Acknowledgments
This research was funded by the UMA18-FEDERJA-100 (Junta de Andalucía),
Proyecto Jovenes Investigadores (B1-2019-04), Proyecto puente
(B4-2021-06), Universidad de Málaga, Spain, to M.N. Swedish Medical
Research Council, Sweden (62X-00715-50-3), to K.F., by Stiftelsen Olle
Engkvist Byggmästare to K.F., and by Hjärnfonden, Sweden (F02018-0286),
Hjärnfonden, Swe-den (F02019-0296), and Karolinska Institutet
Forskningsstiftelser, Sweden, to D.O.B.-E. D.O.B.-E. belongs to the
“Academia de Biólogos Cubanos” group, Cuba.
Figure 1. Ventral dentate gyrus is activated under GALR2 and
the Y1R agonists intranasal coinjection. Effects of the intranasal (in)
administration of Galanin 2 receptor agonist (M1145) and Y1R receptor
agonist, either alone or in combination with or without the GAL 2
receptor antagonist (M871) on c-Fos expression in the granular layer of
ventral dentate gyrus. (a,d) The majority of the c-Fos-IR
profiles were located in the granular cell layer (Gcl). It is also
indicated the polymorphic layer (P) of the dentate gyrus in the ventral
hippocampus (Bregma: -5.6 mm; according to the Paxinos and Watson
stereotaxic atlas (2006)). (b) Quantification of the total
number of c-Fos IR nuclei within the dentate gyrus of the ventral
hippocampus. Data, expressed as mean ± SEM, show the differences between
groups after administration of Control, M1145, Y1R agonist
[Leu31-Pro34]NPY, or the
coadministration of both agonists with or without M871. The intranasal
coadministration of M1145 and the Y1R agonist increased the c-Fos
expression in the ventral hippocampus compared to the effects of both
agonists given alone and the control group. Moreover, this effect was
counteracted by the GALR2 antagonist M871.* P<0.05 vs control,
M1145 and M1145+Y1R; δ P<0.05 vs M1145+Y1R; *** P
<0.001 vs control and M1145 according to one-way ANOVA
followed by Newman-Keuls post-hoc test (n=4 in each group). Inter-group
comparisons are indicated by the vertical lines from the horizontal line
above bars. Intranasal coadministration of M1145 and Y1R agonist(d) increased the c-Fos-IR nuclei in Gcl in the dentate gyrus
compared with the control group (c). Arrows indicate examples
of c-Fos-IR nuclei. Dashed lines outline the Gcl of the dentate gyrus.
Abbreviations: Control= Distilled water; M1145 = Galanin 2 receptor
agonist 132 µg; Y1R = Y1R receptor agonist
[Leu31-Pro34]NPY 132 µg; M1145+
Y1R = Coadministration of M1145 and Y1R; M1145+ Y1R +M871 =
Co-administration of M1145, Y1R and GALR2 antagonist M871 132 µg. Brain
processing was performed 24 hours after treatments; see material and
methods for further details.
