Role of Sleep in Neurogenesis

Haja Nazeer Ahamed, N. Irfan, L. H. Thameemul Ansari, Y. Ismail,

Ubaidulla Uthumansha, Sathvik Sridhar, Javed Shareef,
Sabin Thomas, and Ashok Kumar Janakiraman

Contents
Insights into Neurogenesis: From Physiology to Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
The Captivating Dance of Neurogenesis: Unveiling the Physiology of Brain Renewal . . . . . . . . . 3
The Stage for Creation: The Neurogenic Niche . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
From Seed to Sprout: The Birth and Migration of New Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Building Bridges and Forging Connections: Integration and Maturation . . . . . . . . . . . . . . . . . . . . . 3
The Orchestra of Influences: Modulating the Dance of Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . 4
Sleep-Wake Cycle Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Action of Neuronal Assemblies in Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Sleep Deprivation Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Degrees of Insufficient Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Potential Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Sleep-Induced Neurogenesis in Hippocampus: An Independent Modulator for the
Hippocampal Neuronal Network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

H. N. Ahamed (*) · N. Irfan · Y. Ismail

Crescent School of Pharmacy, B S Abdur Rahman Crescent Institute of Science and Technology,
Chennai, Tamilnadu, India
e-mail: haja@crescent.education; irfan@crescent.education; ismailcsp@crescent.education
L. H. T. Ansari · U. Uthumansha
Department of Pharmaceutics, Crescent School of Pharmacy, B S Abdur Rahman Crescent Institute
of Science and Technology, Chennai, Tamilnadu, India
e-mail: thameemul@crescent.education; ubaidulla@crescent.education
S. Sridhar · J. Shareef
Department of Clinical Pharmacy & Pharmacology, Ras Al Khaimah College of Pharmacy, Ras Al
Khaimah Medical & Health Sciences University, Ras Al Khaimah, United Arab Emirates
e-mail: sathvik@rakmhsu.ac.ae; javedh@rakmhsu.ac.ae
S. Thomas
School of Pharmacy, College of Health Sciences, University of Nizwa, Nizwa, Oman
e-mail: sabin@unizwa.edu.om
A. K. Janakiraman
Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
e-mail: ashok@ucsiuniversity.edu.my

© Springer Nature Singapore Pte Ltd. 2024 1

E. Mohamed (ed.), Handbook of Neurodegenerative Disorders,
https://doi.org/10.1007/978-981-19-3949-5_37-1
2 H. N. Ahamed et al.

Mechanism of Neurogenesis in the Hippocampus and DG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Hypothalamic Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Hypothalamic Neuropeptides, Neurogenesis, and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Hypothalamic Neurogenesis and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Hypothalamic Neurogenesis in Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Conclusions and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Abstract
Genesis of the neurons in the brain is a cardinal process for brain development
from the embryonic stage to throughout the human lifespan. Two major zones of
the brain that are involved in neurogenesis are the subventricular (forebrain) and
sub-granular zone (dentate granule cell layer). Additionally, the Hypothalamus is
another region, that, acts as a smart control synchronizing center of the human
body and a source of neural progenitor cells. This book chapter describes and
illustrates the elements of neurogenesis, neurogenesis on mental health, hippo-
campal neurogenesis, and hypothalamic neurogenesis.

Keywords
Neurogenesis · Sleep · Stress · Neuropeptides · Hippocampus · Hypothalamus

