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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 volume 26, pages 7154–7166 (2021)Cite this article

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Abstract

Impaired ability to generate new cells in the adult brain has been linked to deficits in multiple emotional and cognitive behavioral domains. However, the mechanisms by which abrogation of adult neural stem cells (NSCs) impacts on brain function remains controversial. We used a transgenic rat line, the GFAP-Tk, to selectively eliminate NSCs and assess repercussions on different behavioral domains. To assess the functional importance of newborn cells in specific developmental stages, two parallel experimental timeframes were adopted: a short- and a long-term timeline, 1 and 4 weeks after the abrogation protocol, respectively. We conducted in vivo electrophysiology to assess the effects of cytogenesis abrogation on the functional properties of the hippocampus and prefrontal cortex, and on their intercommunication. Adult brain cytogenesis abrogation promoted a time-specific installation of behavioral deficits. While the lack of newborn immature hippocampal neuronal and glial cells elicited a behavioral phenotype restricted to hyperanxiety and cognitive rigidity, specific abrogation of mature new neuronal and glial cells promoted the long-term manifestation of a more complex behavioral profile encompassing alterations in anxiety and hedonic behaviors, along with deficits in multiple cognitive modalities. More so, abrogation of 4 to 7-week-old cells resulted in impaired electrophysiological synchrony of neural theta oscillations between the dorsal hippocampus and the medial prefrontal cortex, which are likely to contribute to the described long-term cognitive alterations. Hence, this work provides insight on how newborn neurons and astrocytes display different functional roles throughout different maturation stages, and establishes common ground to reconcile contrasting results that have marked this field.

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Fig. 1: Short- and long-term cell generation and survival in the ventral and dorsal dentate gyri, following GCV treatment.
Fig. 2: Short-term behavioral effects of adult brain cytogenesis abrogation.
Fig. 3: Long-term behavioral effects of adult brain cytogenesis abrogation.
Fig. 4: Long-term cognitive behavior characterization.
Fig. 5: Adult-hippocampal cytogenesis abrogation induces long-term decrease in spectral coherence between the dorsal hippocampus (dHIP) and the medial prefrontal cortex (mPFC).
Fig. 6: Time-dependent functional correlates of adult brain cytogenesis.

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Acknowledgements

We would like to thank Prof. Jonathan Flint for providing the GFAP-tk rat line. PP, IC, TSR, JSC, VMS, and ELC received fellowships from the Portuguese Foundation for Science and Technology (FCT). This work was co-funded by FCT (IF/01079/2014 and 2020.02855.CEECIND to L.P.), BIAL Foundation Grant 427/14 and Nature Research Award for Driving Global Impact-2019 Brain Sciences (to LP). This was also co-funded by the Life and Health Sciences Research Institute (ICVS), and by FEDER, through the Competitiveness Internationalization Operational Program (POCI), and by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023. Moreover, this work has been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122); by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020.

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  1. Nuno Dinis Alves

    Present address: Department of Psychiatry, Columbia University, New York, NY, 10032, USA

  2. Nuno Dinis Alves

    Present address: New York State Psychiatric Institute, New York, NY, 10032, USA

  3. These authors contributed equally: António Mateus-Pinheiro, Patrícia Patrício.

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

    António Mateus-Pinheiro, Patrícia Patrício, Nuno Dinis Alves, Joana Martins-Macedo, Inês Caetano, Tiago Silveira-Rosa, Bruna Araújo, Joana Silva-Correia, Vanessa Morais Sardinha, Eduardo Loureiro-Campos, Ana João Rodrigues, João Filipe Oliveira, João M. Bessa, Nuno Sousa & Luísa Pinto

  2. ICVS/3B’s-PT Government Associate Laboratory, Braga, Guimarães, Portugal

    António Mateus-Pinheiro, Patrícia Patrício, Nuno Dinis Alves, Joana Martins-Macedo, Inês Caetano, Tiago Silveira-Rosa, Bruna Araújo, Joana Silva-Correia, Vanessa Morais Sardinha, Eduardo Loureiro-Campos, Ana João Rodrigues, João Filipe Oliveira, João M. Bessa, Nuno Sousa & Luísa Pinto

  3. Department of Internal Medicine, Coimbra Hospital and University Center, Coimbra, Portugal

    António Mateus-Pinheiro

  4. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    Miguel Mateus-Pinheiro

  5. DIGARC, Polytechnic Institute of Cávado and Ave, Barcelos, Portugal

    João Filipe Oliveira

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Contributions

JMM, BA, and TR maintained the GFAP-tk colony, induced the model, performed genotyping, and collected wellbeing measures. AMP and PP conducted all behavioral tests and immunohistochemical experiments, performed the analyses and interpreted the results. MMP and ELC assisted in the behavioral tests and analyzed the USV data. IC and VMS collected the electrophysiology data. IC, AJR, and JFO analyzed and interpreted the electrophysiology data. NDA and JSC processed all brains from electrophysiology experiments and for immunohistochemical analyses. AMP, PP, and LP designed the study, planned the experiments, and wrote the manuscript. AMP, PP, NS, JMB, and LP edited the manuscript.

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Correspondence to Luísa Pinto.

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Mateus-Pinheiro, A., Patrício, P., Alves, N.D. 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. Mol Psychiatry 26, 7154–7166 (2021). https://doi.org/10.1038/s41380-021-01287-8

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