Beyond Hippocampal Neurogenesis: Unraveling the importance of gliogenesis in a rat model of cytogenesis ablation

Beyond Hippocampal Neurogenesis: Unraveling the importance of gliogenesis in a rat model of cytogenesis ablation

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Neurogenesis in the adult human hippocampus was described for the first time in 1998 by Fred Gage’s lab and it was prominently debated for several years. Ever since, strong evidence has been gathered,  being currently a commonly accepted phenomenon. Considering that about 700 new neurons are continuously generated every day, in each hippocampal dentate gyrus (Kempermann et al. 2018), studies related with neuropsychiatric and neurodegenerative diseases have been focused on understanding how new neurons are implicated in the recovery or reestablishment of neuronal function.

However, little attention has been given to the generation of new glial cells (gliogenesis), or its implications for brain physiology.

Hippocampal gliogenesis

Following an interesting study from Encinas and colleagues (2011), on a contrasting radial glial lineage (RGL) proliferation-differentiation model, we were intrigued by the potential role of gliogenesis in the hippocampal subgranular zone in the context of mood disorders.

As such, in 2013, we found that the incorporation of newly born neurons, but also, and importantly, newly born astrocytes (gliogenesis), into the preexisting hippocampal neurocircuitry was necessary for the spontaneous recovery from the adverse effects of stress and for long-term benefits of antidepressant (AD) treatments (Mateus-Pinheiro et al. 2013). This finding was our first experimental indication that the generation of new glial cells could play an important role in both brain physiological and pathological states. Corroborating these results, we demonstrated that the AD imipramine induced the reestablishment of the astrogliogenic process, which was compromised after chronic stress exposure, also leading to the recovery of cognitive impairments (Machado-Santos et al. 2022).


A new tool to study the isolated role of gliogenesis

The study of gliogenesis has been neglected for years but dissecting the individual contribution of this process within adult cytogenesis is of the utmost importance to preserve lifelong hippocampal normal function. In this regard, it has been difficult to find the appropriate experimental approaches to uncover the isolated role of gliogenesis in the adult brain, where it only has been possible to simultaneously ablate neuronal and glial lineages. This fact precluded the ability to withdraw valid conclusions concerning the individual participation of each newborn cell type for the pathogenesis and treatment of neuropsychiatric disorders.

In this matter, our group has been focused on studying and establishing a mechanistic link between brain neuro-glial plasticity and depression. We have recently described a differential role of immature and mature cells within the adult brain, in the manifestation of emotion and cognitive impairments, following hippocampal cytogenesis ablation, by using a transgenic rat line, – the GFAP-tk – to selectively eliminate neural stem cells and assess the repercussion on distinct behavioral domains (Mateus-Pinheiro et al. 2021). Considering the potential of this model to transiently, but effectively, eliminate all newly born neural stem cells (affecting both neuro- and gliogenesis), we thought about introducing an exogenous source of glial restricted progenitors,  by transplanting Glial Restricted Precursors (GRPs), or their secretome, into the adult hippocampal dentate gyrus. This approach would allow us to understand the specific role of (exogenous) newly born glial cells, in a time window where endogenous cytogenesis is compromised.


The story behind GRPs

Disclosing the relevance of progenitors restricted to the glial lineage, in specific GRPs, was already explored in several brain pathologies and in demyelinating diseases, namely in Amyotrophic Lateral Sclerosis and Multiple Sclerosis, as well as in traumatic conditions such as Spinal Cord Injury. Only one study was performed in the context of neurogenesis, where GRPs transplanted into the aging brain were able to stimulate the generation of new neurons in the hippocampal circuitry (Hattiangady et al. 2007). Nevertheless, no other study had been performed to uncover the role of GRPs (or other source of glial progenitors) in a neuropsychiatric context, particularly related to cytogenesis in the adult hippocampus and consequent behavioral fluctuations.


Main results

In this context, and using the tools previously described, we were able to be the first group to demonstrate the specific contribution of glial precursors not only to normalize gliogenesis, but also rescuing neurogenic levels in the hippocampal dentate gyrus of animals with cytogenesis deficits, and importantly, to recover anxiety- and depressive-like behaviors, characteristic of depression. Behind these alterations, GRPs significantly impacted the proteome profile of the hippocampal dentate gyrus, either at the dorsal pole (where cells were transplanted) and at the ventral pole.

Unravelling dorsal-ventral DG interconnection

While most of the studies in hippocampal dorsal and ventral dentate gyrus convincingly reveal a functional separation between these two regions, our work is also a novelty in the field, since it shows an indirect effect of GRPs transplanted into the dorsal DG (dDG), in the ventral DG (vDG). Even though it is not possible yet to pinpoint the exact mechanism behind GRPs influence in the DG, increased cytogenic levels in the vDG and emotional deficits recovery strongly suggest a functional interconnection between dDG and vDG.

The next steps

The present work is one of the first steps to state gliogenesis as vital for the normal brain function throughout life and opens an opportunity window to uncover the mechanistic processes and brain connectivity between dorsal-ventral hippocampus. Our journey in this field is just in the beginning, so we will continue to investigate to reveal the underlying paths of behavioral and molecular alterations that were herein observed.


Works cited:

- A. Mateus-Pinheiro, L. Pinto, J.M. Bessa, M. Morais, N.D. Alves, S. Monteiro, et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl. Psychiatry, 3 (2013), p. e210;

- A. Mateus-Pinheiro, P. Patrício, N.D. Alves, J. Martins-Macedo, I. Caetano, T. Silveira-Rosa, et al. Hippocampal cytogenesis abrogation impairs inter-regional communication between the hippocampus and prefrontal cortex and promotes the time-dependent manifestation of emotional and cognitive deficits. Molecular psychiatry, 26 (2021), pp. 7154–7166;

- A.R. Machado-Santos, E. Loureiro-Campos, P. Patrício, B. Araújo, N.D. Alves, A. Mateus-Pinheiro et al. Beyond New Neurons in the Adult Hippocampus: Imipramine Acts as a Pro-Astrogliogenic Factor and Rescues Cognitive Impairments Induced by Stress Exposure. Cells, 11 (2022), p. 390;

- B. Hattiangady, B. Shuai, J. Cai, T. Coksaygan, M.S. Rao, & A.K. Shetty. Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus. Stem Cells, 25 (2007), pp. 2104–2117.

- G. Kempermann, F.H. Gage, L. Aigner, H. Song, M.A. Curtis, S. Thuret, et al. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell, 23 (2018), pp. 25-30;

- J.M. Encinas, T.V. Michurina, N. Peunova, J.H. Park, J. Tordo, D.A. Peterson, et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell, 8 (2011), pp. 566-579.

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Life Sciences > Biological Sciences > Neuroscience > Cellular Neuroscience > Glial biology > Gliogenesis
Glial Progenitors
Life Sciences > Biological Sciences > Neuroscience > Development of the Nervous System > Glial Progenitors
Adult Neurogenesis
Life Sciences > Biological Sciences > Neuroscience > Development of the Nervous System > Neurogenesis > Adult Neurogenesis
Life Sciences > Health Sciences > Clinical Medicine > Psychiatry
Stem-cell Niche
Life Sciences > Health Sciences > Biomedical Research > Stem Cell Biology > Stem-cell Niche
Life Sciences > Biological Sciences > Biological Techniques > Mass Spectrometry > Proteomics