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Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration.

ABSTRACT: The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour ?-retroviral tracing, transmission electron microscopy and patch-clamp. We found increased neurogenesis during the progression of prion disease, which partially counteracts the effects of chronic neurodegeneration, as evidenced by blocking neurogenesis with cytosine arabinoside, and helps to preserve the hippocampal function. Evidence obtained from human post-mortem samples, of both variant Creutzfeldt-Jakob disease and Alzheimer's disease patients, also suggests increased neurogenic activity. These results open a new avenue into the exploration of the effects and regulation of neurogenesis during chronic neurodegeneration, and offer a new model to reproduce the changes observed in human neurodegenerative diseases.

SUBMITTER: Gomez-Nicola D

PROVIDER: S-EPMC4107745 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration.

Gomez-Nicola Diego D Suzzi Stefano S Vargas-Caballero Mariana M Fransen Nina L NL Al-Malki Hussain H Cebrian-Silla Arantxa A Garcia-Verdugo Jose Manuel JM Riecken Kristoffer K Fehse Boris B Perry V Hugh VH

Brain : a journal of neurology 20140618 Pt 8

The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour γ-retroviral tracing, transmission electron mi ...[more]

PMID: 24941947

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Project description:GABAergic interneurons play a role in regulating adult neurogenesis within the dentate gyrus (DG) of the hippocampus. Neurogenesis occurs within a stem cell niche in the subgranular zone (SGZ) of the DG. In this niche, populations of neural progenitors give rise to granule cells that migrate radially into the granule cell layer (GCL) of the DG. Altered neurogenesis in temporal lobe epilepsy (TLE) is linked to a transient increase in the proliferation of new neurons and the abnormal inversion of Type 1 progenitors, resulting in ectopic migration of Type 3 progenitors into the hilus of the DG. These ectopic cells mature into granule cells in the hilus that become hyperexcitable and contribute to the development of spontaneous recurrent seizures. To test whether grafts of GABAergic cells in the DG restore synaptic inhibition, prior work focused on transplanting GABAergic progenitors into the hilus of the DG. This cell-based therapeutic approach was shown to alter the disease phenotype by ameliorating spontaneous seizures in mice with pilocarpine-induced TLE. Prior optogenetic and immunohistochemical studies demonstrated that the transplanted GABAergic interneurons increased levels of synaptic inhibition by establishing inhibitory synaptic contacts with adult-born granule cells, consistent with the observed suppression of seizures. Whether GABAergic progenitor transplantation into the DG ameliorates underlying abnormalities in adult neurogenesis caused by TLE is not known. As a first step to address this question, we compared the effects of GABAergic progenitor transplantation on Type 1, Type 2, and Type 3 progenitors in the stem cell niche using cell type-specific molecular markers in naïve, non-epileptic mice. The progenitor transplantation increased GABAergic interneurons in the DG and led to a significant reduction in Type 2 progenitors and a concomitant increase in Type 3 progenitors. Next, we compared the effects of GABAergic interneuron transplantation in epileptic mice. Transplantation of GABAergic progenitors resulted in reductions in inverted Type 1, Type 2, and hilar ectopic Type 3 cells, concomitant with an increase in the radial migration of Type 3 progenitors into the GCL. Thus, in mice with Pilocarpine induced TLE, hilar transplants of GABA interneurons may reverse abnormal patterns of adult neurogenesis, an outcome that may ameliorate seizures.

Project description:Cholinergic projection neurons in the medial septum and diagonal band of Broca are the major source of cholinergic modulation of hippocampal circuit functions that support neural coding of location and running speed. Changes in cholinergic modulation are known to correlate with changes in brain states, cognitive functions, and behavior. However, whether cholinergic modulation can change fast enough to serve as a potential speed signal in hippocampal and parahippocampal cortices and whether the temporal dynamics in such a signal depend on the presence of visual cues remain unknown. In this study, we use a fiber-photometric approach to quantify the temporal dynamics of cholinergic activity in freely moving mice as a function of the animal's movement speed and visual cues. We show that the population activity of cholinergic neurons in the medial septum and diagonal band of Broca changes fast enough to be aligned well with changes in the animal's running speed and is strongly and linearly correlated to the logarithm of the animal's running speed. Intriguingly, the cholinergic modulation remains strongly and linearly correlated to the speed of the animal's neck movements during periods of stationary activity. Furthermore, we show that cholinergic modulation is unaltered during darkness. Lastly, we identify rearing, a stereotypic behavior where the mouse stands on its hindlimbs to scan the environment from an elevated perspective, is associated with higher cholinergic activity than expected from neck movements on the horizontal plane alone. Taken together, these data show that temporal dynamics in the cholinergic modulation of hippocampal circuits are fast enough to provide a potential running speed signal in real-time. Moreover, the data show that cholinergic modulation is primarily a function of the logarithm of the animal's movement speed, both during locomotion and during stationary activity, with no significant interaction with visual inputs. These data advance our understanding of temporal dynamics in cholinergic modulation of hippocampal circuits and their functions in the context of neural coding of location and running speed.

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Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration.

Publications

Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration.

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