Physiology & Behavior 227 (2020) 113136

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Physiology & Behavior

journal homepage: www.elsevier.com/locate/physbeh

Noise and brain T

Archana Arjunan (Research Scholar), Ravindran Rajan (Associate Professor & Head)
⁎

Department of Physiology, Dr. Arcot Lakshmanaswami Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai –
600 113, India

ARTICLE INFO ABSTRACT

Keywords: Noise has become inexorable stress due to the increase in urbanization, automobile usage, Noise based occu­
Antioxidants pation, and lifestyle modifications such as recreation in day to day life of an individual. Noise not only affects the
Cognition auditory system but can also debilitate other non-auditory systems as evidenced in animal and human models.
Epigenetics Various studies have reported that noise has the potential to tarnish the Central Nervous System in hetero­
Neurotransmitter
geneous ways. This article reviews the researches on Noise and Brain with the spotlight on the effect of noise on
Noise
Stress
health that includes a) noise-induced impaired cognition on neurobehaviour, b) brain areas which are pre­
dominantly affected by the noise-induced oxidative stress, c) alteration of the neurotransmitter level in various
brain regions, d) alteration of the molecular mechanism induced by noise stress on brain cellular level, e) Noise-
induced deterioration of the morphological structures of brain and f) epigenetic modification by noise on brain.

1. Introduction 2. Noise and antioxidants

Noise is considered as a common environmental pollutant that is
more than just a nuisance. It constitutes a danger that is real to people's
health by producing both physical and psychological stress [29]. Ac­
cording to the World Health Organization (WHO), noise is considered
as the second highest environmental stressor from the public health
perspective [15]. In modern lifestyle, application of various auto­
mobiles, urban traffic, household appliances, media [23], in­
dustrialization, using weapons in Military and Army forces have in­
creased the noise stress/ pollution to the individuals who are working
in such environment [27]. Noise is described as an unwanted sound,
that is either chronic or intermittent, and can be described in terms
including its frequency, intensity, frequency spectrum, and shape of
sound pressure through time [7]. If the level of noise exceeds 90 decibel
dBA it becomes a source of stress [67] and affects the health in both
physical and psychological perspectives. Various studies suggest that
noise can delimitate the cellular homeostasis in Hearing [27], immune
system [66], Nervous system [5,7,67], sleep disturbances [5] and
Cardiovascular System [5,23].
In this review, the focus has been emphasized on the effects of noise
especially in the impairment of the CNS via increased oxidative stress,
imbalance in neurotransmitter level, altered cellular cytoarchitecture
by the detoriatiation of the molecular functions, impaired cognition,
and genetic modification.
2.1. Relationship between oxidative stress and antioxidants in noise stress
Oxidative stress refers to the cytopathological consequences of the
mismatch between the production of free radicals and the ability of the
cells to defend against them. Free radicals are normal products of cel­
lular aerobic metabolism. Superoxide (o-) and hydroxyl (OH'),
Hydrogen peroxide (H2O2), and peroxynitrite (ONOO-) have an im­
portant contribution to the cellular redox state. These molecules are
referred to as reactive oxygen species (ROS). The major sources of ROS
are mitochondrial oxidative metabolism, enzymatic reactions involving
mixed-function oxidation, and autoxidation of small molecules [63].
Oxidative stress originating from outside the body is a feature of life in
the modern world. Negative lifestyle patterns can be ominous and can
also converge with environmental stressors to attack the health of the
living organisms through related oxidative pathways [30].
To reduce the burden of oxidative stress, the body produces anti­
oxidants that are either generated by endogenous (enzymatic and non-
enzymatic antioxidants) or exogenous mechanisms. The major anti­
oxidant enzymes that are directly involved in the neutralization of ROS
and RNS are superoxide dismutase (SOD), catalase (CAT), glutathione
peroxidase (GPx) and glutathione reductase (GRx). The non-enzymatic
antioxidants are also divided into metabolic antioxidants and nutrient
antioxidants. Metabolic antioxidants are endogenous antioxidants,
produced by metabolism in the body, such as lipoic acid, glutathione, L-

⁎
Corresponding author.
E-mail address: ravindran89@gmail.com (R. Rajan).

https://doi.org/10.1016/j.physbeh.2020.113136
Received 25 December 2019; Received in revised form 13 July 2020; Accepted 11 August 2020
Available online 14 August 2020
0031-9384/ © 2020 Elsevier Inc. All rights reserved.
A. Arjunan and R. Rajan Physiology & Behavior 227 (2020) 113136