Insights into Neurogenesis: From Physiology to Pathophysiology

The creation of a new neuron in the brain is called Neurogenesis and it is essential for
the development of an embryo, and it also persists in some parts of the brain long
after birth (Catlow et al. 2016). The immutable edifice of the adult brain, once
thought impervious to change, has undergone a transformative redefinition with the
revelation of adult neurogenesis. This intricate process involves the emergence of
nascent neurons from the chrysalis of stem cells, intricately weaving themselves into
the existing circuits of the brain (Zhao and Moore 2018). Once confined to the realm
of embryonic development, adult neurogenesis now bathes the mature mind in a
luminescence of perpetual renewal, with a particular effervescence observed in the
lush landscapes of the hippocampus. This groundbreaking discovery challenges and
rewrites the script of traditional notions surrounding brain plasticity, introducing a
paradigm where the adult brain is a dynamic and adaptable organ finely tuned to the
symphony of experiences. The metaphorical emergence of new neurons, akin to
saplings basking under a nurturing sun, encompasses the intricate ballet of sprouting,
migrating, and integrating into the complex network of existing neural pathways
(Zamproni et al. 2021).
As scientific exploration delves deeper into the caverns of neurogenesis, the
luminescence emanating from this phenomenon illuminates potential pathways for
understanding and addressing various facets of mental health, aging, and neurolog-
ical disorders (Ming and Song 2011). The once-static landscape of the adult brain
Role of Sleep in Neurogenesis 3

now shimmers with the possibility of therapeutic interventions, whispering promises

of minds not merely enduring, but flourishing with the echo of renewal. In this
reimagined conception of the brain, where neurons act as sculptors and experiences
serve as the chisels, the human mind emerges not as a static tableau but as a canvas
perpetually primed for the masterpiece of adaptation (Zaidel 2014). The narrative of
the brain transforms from a fixed entity to a dynamic and ever-evolving tapestry,
inviting a deeper appreciation for the resilience and adaptability inherent in the
human cognitive experience.

The Captivating Dance of Neurogenesis: Unveiling the Physiology

of Brain Renewal

The human brain, once thought to be a static organ frozen in time, now pulsates with
the dynamic rhythm of neurogenesis. The fascinating process of the brain’s excep-
tional ability to adapt and renew itself—the creation of new neurons from specialized
neural stem cells—unlocks the mysteries of brain plasticity.

The Stage for Creation: The Neurogenic Niche

The journey of a new neuron begins in a specialized haven within the brain called the
neurogenic niche. Imagine this niche as a lush, verdant garden, where neural stem
cells, like tiny gardeners, tend to the delicate dance of creation. Here, amid a
symphony of molecular signals and genetic instructions, these special cells undergo
a series of transformations (Peretto and Bonfanti 2015).

From Seed to Sprout: The Birth and Migration of New Neurons

Like seeds bursting forth in spring, neural stem cells divide, giving rise to immature
neurons. These fledgling cells, guided by a complex choreography of signals,
embark on a journey of migration. They navigate the intricate pathways of the
brain, seeking their place within existing neural networks (Urbán and Guillemot
2014).

Building Bridges and Forging Connections: Integration

and Maturation

Once they reach their destination, the new neurons begin the intricate task of
integration. They sprout delicate tendrils, forming synapses, the bridges of commu-
nication that connect them to their neighbors. Neurotrophic factors, akin to growth
hormones, nourish and guide these developing neurons, nurturing them into mature
members of the brain’s intricate circuitry (Doidge, 2007).
4 H. N. Ahamed et al.

The Orchestra of Influences: Modulating the Dance of Neurogenesis

The exquisite dance of neurogenesis is not a solitary performance. A multitude of

factors, like the rhythm of exercise, the vibrant tapestry of enriched environments,
and even the delicate interplay of neurotransmitters, can influence and modulate this
process (Grońska-Pęski et al. 2021). Understanding these influences holds immense
promise for the future of brain health.

A Symphony of Renewal: Implications for Brain Health and Beyond

As we delve deeper into the physiology of neurogenesis, we open the door to the
possibility of therapeutic approaches for a variety of illnesses, from neurological
abnormalities to the inevitable aging-related cognitive loss. By understanding how to
nurture the birth and integration of new neurons, we may 1 day be able to help brains
stay resilient and adaptable throughout life (Sailor et al. 2006). In essence, the
physiology of neurogenesis is not merely a biological process, but a testament to
the brain’s remarkable capacity for self-renewal. It is a story of resilience, of
adaptation, and of the enduring potential for the human mind to create, learn, and
grow, even in the face of time’s relentless march (Gu et al. 2020).

