Abstract
Rationale
Previous studies suggested that the dorsal column of the periaqueductal grey matter (dPAG) can be a target of neural pathways from hypothalamic nuclei involved in triggering fear-related defensive responses. In turn, evidence is provided suggesting that microinjection of the nitric oxide (NO) donor SIN-1 into the anterior hypothalamus (AH) of mice evokes panic-like behaviours and fear-induced antinociception. However, it is unknown whether the dPAG of mice mediates these latter defensive responses organised by AH neurons.
Objectives
This study was designed to examine the role of dPAG in mediating SIN-1-evoked fear-induced defensive behavioural and antinociceptive responses organised in the AH of mice.
Methods
First, neural tract tracing was performed to characterise the AH-dPAG pathways. Then, using neuropharmacological approaches, we evaluated the effects of dPAG pretreatment with either the non-selective synaptic blocker cobalt chloride (CoCl2; 1 mM/0.1 μL) or the competitive N-methyl-d-aspartate (NMDA) receptor antagonist LY235959 (0.1 nmol/0.1 μL) on defensive behaviours and antinociception induced by microinjections of SIN-1 in the AH of male C57BL/6 mice.
Results
AlexaFluor488-conjugated dextran-labelled axonal fibres from AH neurons were identified in both dorsomedial and dorsolateral PAG columns. Furthermore, we showed that pre-treatment of the dPAG with either CoCl2 or LY235959 inhibited freezing and impaired oriented escape and antinociception induced by infusions of SIN-1 into the AH.
Conclusions
These findings suggest that the panic-like freezing and oriented escape defensive behaviours, and fear-induced antinociception elicited by intra-AH microinjections of SIN-1 depend on the activation of dPAG NMDA receptors.
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Data availability
The data that support the findings of this study are available on request from the corresponding authors N.C. Coimbra and L.L. Falconi-Sobrinho.
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Funding
The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grant numbers 2007/01174–1, 2012/03798–0, 2017/11855–8, and 2020/15050–7) and Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) (grant numbers 483763/2010–1, 474853/2013–6 and 427397/2018–9). L.L. Falconi-Sobrinho was supported by FAPESP (Scientiae Magister grant 2013/10984–8; post-doctoral grant 2019/05255–3) and CNPq (Sc.M. fellowship grant 134267/2013–3; Scientiae Doctor fellowship grant 145258/2015–7). T. dos Anjos-Garcia was financially supported by CNPq (Sc.M. fellowship grant 130124/2012–5; Sc.D. fellowship grant 141124/2014–8) and FAPESP (postdoctoral grant 2017/22647–7). P. M. Hernandes was supported by CNPq (Sc.D. fellowship grant 142030/2020–1). B.M. de Paula Rodrigues was financially supported by CAPES (M.Sc. and Sc.D. fellowships, CAPES–PROEX-Psicobiologia-FFCLRP-USP grant 0487 and CAPES-PROEX grant 8887.475628/2020–00, respectively). R.C. Almada was supported by FAPESP (postdoctoral fellowship process 2012/22681–7, Young Investigator Program: research grant process 2018/03898–1 and researcher fellowship process 2019/01713–7) and CAPES (postdoctoral fellowship process PNPD20131680-33002029012P3). N. C. Coimbra is a researcher supported by CNPq (PQ1A grants 301905/2010–0 and 301341/2015–0; PQ2 grant 302605/2021–5).
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L.L.F.-S. designed and executed the experiments, analysed and interpreted the data, designed the figures and wrote the manuscript. T. dos A.-G. collaborated on pharmacological approaches. P.M.H and R.C.A collaborated in neuroanatomical approaches. B.M.de P.R. performed the place preference behaviour-related experiments. N.C.C designed the experiments, invented the enriched polygonal arena test, performed the place preference experiments, recorded the neural tract tracing images, analysed and interpreted the data, and wrote the manuscript. All authors approved the final version of the manuscript and are entirely responsible for the scientific content of this article.
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Falconi-Sobrinho, L.L., dos Anjos-Garcia, T., Hernandes, P.M. et al. Unravelling the dorsal periaqueductal grey matter NMDA receptors relevance in the nitric oxide-mediated panic‑like behaviour and defensive antinociception organised by the anterior hypothalamus of male mice. Psychopharmacology 240, 319–335 (2023). https://doi.org/10.1007/s00213-023-06309-7
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DOI: https://doi.org/10.1007/s00213-023-06309-7