arginine, coenzyme Q10, melatonin, uric acid, bilirubin, metal-che­
lating proteins, transferrin, etc. Nutrient antioxidants are exogenous
antioxidant natured compounds which cannot be produced in the body
and must be provided through food or supplements, such as vitamin E,
vitamin C, carotenoids, trace metals (selenium, manganese, zinc), fla­
vonoids, omega-3, and omega-6 fatty acids, etc. [52].
Overproduction of free radicals and ROS can cause oxidative da­
mage to biomolecules, leading to various chronic diseases such as
atherosclerosis, cancer, diabetes, rheumatoid arthritis, post-ischemic
perfusion injury, myocardial infarction, cardiovascular diseases,
chronic inflammation, stroke and septic shock, aging and other de­
generative diseases in humans [4]. In comparison to all the other sys­
tems, the brain is considered to be the most vulnerable organ that can
be subjected to free radical damage due to peroxidation, and this fea­
ture is due to its highest percentage of unsaturated fats which is en­
ormously supplied with molecular oxygen [39] and lower antioxidant
activity when compared to other tissues [4,31,70].
Various studies have evidenced that noise stress instigates increased
ROS and RNS generation which are capable of breaching lipid and
protein molecules and damaging DNA thereby triggering the loss of
function and leading to cell death following the noise exposure
[39,48,67].
2.2. Lipid peroxidation (LPO)
Lipid peroxides are an important class of biomolecules generated by
oxidative stress in cells [24]. The complex process of lipid peroxidation
involves the interaction of oxygen-derived free radicals with poly­
unsaturated fatty acids and finally results in a variety of highly reactive
electrophilic aldehydes that are capable of easily attaching covalently
to proteins by forming adducts with cysteine, lysine, or histidine re­
sidues. Among the aldehydes formed, malondialdehyde (MDA), 4-hy­
droxynonenal (HNE), and acrolein represent the major products of lipid
peroxidation which affect the glutamate level in brain [70] Numerous
studies have confirmed that acute stress and sub-acute stress have in­
creased the LPO level in discrete regions of the brain (Table 1). No
deviations in the LPO level were reported between animals exposed to
chronic noise stress and naïve animals [57] and also Manikandan et al.,
reported that the presence of increased LPO in Hippocampus and
medial Prefrontal Cortex in chronic stress-induced animals [39].
2.3. Nitric oxide (NO) and hydrogen peroxide (H2O2)
NO is a highly reactive signal molecule in the CNS. It is a unique
messenger molecule that serves various physiological functions
throughout the body [67]. Table 1 showed that during sub-acute noise,
the NO and H2O2 levels were increased in various discrete brain regions
in rats [67]. Elevated NO indicates increased nitrosative stress, leading
to cell degeneration and necrosis by causing inhibition of mitochondrial
cytochrome oxidase in neurons [76].
H2O2 is capable of serving as a messenger to carry a redox signal
from the site of its generation to a target site. Among the various oxygen
metabolites, H2O2 is considered as the most suitable messenger for
redox signaling. Hydrogen peroxide modulates the activity of tran­
scription factors: in mammalian cells (AP-1, NRF2, CREB, HSF1, HIF-1,
TP53, NF-κB, NOTCH, SP1, and SCREB-1) [62].
2.4. Superoxide dismutase (SOD)
SOD, the first line of defense against free radicals, catalyzes the
dismutation of superoxide anion radical (O2•ˉ) into hydrogen peroxide
(H2O2) by reduction [52]. There are three distinct isoforms of SOD
(1,2,3) that have been identified. SOD1 and SOD2 are mainly involved
in the elimination of O2 - in the cytosol and mitochondria, respectively
[31]. Table 1 shows a remarkable increase in SOD in discrete brain
regions of noise stress group animals. SOD is an important enzyme fa­
mily in living cells for maintaining normal physiological conditions and
for coping with stress by protecting the biological integrity of the cells
and tissues against harmful effects of superoxide free radical [49].
2.5. Glutathione peroxidases (GPX)
Table 1 shows that acute subacute and chronic noise stress increased
the GPx in discrete regions of the brain. GPX contains a family of
multiple isoenzymes (GPX 1–8) which catalyze the reduction of H2O2
and lipid peroxides utilizing GSH as an electron donor. GPX is located in

Table 1.
Noise stress and antioxidant level in Brain.
S.No Model Noise Stress Antioxidant Brain Regions References

1 Wistar albino/ Acute (100 dB-4 h / 1 Day) SOD, CAT, GPx, GSSH, LPO Increased in CC, CB, Midbrain, Pons, Medulla, HY, HI [57]
Male GSH, GSH/GSSH Ratio,Protein thiols Decreased inCC, CB, Midbrain, Pons, Medulla, HY, HI
Sub acute Stress (100 dB-4 h/ 15 Days) SOD Increased in Midbrain, Medulla, Pons, Hippocampus
CAT Increased in CC, CB, Midbrain, HY
GPx, GSSH Increased in CC, CB, Midbrain, Pons, Medulla, HY, HI
GSH,GSH/GSSH Ratio, Protein Thiols Decreased in CC, CB, Midbrain, Pons, Medulla, HY, HI
LPO Increased in CB, Pons, Medulla, HY, HI
Chronic Stress (100 dB- 4 h/30 Days) SOD Increased in Midbrain, Pons, Medulla
CAT Increased in CC, Midbrain
GPx Increased in CB, Pons, HY
GSH, GSH/GSSH, Protein thiols Decreased in CC, CB, Midbrain, Pons, Medulla, HY, HI
GSSH Increased in CC, CB, Midbrain, Pons, Medulla, HY, HI
LPO Not deviate from the control in any regions of brain
2 Wistar albino/ Sub acute Stress (100 dB-4 h/ 15 Days NO, LPO, Vit- C, GST, GPx, SOD Increased in CC, CB,CS,BS,HY,HI [67]
Male CAT Increased in CC, CB,CS,HY,HI
Protein Thiols, GSH, GR, Decreased in CC, CB,CS,BS,HY,HI
3 Wistar albino/ Sub acute Stress (100 dB-4 h/ 15 Days H2O2,NO,LPO,SOD,CAT,GPx,GST Icreased in CC, CB,CS,BS,HY,HI [38]
Male Protein Thiols, GSH, GR, Vit-C, Vit-E Decreased in CC, CB,CS,BS,HY,HI
4 Wistar albino/ Chronic stress 100 dB-4 h/1,15,30 Days SOD, GPx, CAT, LPO Increased in HI, mPFC [40]
Male GSH Decreased in HI, mPFC
5 Mice 80 dB-2 h/Day 1wk / 3 wk MDA 1 Wk – Increased MDA in HI [10]
3 Wk – Increased MDA in HI & AC
SOD 1 Wk – Decreased in HI
3 Wk – Decreased in HI & AC