Sleep-Wake Cycle Modulation

Circadian rhythms regulate the rhythmic activities of sleeping and waking. Wake-
fulness is a condition in which perceptual-sensory and voluntary motor activity are
fully manifested. Sleep is distinguished by quick reversibility, decreased motor
activity, responsiveness, and metabolism, and is separated into two different, cycli-
cally repeated stages: The two types of sleep are non-REM and rapid eye movement
(REMS) (Schwartz and Roth 2008). Sleep is essential for learning, memory,
neurogenesis, oxidative stress reversal, immunological regulation, and neurogenesis,
according to research. The regulation of sleep-wake cycles can be explained by the
two-process model, in which the output of a circadian pacemaker is linked to one
process, which represents homeostatic sleep drive. When the two processes are
integrated, they establish the beginning and conclusion of the sleep phase: sleep is
initiated when homeostasis rises over a particular threshold, and awakening takes
place when it falls below a particular threshold (Abhilash and Shafer 2023). It is
assumed that the two thresholds are oscillated by the circadian rhythm daily.
An internal circadian clock found in the anterior hypothalamic suprachiasmatic
nucleus (SCN) controls the pattern of sleep and wakefulness. The SCN neurons
function as functional pacemakers because they are circadian oscillators. According
to Welsh et al. (2009), these oscillations are regulated by an intrinsic cellular
rhythmicity that lasts for a full day, even in the absence of external stimuli like
light, dietary patterns, and social surroundings.
Role of Sleep in Neurogenesis 5

Action of Neuronal Assemblies in Sleep

Despite the presence of an SCN biological clock, the global coordination of the
NREMS seems to be the product of an emergent characteristic of locally coupled
processes in neural networks. Cortical columns or neuronal assemblies are terms
used to describe anatomically defined neural networks. According to Fernandes et al.
(2015), neural assemblies are believed to represent the fundamental building blocks
of the brain’s processing during alertness, oscillating between functional states like
wakefulness and sleep. While most neural assemblies are in a wake-like state while
they are awake, most are in a sleep-like state when they are sleeping. In contrast,
neuronal assemblies in a wake-like state can happen during the whole alertness
period, whereas neuronal assemblies in a sleep-like state can happen during the
whole sleep phase. The brain assembly paradigm states that electrical and hormonal
interactions between assemblies are what generate synchronization (Krueger et al.
2008).
According to this model, states evolve throughout time as a result of threshold-
based transitions, interactions with other assemblies, and the distinctive behavior of
individual networks. Neural assemblies are quickly forced into sleep after achieving
a sleep-like state within individual neural networks (Nowak et al. 2017). The degree
of this response is correlated with each neural assembly’s connectivity. Concurrently,
neuronal assemblies react more quickly to signals from the circadian clock that
indicate the body should be sleeping, which induces sleep. According to computer
silico experiments, overstimulated neural assemblies will eventually enter a sleep-
like condition (Deolindo et al. 2018). This will cause neighboring neuronal assem-
blies to follow suit, ultimately leading to whole-animal slumber. Thus, our model
accounts for both the global sleep state’s genesis and the expanding characteristics of
specific networks.

Sleep Deprivation Investigations

Degrees of Insufficient Sleep

Sleep deprivation causes psychological and physiological alterations, affecting a

variety of cognitive areas including attention and working memory. In order to
evaluate the effects of sleep deprivation on neurogenesis, a number of studies used
experimental paradigms to disturb rodent sleep for varied lengths of time (Alhola
and Polo-Kantola 2007). Wakefulness is pushed in situations of whole or partial
sleep deprivation using a number of approaches, including gentle handling, forced
mobility in a gently spinning wheel, and putting rats on water-covered platforms.
The diversity of extra groups or experimental conditions accounted for effects
unassociated with sleep deprivation (like exercise or stress) (Alhola and Polo-
Kantola 2007).
6 H. N. Ahamed et al.