Figure 2. Intranasal coadministration of Galanin receptor 2 and
Y1R agonists increases cell proliferation in the ventral dentate gyrus
of adult rats. Proliferating cell nuclear antigen immunolabelling (PCNA)
immunolabelling (PCNA+) in the dentate gyrus of the ventral hippocampus,
after the intranasal (in) administration of Galanin 2 receptor agonist
(M1145) and Y1R receptor agonist, either alone or in combination with or
without the GAL 2 receptor antagonist (M871). (a,d) The
majority of the PCNA positive cells were located in the subgranular zone
(Sgz) of the dentate gyrus at the border between the granular cell layer
(Gcl) and the polymorphic layer (P) of the dentate gyrus in the ventral
hippocampus. They appeared as clusters of 3–4 cells. (Bregma: -5.6 mm;
according to the Paxinos and Watson stereotaxic atlas (2006)).(b) Quantification of total PCNA-IR cells in the dentate gyrus
of the ventral hippocampus. Data represent mean ± SEM to show the
differences between groups after administration of Control, M1145, Y1R
agonist [Leu31-Pro34]NPY, or the
coadministration of both agonists with or without M871. M1145 and the
Y1R agonist coadministration increased the number of cells with PCNA+
expression in the ventral hippocampus compared to the effects of the two
peptides given alone and the control group. Furthermore, this effect was
counteracted by the GALR2 antagonist M871. *P <0.05 vs
control, M1145 and M1145+Y1R; **P <0.01 vs M1145+Y1R; ***P
<0.001 vs control and M1145 according to one-way ANOVA
followed by Newman-Keuls post-hoc test. Inter-group comparisons are
indicated by the vertical lines from the horizontal line above bars. N=4
in each group. M1145 and Y1R agonist intranasal coadministration(d) increased the PCNA immunolabelling in Sgz in the dentate
gyrus compared with the control group (c). Arrows indicate
examples of clusters of PCNA positive nerve cells. Dashed lines outline
the Gcl of the dentate gyrus. Abbreviations: Control= Distilled water;
M1145 = Galanin 2 receptor agonist 132 µg; Y1R = Y1R receptor agonist
[Leu31-Pro34]NPY 132 µg; M1145+
Y1R = Coadministration of M1145 and Y1R; M1145+ Y1R +M871 =
Co-administration of M1145, Y1R and GALR2 antagonist M871 132 µg. Brain
processing was performed 24 hours after treatments; see material and
methods for further details.
Figure 3. Effects induced by M1145 and Y1R agonist on
hippocampal brain-derived neurotrophic factor immunoreactive (BDNF-IR)
cells of the dentate gyrus (DG) hippocampal region. (a) BDNF-IR cells
were located mainly in the subgranular zone (Sgz) of the dentate gyrus
at the border of the granular cell layer (Gcl), some scattered cells
were found in the polymorphic layer (P) of the dentate gyrus in the
ventral hippocampus (Bregma: –5.6 mm; according to the Paxinos and
Watson (2006) stereotaxic atlas). (b) Quantitative analysis of BDNF-IR
cells of the DG. The intranasal coadministration of M1145 and the Y1R
agonist significantly increased BDNF-IR cells in the ventral DG. This
effect was blocked in the presence of the GALR2 antagonist M871. *
P<0.05 vs control, M1145 and M1145+Y1R; δ P<0.05 vs
M1145+Y1R; *** P <0.001 vs control and M1145 according to
one-way ANOVA followed by Newman-Keuls post-hoc test (n=4 in each
group). The vertical lines from the horizontal line above the bars
indicate the inter-group comparisons. (c,d) Representative
microphotographs showing the increase in the BDNF-positive cells in the
DG after M1145 and Y1R agonist coinjection (d) compared with the control
group (c). Black arrows point to BDNF-IR cells. Dashed lines outline the
Gcl of the dentate gyrus. Abbreviations: Control= Distilled water; M1145
= Galanin 2 receptor agonist 132 µg; Y1R= Y1R receptor agonist
[Leu31-Pro34]NPY 132 µg; M1145+
Y1R = Coadministration of M1145 and Y1R; M1145+ Y1R +M871 =
Co-administration of M1145, Y1R and GALR2 antagonist M871 132 µg. Brain
processing was performed 24 hours after treatments; see material and
methods for further details.
