Introduction
Neurogenesis is a process within neuronal plasticity, the capacity of
the brain to reorganize its structure, function, and connections in
response to extrinsic or intrinsic stimuli
(Baptista & Andrade, 2018). In this
regard, new neurons are produced in the brain via a manner known as
adult hippocampal neurogenesis (AHN). Among the neurogenic areas studied
in the human brain, hippocampal formation emerges as crucial, exerting a
noteworthy role in brain function
(Spalding et al., 2013;
Toda, Parylak, Linker, & Gage, 2019). In
the dentate gyrus (DG) of the hippocampus is located the neurogenic
niche, aimed to maintain AHN and implicated in many processes under
normal physiological conditions during adulthood. In fact, AHN is
demonstrated to be preserved throughout human life, even until the ninth
decade of life, being essential to keep related physiological functions
(Boldrini et al., 2018;
Moreno-Jimenez et al., 2019;
Terreros-Roncal et al., 2022).
Furthermore, a functional separation has been demonstrated in the
hippocampus, where stress and modulation of emotional behavior is
processed by the anterior portion in humans (ventral, in rodents) while
cognitive functions and memory is related to the posterior part (dorsal,
in rodents) (Fanselow & Dong, 2010;
Kheirbek et al., 2013;
Tanti & Belzung, 2013).
Intriguingly, dysregulation of AHN is related to several brain
disorders, such as major depressive disorder (MDD), age-dependent
cognitive decline, Alzheimer’s disease (AD), amyotrophic lateral
sclerosis, Huntington’s disease, Parkinson’s disease, dementia with Lewy
bodies, and frontotemporal dementia (I. B.
Kim & Park, 2021; Martos, Tuka, Tanaka,
Vecsei, & Telegdy, 2022; Moreno-Jimenez
et al., 2019; Terreros-Roncal et al.,
2022). MDD is one of the prominent mental health conditions in the
world with more than 300 million people diagnosed. MDD is defined by a
collection of behavioral, emotional and cognitive symptoms, and confer a
challenge for the medical community by increasing the risk of
suicidality and death. Suicide is considered the worst outcome or
consequence of MDD, over 700,000 human lives lost every year
(Elias, Zhang, & Manners, 2022).
Moreover, during the COVID-19 pandemic, multiple challenges have arisen,
such as loneliness or financial hardship, producing about 34%
prevalence of depression in general population, with 5–15% suicidal
ideation in that period (Giner,
Vera-Varela, de la Vega, Zelada, & Guija, 2022).
The majority of current antidepressants target monoamines, with
remarkable shortcomings such as adverse events and delayed onset of
efficacy (Harmer, Duman, & Cowen, 2017).
Notably, studies determine that approximately 50% of such patients fail
to respond and about 65% of them fail to achieve remission, which
classifies these patients with treatment-resistant depression (TRD)
(Chen, 2019). Recently, the discovery of
ketamine as an effective antidepressant led to the authorization of a
nasal spray form ofesketamine(Hashimoto, 2020). Esketamine provides
fast-acting symptomatic relief in TRD patients, but the significant
risks associated with esketamine limit its use for a broad patient
population. Overall, nowadays MDD patients have no adequate treatment
options, implicating that additional underlying mechanisms need to be
considered in order to improve the efficacy of treatments. In recent
decades, progress in the MDD field has been made possible in part
through the use of rodent models
(Planchez, Surget, & Belzung, 2019).
Accordingly, boosting hippocampal neurogenesis in these patients emerges
as a potential therapeutic approach
(Colucci-D’Amato, Speranza, & Volpicelli,
2020; Miller & Hen, 2015). Critical
components of AHN are cell proliferation, neuronal differentiation, and
survival, strictly controlled by multiple intrinsic or extrinsic
epigenetic factors that could promote or suppress neurogenesis
(Toda et al., 2019). These factors confer
a pivotal role in understanding the importance of adult neurogenesis on
physiological and pathological conditions
(Kempermann et al., 2018). In this way,
the neurogenic-promoting effects of neurotransmitters/neuropeptides and
neurotrophic factors are crucial regulators of neurogenic niche
activities in health and disease (Kuhn,
2015).
Among them,neuropeptide
Y (NPY) is one of the most abundant neuropeptides in the nervous
system. NPY is a 36 amino acid polypeptide neurotransmitter highly
conserved in mammals and involved in basic biological and
pathophysiological functions, such as neuroendocrine secretions, mood
regulation, feeding behavior, circadian rhythms, neuronal excitability,
neuroplasticity and memory (Kormos &
Gaszner, 2013; Zaben & Gray, 2013).