Potential Mechanism

It is yet unknown what the underlying mechanisms are that cause sleep deprivation
to negatively affect different stages of adult neurogenesis. Stress and related hor-
mones, particularly glucocorticoids, have been suggested to act as an independent
mediator of these effects (Meerlo et al. 2009). For instance, utilizing the small-
platform technique, rats who got too little sleep had significantly higher corticoste-
rone levels while experiencing slower cell proliferation. The decrease in dentate
gyrus cell growth was completely eliminated in adrenalectomized rats, which pro-
duce low levels of corticosterone (Guzmán-Marín et al. 2003).
These results are controversial because they go against previous studies that
found low levels of corticosterone to be necessary to maintain the anti-neurogenic
effects of sleep deprivation on the hippocampus. Moreover, low corticosterone
levels promote cell proliferation while high corticosterone levels limit cell develop-
ment (Egeland et al. 2017). Adult neurogenesis is influenced by a number of
molecular components, including cytokines, hormones, neurotransmitters, and tro-
phic factors. Many of these parameters are influenced by sleep deprivation,
suggesting a relationship between inadequate sleep and decreased hippocampus
neurogenesis (Fig. 1) (Alkadhi et al. 2013).
Serotonin, for example, stimulates hippocampus neurogenesis via the serotonin-
1A receptor. Serotonergic action is generally reduced during sleep, which may
explain why sleep deprivation has a suppressive effect on neurogenesis. However,
it’s possible that this decreased serotonergic activity during sleep (Negro et al. 2020)
is necessary for optimal serotonergic activity during wakefulness and, thus, could be

Fig. 1 A potential
mechanism of neurogenesis
Role of Sleep in Neurogenesis 7

essential for the impacts of waking experiences on neurogenesis. In rats, serotonin-

1A receptor system sensitivity is decreased by chronic sleep deprivation but not by
short-term sleep deprivation. Similar to this, a number of studies show that while
protracted sleep deprivation decreases hippocampal cell proliferation, acute sleep
deprivation has no influence on it (Novati et al. 2008).

Sleep-Induced Neurogenesis in Hippocampus: An Independent

Modulator for the Hippocampal Neuronal Network

Sleep has a pivotal role in maintaining the quality of life for the life span. It is
associated with various health benefits and maintaining good health including
mental health. Nerve cell longevity including increased cell proliferation and cell
survival is linked with sleep. On the contrary, sleeplessness including sleep depri-
vation, and sleep diminution is linked with the impediment of neuron proliferation
and survival (Mueller et al. 2015). Sleep has been demonstrated to trigger
neurogenesis in the subcortical area, where the neural stem and progenitor cells
give rise to new neurons from the early to adult stages of brain development
(Malykhin et al. 2010). Many extrinsic and intrinsic variables that impact the
maturation, specialization, and integration of the nerve population in the hippocam-
pal dentate gyrus influence the hippocampal neurogenesis (Toda et al. 2019). In both
adult humans and rodents, a reciprocal association has been shown between hippo-
campus neurogenesis and adequate sleep. In rat hippocampus dentate gyrus
neurogenesis, new proliferating neurons are present within the sub-granular zone
(SGZ) where it gets mature and transmutes into glutamatergic neurons (Cameron
and McKay 2001; Jiang et al. 2023). According to Navarro-Sanchis et al. (2017),
adult humans share the same neurogenesis pathway, and clinical data indicates that
mature neurons migrate into the striatum while overlapping neurogenic proliferation
occurs in the hippocampus SGZ. The typical physiological adaptations that include
learning and memory, cognitive function, and emotion regulation are therefore
influenced by the integration of mature neurons with other subcortical locations
(Tyng et al. 2017).

Mechanism of Neurogenesis in the Hippocampus and DG

The hippocampal dentate gyrus is a specific subcortical area for neurogenesis. In the
SGZ, a thin layer situated between the granular cell layer and the hilus of the
hippocampus formation, progenitor cells are actively converted into neurons, astro-
cytes, or oligodendrocytes (Kempermann et al. 2015). These progenitor cells are
transiently active in SGZ and proliferate to produce clusters of new cells in the
neurogenic area (Llorente et al. 2022). According to estimates, the dentate gyrus
produces 5000–9000 new cells every day. Rats using a variety of experimental
procedures have shown that hippocampus neurogenesis is up- and down-regulated
during the sleep-wake cycle (Van der Borght et al. 2009). Human growth hormone is
8 H. N. Ahamed et al.

one substance that shows sleep-facilitated release, and in certain species, lack of
sleep has a detrimental effect on neurogenesis. The formation of spines and func-
tional synapses in newly formed neurons is stimulated by neuron connections from
cortical and subcortical gateways (Leproult and Van Cauter 2009). The inhibitory
neurotransmitter gamma amino butyric acid (GABA) depolarizes immature neurons,
and this synaptic input is crucial for differentiation in neuronal proliferation and
differentiation.