Figure 4 . Demonstration of GALR2/Y1R heteroreceptor complexes
by in situ PLA and morphological changes on hippocampal neuronal
cells. (a) The presence of positive PLA signals (red circles)
was determined by using the in situ proximity ligation assay
(in situ PLA) on hippocampal neuronal cells after treatment with
Galanin receptor 2 agonist (M1145, 100nM) and Y1R receptor agonist
(100nM), either alone or in combination with or without the GALR2
receptor antagonist (M871, 1μM). M1145 and Y1R agonist incubation
significantly increased PLA positive signals. Quantification of PLA
signals was performed by measuring red PLA positive blobs per nucleus
per sampled field by an experimenter blind to treatment conditions. This
effect was blocked by treatment with the GALR2 antagonist M871. *P
<0.05 vs control and M1145; **P <0.01 vs Y1R and
M1145+Y1R+M871; ***P <0.001 vs control and M1145 according to
one-way ANOVA followed by Newman-Keuls post-hoc test. Inter-group
comparisons are indicated by the vertical lines from the horizontal line
above bars. Data are expressed as mean ± SEM. (b) GALR2 and Y1R
agonists modulation of neurites length. The length of neurites per cell
were determined after immunofluorescent labeling of neurons and neuronal
nuclei (Pan Neuronal Marker (ABN2300) /neuronal nuclei (DAPI)).
Quantification is shown in Figure 4b, where the data are presented as
mean ± SEM. The combined M1145 and Y1R agonist group is significantly
different from the rest of the groups. *P <0.05 vs Y1R and
M1145+Y1R+M871; **P <0.01 vs control and M1145; ***P
<0.001 vs control and M1145 according to one-way ANOVA
followed by Newman-Keuls post-hoc test. (c,d) Representative
microphotographs of the significant increase in the density of GALR2/Y1R
heteroreceptor complexes (PLA clusters) and neurites length per
hippocampal neuronal positive cell after M1145 and Y1R agonist treatment(d) compared with the control group (c) . Receptor
complexes are shown as red PLA blobs (clusters, indicated by white
arrows) found in high densities per hippocampal neuronal cell using
confocal laser microscopy. The nuclei are shown in blue by DAPI staining
and the cells in green are hippocampal neurons-positive (Pan Neuronal
Marker, ABN2300) using confocal laser microscopy. White arrowheads point
to neurite extensions. Abbreviations: Control= Culture medium; M1145 =
Galanin 2 receptor agonist 100 nM; Y1R agonist = Y1R receptor agonist
[Leu31- Pro34]NPY 100nM; M1145+
Y1R = Coadministration of M1145 and Y1R; M1145+ Y1R +M871 =
Coadministration of M1145, Y1R and GALR2 antagonist 1μM.
Figure 5. Behavioral actions induced by Galanin 2 receptor
agonist (M1145) and the Neuropeptide Y (NPY) Y1 receptor agonist (Y1R
agonist) alone and in combination in the forced swimming test (FST). An
antidepressant-like effect in the FST was observed after M1145 and Y1R
agonist intranasal co-administration following a 24 hours delay.
Furthermore, this effect is counteracted by the GAL 2 receptor (GALR2)
antagonist M871. Cumulative behavioral duration of Immobility(a) and swimming (b) time in the FST. Data represent
mean ± SEM. N=6 animals in each group. For a: *P <0.05 vs
Control and M1145; **P <0.01 vs Y1R agonist, M1145+Y1R+M871
and M1145+Y1R+ANA-12; ***P <0.001 vs Control and M1145. For b:
*P <0.05 vs Control and M1145; ★P <0.05 vs Y1R
agonist, M1145+Y1R+M871 and M1145+Y1R+ANA-12; ***P <0.001 vs
Control and M1145 according to one-way ANOVA followed by Newman-Keuls
post-hoc test. Inter-group comparisons are indicated by the horizontal
and vertical lines above bars. Abbreviations: Control= Distilled water;
M1145 = Galanin 2 receptor agonist 132 µg; Y1R = Y1R receptor agonist
[Leu31-Pro34]NPY 132 µg;
M1145+Y1R= Coadministration of M1145 and Y1R; M1145+Y1R+M871 =
Coadministration of M1145, Y1R and GALR2 antagonist M871 132 µg;
M1145+Y1R+ANA-12 = Coadministration of M1145, Y1R and TrkB antagonist
ANA-12 0,5 mg/Kg.
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