alzheimer's disease (AD). The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex and may be differentially vulnerable in various neurodegenerative diseases. However, the impact of chronic neuroinflammation on the cholinergic function is still unclear.MethodsTo gain further insight into age-related cholinergic decline, we investigated the cumulative effects of aging and chronic neuroinflammation on the structure and function of the septal cholinergic neurons in transgenic mice expressing interleukin-6 under the GFAP promoter (GFAP-IL6), which maintains a constant level of gliosis. Immunohistochemistry combined with unbiased stereology, single cell 3D morphology analysis and in vitro whole cell patch-clamp measurements were used to validate the structural and functional changes of BFCN and their microglial environment in the medial septum.ResultsStereological estimation of MS microglia number displayed significant increase across all three age groups, while a significant decrease in cholinergic cell number in the adult and aged groups in GFAP-IL6 mice compared to control. Moreover, we observed age-dependent alterations in the electrophysiological properties of cholinergic neurons and an increased excitability profile in the adult GFAP-IL6 group due to chronic neuroinflammation. These results complimented the significant decrease in hippocampal pyramidal spine density seen with aging and neuroinflammation.ConclusionsWe provide evidence of the significant impact of both aging and chronic glial activation on the cholinergic and microglial numbers and morphology in the MS, and alterations in the passive and active electrophysiological membrane properties of septal cholinergic neurons, resulting in cholinergic dysfunction, as seen in AD. Our results indicate that aging combined with gliosis is sufficient to cause cholinergic disruptions in the brain, as seen in dementias.

Dataset Information

Topographical Visualization of the Reciprocal Projection between the Medial Septum and the Hippocampus in the 5XFAD Mouse Model of Alzheimer's Disease.

Publications

Topographical Visualization of the Reciprocal Projection between the Medial Septum and the Hippocampus in the 5XFAD Mouse Model of Alzheimer's Disease.

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