Hypothalamic Neurogenesis

The hypothalamus is a deep and small structure that covers 1% volume of the brain
and is positioned under the thalamus. It is systematically divided into multiple
sub-regions, including some distinct nuclei and it participates in many central
regulations such as energy equilibrium, alertness, sleep, osmoregulation, hormonal
balance, temperature, and sexual behaviors (Stachenfeld 2008). Recent studies
proved that the hypothalamic progenitor/stem cell is principally involved in the
adult hypothalamic neurogenesis fabrication of neural circuits. Also, the neuropep-
tides secreted in the hypothalamus during the new neuron generation facilitate
embryonic and adult brain development (Fig. 2) (Plakkot et al. 2023).
Neoteric neuro-research evidence illustrates that newly generated hypothalamic
neurons pointedly play a role in the homeostasis of our body, specifically, controlling
body mass, metabolism, energy steadiness as well as social behaviors (Plakkot et al.
2023).

Fig. 2 Position of the thalamus, the hypothalamus of the brain

Role of Sleep in Neurogenesis 9

Hypothalamic Neuropeptides, Neurogenesis, and Regulation

Numerous peptides, including those involved in sexual control, are secreted by the
neuron population in several areas of the hypothalamus (Table 1). Important neuro-
nal function regulators include brain-derived neurotrophic factor (BDNF) and nerve
growth factor (NGF). A study found that BDNF infusion in adult rat lateral ventri-
cles stimulates the development of new neurons in the hypothalamus (Bathina and
Das 2015). Analogous research demonstrated that the formation of neural progenitor
and neural stem cells in the adult rodent brain is regulated by the proteins BDNF,
transforming growth factor α, VEGF (vascular endothelial growth factor),
neurotrophic factor (CNTF), and FGF2 (Bath and Lee 2010) (Table 2).
In the hypothalamic neurogenic cascades, Evans et al. first, reported the hypo-
thalamic immature mitotic neurons and the hypothalamic neurogenic niche was
observed in the lining of the ventral portion (third ventricle). The adult age third
ventricle surface becomes a neurogenesis source and a high number of immature
neuron migrations are spotted in the niche region of hypothalamic neurogenesis.
These hypothalamus migrating neurons modulate the brain plasticity and web the
brain’s functional circuits (Hussain et al. 2024).

Table 1 Medication and antidepressant medications that have an impact on neurogenesis

Medication Treatment schedule Results
Hypnotic drug: Twice a day; 2 days for acute Acute tests showed that the
Zolpidem experiment and 21 days for hilus was larger than the SGZ
chronic experiments and that cell proliferation was
reduced in both young people
(10–15%) and the elderly
(30–40%). Young mice’s SGZ
cell survival decreased slightly
as a result of the long-term
experiment, while it increased
slightly in older mice
(Methippara et al. 2010)
Psychostimulant drugs: Given to rats which were Barred waning in neuronal
Modafinil or Caffeine completely sleep deprived proliferation and
for 2 days differentiation later sleep
deficit (Bishir et al. 2020)
Medications that treat Electroconvulsive seizures While several kinds of
depression have been investigated on antidepressants enhance
Tricyclic antidepressants adult male Sprague-Dawley proliferating cells by 20–40%,
(TCA), selective serotonin (SD) rats chronic treatment for
reuptake inhibitors (SSRI), electroconvulsive seizures
and monoamine oxidase boosts cell proliferation by
inhibitors (MAOI) 50% (Malberg et al. 2000)
Haloperidol is a Adult male SD rats test The long-term use of the
non-antidepressant medications did not
psychotropic medication substantially alter the quantity
of BrdU-positive cells (Gilbert
et al. 2005)
10 H. N. Ahamed et al.