Regarding hippocampal neurogenesis, a pro-neurogenic role of NPY on
hippocampal stem cells has been evidenced both in vitro
(Howell et al., 2003;
Howell et al., 2007) and in vivo
(Decressac et al., 2011;
Geloso, Corvino, Di Maria, Marchese, &
Michetti, 2015). In preclinical models, it was found reduced brain NPY
in genetic and environmental models of MDD
(Cohen, Vainer, Zeev, Zohar, & Mathe,
2018; Jimenez Vasquez, Salmi, Ahlenius,
& Mathe, 2000; Jimenez-Vasquez,
Overstreet, & Mathe, 2000). Reliable with the animal data, brain NPY
is reduced in postmortem brains from MDD patients who committed suicide
(Kautz, Charney, & Murrough, 2017;
Sah & Geracioti, 2013). With regard to
treatment effects, all antidepressant procedures tested preclinically to
date increase brain NPY (Bjornebekk, Mathe,
& Brene, 2006; Husum, Mikkelsen, Hogg,
Mathe, & Mork, 2000). In line with these findings, transgenic rats
overexpressing hippocampal NPY show decreased depression-like behaviors
(Thorsell et al., 2000). Furthermore,
recently was demonstrated that intranasal NPY and the NPYY1
receptor (Y1R) agonist administration had antidepressant effects in
rodents (Nahvi et al., 2021;
Serova, Mulhall, & Sabban, 2017) and in
MDD patients (Mathe, Michaneck, Berg,
Charney, & Murrough, 2020). In this respect, the Y1R have been
proposed as a critical target by mediating dentate neurogenesis and
antidepressant effects (Rana et al.,
2022).
Brain-derived
neurotrophic factor (BDNF) is a pivotal molecule involved in the
neuroprotective effects of the antidepressants by regulating different
neurogenic processes in the hippocampus
(Castren & Kojima, 2017;
Colucci-D’Amato et al., 2020;
Miranda, Morici, Zanoni, & Bekinschtein,
2019). Moreover, a reduction in BDNF was reported in the hippocampus of
post-mortem brain tissues of MDD and suicide victims
(Dwivedi, 2012;
Pandey et al., 2008) while injection of
BDNF in the hippocampus reduces depression-like behavior in rodents
(Hoshaw, Malberg, & Lucki, 2005).
Besides, BDNF was significantly increased 24 h following treatment with
NPY in the trimethyltin (TMT)-induced model of hippocampal
neurodegeneration (Corvino et al., 2014).
We have demonstrated NPY andgalanin(GAL) interactions in different limbic system regions at molecular-,
cellular-, and behavioral-specific levels
(Mirchandani-Duque et al., 2022;
Narvaez et al., 2016;
Narvaez et al., 2018;
Narvaez et al., 2015). GAL is broadly
distributed in the central nervous system contributing to numerous
physiological effects (Katsetos et al.,
2001). Regarding hippocampal neurogenesis, theGAL2
receptor agonist,GAL
2–11 was involved in proliferative and trophic actions in vitro
(Abbosh, Lawkowski, Zaben, & Gray, 2011).
Concerning depression, GALR2 activation induced antidepressant effects
in rodents and the increased GALR2 expression in the ventral hippocampus
was related to antidepressant effects
(Kuteeva et al., 2008;
Luo et al., 2019). Moreover,
GalR2-knockout mice displayed depression-like behaviors
(Lu, Ross, Sanchez-Alavez, Zorrilla, &
Bartfai, 2008). Recently, we described a facilitatory interaction
between NPY and GAL through the Y1R-GALR2 heteroreceptor complexes
formation. Intranasally combined GALR2 and Y1R agonists improved spatial
memory performance related to increased cell proliferation in the
dentate gyrus of the dorsal hippocampus
(Borroto-Escuela et al., 2022).
The purpose of the current work was to assess the role of the NPY and
GAL interaction in the neurogenic actions on the ventral hippocampus.
Following GALR2 and Y1R agonists intranasal administration, we analyzed
the ventral hippocampal activation and their proliferating actions
through c-Fos expression and proliferating cell nuclear antigen (PCNA).
To examine the associated cellular mechanism we assessed the expression
of the brain-derived neurothrophic factor (BDNF) on the ventral
hippocampal dentate gyrus (DG). Moreover, we studied the formation of
Y1R-GALR2 heteroreceptor complexes with in situ proximity ligation assay
(PLA) and analyzed morphological changes on hippocampal neuronal cells.
Finally, the functional outcome of the NPY and GAL interaction on the
ventral hippocampus was evaluated in the forced swimming test, employing
the intranasal procedure that takes advantage of a direct nose-to-brain
transport of therapeutics.