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Persistent modification of forebrain networks and metabolism in rats following adolescent exposure to a 5-HT7 receptor agonist

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Abstract

Rationale

The serotonin 7 receptor (5-HT7-R) is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive or sleep regulation.

Objectives

We investigated long-term consequences of sub-chronic treatment, during adolescence (43–45 to 47–49 days old) in rats, with a novel 5-HT7-R agonist (LP-211, 0 or 0.250 mg/kg/day).

Methods

We evaluated behavioural changes as well as forebrain structural/functional modifications by in vivo magnetic resonance (MR) in a 4.7 T system, followed by ex vivo histology.

Results

Adult rats pre-treated during adolescence showed reduced anxiety-related behaviour, in terms of reduced avoidance in the light/dark test and a less fragmented pattern of exploration in the novel object recognition test. Diffusion tensor imaging (DTI) revealed decreased mean diffusivity (MD) in the amygdala, increased fractional anisotropy (FA) in the hippocampus (Hip) and reduced axial (D||) together with increased radial (D⊥) diffusivity in the nucleus accumbens (NAcc). An increased neural dendritic arborization was confirmed in the NAcc by ex vivo histology. Seed-based functional MR imaging (fMRI) identified increased strength of connectivity within and between “limbic” and “cortical” loops, with affected cross-correlations between amygdala, NAcc and Hip. The latter displayed enhanced connections through the dorsal striatum (dStr) to dorso-lateral prefrontal cortex (dl-PFC) and cerebellum. Functional connection also increased between amygdala and limbic elements such as NAcc, orbito-frontal cortex (OFC) and hypothalamus. MR spectroscopy (1H-MRS) indicated that adolescent LP-211 exposure increased glutamate and total creatine in the adult Hip.

Conclusions

Persistent MR-detectable modifications indicate a rearrangement within forebrain networks, accounting for long-lasting behavioural changes as a function of developmental 5-HT7-R stimulation.

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Acknowledgments

Research performed under “NeuroGenMRI” (ERA-net “PrioMedChild”), Italian Ministry of Health (Italian partner, grant to W.A.; EU coordinator: L. Reneman); partially funded from “Gambling”, Department of Antidrug Policies c/o Presidency of the Council of Ministries, Italy (grant to G.L. and W.A.) and from “EMTICS” (Seventh Framework Programme FP7/2007-2013), agreement no 278367 (Animal Model partner, grant to G.L.). We acknowledge Dr. Flavia Chiarotti for stimulating discussion on bootstrap statistical analyses; Mr. Massimo Giannini for the excellent maintenance of the MR equipment; Dr. Nadia Francia for all management issues; Miss Neha Patel and Miss Saira Shamsi (in ERASMUS stage) for practical support; Mrs. Luigia Cancemi and Mr. Giovanni Dominici for animal care. There is no conflict of interest to disclose.

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Authors and Affiliations

  1. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy

    Rossella Canese, Francesca Zoratto, Luisa Altabella, Paola Porcari, Laura Mercurio, Giovanni Laviola & Walter Adriani

  2. Institute for Advanced Biomedical Technologies, University “G. D’Annunzio”, Chieti, Italy

    Francesco de Pasquale

  3. Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy

    Erica Butti & Gianvito Martino

  4. Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, Bari, Italy

    Enza Lacivita & Marcello Leopoldo

  5. Bambino Gesù Children’s Hospital IRCCS, Rome, Italy

    Francesca Zoratto

  6. Physics Department, Sapienza University of Rome, Rome, Italy

    Paola Porcari

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  1. Rossella Canese
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  2. Francesca Zoratto
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  3. Luisa Altabella
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  5. Laura Mercurio
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  6. Francesco de Pasquale
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  11. Giovanni Laviola
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  12. Walter Adriani
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Corresponding author

Correspondence to Rossella Canese.

Additional information

Rossella Canese and Francesca Zoratto contributed equally to this work as co-first authors.

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Figure 1S

Voxels showing differences between the correlation maps, related to a particular seed for the adolescent-treated animals, with respect to the threshold (namely, the 99th percentile of the resampled distribution of control animals). Ten maps were obtained with a seed positioned (green square) in the following areas: a,b) Amygdala right, left; c,d) Hippocampus (Hip) right, left; e,f) Nucleus Accumbens (NAcc) right, left; g,h) Orbital pre-frontal cortex (OFC) right, left; j,k) Dorsal Striatum (dStr) right, left. For each map, seven sagittal images denote those pixels whose connectivity to the seed was enhanced as a long-term consequence of adolescent LP-211 exposure. The emerging networks are summarized in Table 2. (PPT 2.80 mb)

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Canese, R., Zoratto, F., Altabella, L. et al. Persistent modification of forebrain networks and metabolism in rats following adolescent exposure to a 5-HT7 receptor agonist. Psychopharmacology 232, 75–89 (2015). https://doi.org/10.1007/s00213-014-3639-6

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  • DOI: https://doi.org/10.1007/s00213-014-3639-6

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