Table 2 Neuropeptide synthesized in different hypothalamus parts and its function

Hypothalamus
regions/neurons Neuropeptide Function
The arcuate nucleus NPYa, AgRP, and anorexigenic Food intake
of the hypothalamus peptides, POMC (Huang et al.
2021)
Ventromedial Substance P, enkephalins, Sexual behaviors and analgesia
nucleus, Medio and NPY
basal
(MB) hypothalamus
The periventricular producing corticotrophin-releasing Blood circulation
part and supraoptic hormone (CRH), TRH, oxytocin,
nuclei and vasopressin (Ferguson et al.
2008)
Lateral Orexin, Melanin-concentrating Regulation of sleep/wakefulness
hypothalamic area hormone (MCH) (Skrapits et al.
(LHA) 2015)
Hypothalamic Crh+ Galanin Primarily responsible for
neurons regulating the body’s reactions to
stress, including eating (Corradi
et al. 2022)
a
NPY Neuropeptide Y, AgRP Orexigenic agouti-related peptide, POMC Proopiomelanocortin

Hypothalamic Neurogenesis and Sleep

The hypothalamus plays a crucial role in mammals’ most important physiological

function “sleep” through the neuropeptide-producing neurons. Orexin neurons pro-
duce the orexin which is responsible for sleep and lack of orexin/hypocretin-
producing neurons (orexin neurons) cause narcolepsy (sleep disorder) (Singh and
Biswas 2023). Orexin A peptide is composed of 33 amino acid residues (Fig. 3a),
and orexin B peptide (Fig. 3b) is composed of 28 amino acids. Orexin neurons/
receptor inhibition (Fig. 3c) by light or antagonist during the night causes time-of-
day-dependent NREM sleep initiation. Another lateral hypothalamic area (LHA)
neuron is an MCH (Melanin-concentrating hormone) producing neuron that is also
linked to sleep/wakefulness management (Konadhode et al. 2015).
To be more precise, these neurons that produce MCH are dormant during awake
and activate during sleep (España and Scammell 2011). The anterior hypothalamic
rostral γ-aminobutyric acid (GABA)-ergic cells are less active during non-REM
sleep and more active during REM sleep or wakefulness (Fig. 4) (Siegel, 2004).

Hypothalamic Neurogenesis in Stress

Acute and chronic stress is one of the forceful environmental factors that modify
brain function, neuron generation (neurogenesis), and brain structure. In
Role of Sleep in Neurogenesis 11

Fig. 3 (a) Secondary structure of Orexin A peptide with sequence; (b) secondary structure of
Orexin B peptide with sequence; (c) secondary structure of Orexin receptor

particular, it lessens the production of fresh neural or precursor neurons in the

human, sheep, and mouse hypothalamic neurogenic niche of the brain (McEwen
et al. 2016). Early life stress (ELS) is a factor that has a direct correlation to
changes in the population of new neurons in the hypothalamus later in life. In their
study of chronic ELS, Pascal Bielefeld et al. (2021) found that mice’s hypothal-
amus area showed suppression of neurogenesis. Reduced levels of β-tanycytes are
observed in the hypothalamus, while proliferating cells are found in the paren-
chymal portions of the third ventricle (Bielefeld et al. 2021). Also in ME, a strong
drop in Nestin-GFP+/Sox2+ cell proliferation. These results conclude that the
ELS produced long-term effects in the ventral parenchymal areas of cell
proliferation.
Alonso et al. 2023 reported two factors (corticotrophin-releasing factor (CRF)
and vasopressin (AVP)) crucially involved in controlling the stress response through
synergizing the CRF1 and V1b receptors (Fig. 5a, b). The blockade or antagonizing
of these two receptors will be the specific target for the patient suffering from stress
(Beurel and Nemeroff 2014).
12 H. N. Ahamed et al.

Fig. 4 Hypothalamic neurons involved in the different stages of sleep stages. *NREM-Non–rapid
eye movement, REM- Rapid eye movement

Fig. 5 (a) Secondary

structure of corticotropin-
releasing hormone receptor 1;
(b) Secondary structure of
Vasopressin V1b Receptor
Role of Sleep in Neurogenesis 13

Conclusions and Perspectives

Research reports of the last two decades concluded that the hypothalamic
neurogenesis and organization of neural networks are modified periodically based
on different stimuli such as sleep and stress. In this context, various hypothalamic
neuropeptides and receptors are involved in the management of homeostasis of the
human body, importantly, sleep and stress. In this AI era, designing and developing
binding site pharmacophoric group-based inhibitors for orexin and MCH-producing
receptors will be the potent treatment of various sleep disorders. Similarly, CFR and
V1b receptor-based drug design will increase the neurogenesis in the hypothalamus
leading to the modification of the neural circuit of stress management.
Most of our understanding of adult neurogenesis derives from studies conducted
in labs using animal models. Despite the technical difficulties of measuring new
neurons in live subjects, adult neurogenesis has been proven in humans. Taking into
consideration all the animal model studies that are discussed in this article, there are a
number of problematic and inconsistent results. Given that each species’ unique
characteristics, both genetic and individual, may influence neurogenesis and sleep
regulation, results achieved with certain species and under particular experimental
settings cannot be repeated in other species. Thus, animal model studies of
neurogenesis must be expanded to obtain more strong conclusions on the underlying
processes of sleep’s modulatory effects on neurogenesis.
More investigation is required to determine the anti-neurogenic effects of sleep
deprivation on various hippocampal regions, given the evidence of functional
differentiation of diverse hippocampus subfields. In order to fully comprehend the
functional implications of neurogenesis, it is also critical to look into how sleep
deprivation affects neurogenesis in other parts of the brain. The effects found in the
basal rate of cell development in REMS vs. NREM deprivation must also be
replicated to establish more compelling results. It is imperative to comprehend the
neuro-genic connection among sleep, learning, hippocampus-dependent memory,
and mood disorders. Additionally, human clinical trials are necessary to explore the
functional consequences of increased neurogenesis resulting from antidepressant
treatment. Determining whether neurogenesis in MDD patients is linked to behav-
ioral and molecular responses to antidepressant treatments is crucial (Boas et al.,
2019; Duric and Ronald, 2013; Park, 2019). Lastly, since adult human neurogenesis
may have unidentified side effects that have an impact on other cognitive and
affective processes, the negative hypnotic effects of neurogenesis need to be under-
stood and assessed in humans.
The idea that neuronal neurogenesis stops at puberty seems to be fading in light of
the adult brain’s flexibility and ability to change structurally in response to experi-
ence. While adult neurogenesis appears to be limited or nonexistent in other areas of
the central nervous system, it is now thought to continue actively throughout life in
the SVZ and SGZ of the hippocampus dentate gyrus. In non-neurogenic tissues,
neurogenesis can occur after pathogenic stimulation, including brain injury.
Although research on adult human neurogenesis is still in its early stages, data
14 H. N. Ahamed et al.

from animal models suggests that hippocampus plasticity may be influenced by

newly formed neurons in adulthood.
Adult neurogenesis in rats reduced by the chronic sleep disruption. Conversely,
brief sleep deprivation seems to promote cell growth and survival. Prolonged sleep
deprivation can damage the integrity of the hippocampal formation and ultimately
cause cognitive impairment, which can exacerbate mood disorders and other medical
conditions. Whether adult neurogenesis contributes to this kind of regulation is yet
unknown. Therefore, addressing adult neurogenesis during sleep disorders could be
a promising strategy to reverse the possible negative effects of chronic sleep
disorders on emotional and cognitive functioning.

Cross-References

▶ An Understanding of Different Mechanisms Leading to Neurodegenerative

Diseases
▶ Mechanisms of Neuronal Apoptosis and Excitotoxicity
▶ Mitochondrial Transplantation as a Newer Therapeutic Approach for Neurode-
generative Diseases
▶ Neuroinflammation & Microglial Activation in Schizophrenia: An Overview
▶ Nutrition and Brain Neurotransmitters
▶ Three Neurodegenerative Diseases: A Single Hope

Competing Interests The authors declare that they have no known competing interests that could
have appeared to influence the work reported in this paper.

Ethics Approval No animals were used in this work.

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