CC- Cerebral Cortex, CB – Cerebellum, CS – Corpus Striatum, BS – Brain Stem, HY – Hypothalamus, HI – Hippocampus, AC- Auditory Cortex, mPFC- medio Pre Frontal
Cortex.

2
A. Arjunan and R. Rajan
both cytosol and mitochondria. GPX1 has been regarded as one of the
major antioxidant enzymes in the brain, which is expressed pre­
dominantly in microglia but not in neurons, and up-regulation of GPX1
could be one of the protective responses against neuronal injury [31].
2.6. Catalase (CAT)
Table 1 shows that acute, subacute, and chronic noise stress in­
creased the catalase in discrete regions of the brain. Catalase is re­
sponsible for the conversion of H2O2 to water and oxygen using either
iron or manganese as a cofactor. It is located in peroxisomes and is also
found in the cytoplasm and mitochondria. The role of catalase is minor
at low levels of H2O2 but becomes increasingly important at higher
levels of H2O2 [31].
2.7. GSH
Glutathione reductase, a flavoprotein enzyme, regenerates GSH
from GSSG, with NADPH as a source of reducing power [52]. Glu­
tathione (γ-glutamylcysteinyl glycine, GSH) is a sulfhydryl (-SH) anti­
oxidant, antitoxin, and enzyme cofactor. It exists in two forms: 1. The
antioxidant “reduced glutathione” (GSH), 2. The oxidized form “glu­
tathione disulfide (GSSH). The GSH/GSSH ratio can serve as a sensitive
indicator of oxidative stress. GSH plays a major role in several biolo­
gical functions such as protein synthesis, enzyme catalysis, transmem­
brane transport, and cell maturation [30]. Several studies have reported
that GSH is involved in inhibiting apoptotic cell death and DNA damage
in cells [31]. GSH level and GSH/GSSH ratio were found to be de­
creased in various brain regions when rats were exposed to acute,
subacute, and chronic noise stress (Table 1).
2.8. Vitamin E and vitamin C
When animals are exposed to subacute noise, the stress decreases
the vitamin E and vitamin C in various brain regions [76]. Vitamin E is
a lipid-soluble antioxidant that can attenuate the effects of peroxide and
protect against lipid peroxidation in cell membranes [31]. Vitamin C
also known as ascorbic acid is a water-soluble vitamin. It is essential for
collagen, carnitine, and neurotransmitters biosynthesis [52] and is in­
volved in the removal of free radicals by electron transfer and can also
act as a cofactor for antioxidant enzymes [31].
3. Noise and neurotransmitters
Efficient communication among a large number of brain cells (i.e.,
neurons) is necessary for the normal functioning of the nervous system.
It involves the release of neurotransmitters that bind to specialized
receptors on the target cell, changing its activity and it can be divided
into three classes: (1) amino acids (e.g., γ¬aminobutyric acid [GABA],
glycine, and glutamate); (2) biogenic amines (e.g., serotonin, dopa­
mine, norepinephrine, epinephrine, and histamine); and (3) other (e.g.,
acetylcholine, adenosine triphosphate, and adenosine) [72].
This review emphasizes that noise alters the neurotransmitter level
in the experimental rat brain. Various studies have reported that
Oxidative stress can alter the neurotransmitter synthesis in neurons,
and also numerous neurotransmitter systems are sensitive to ROS, in­
cluding adrenergic, dopaminergic, serotonergic and GABAergicsystems
[55]. The effects of ROS on neurotransmission can occur via various
mechanisms.
3.1. Glutamate
Glutamate is the excitatory neurotransmitter that is present in the
majority of synapses throughout the brain and spinal cord and acts on
metabotropic and inotropic receptors including the NMDA receptors. It
excites all CNS neurons and is generally present at millimolar
3
Physiology & Behavior 227 (2020) 113136
concentrations which when exceeded can be lethal to neurons [11,34].
Table 2 shows that chronic noise increases the Glutamate level in
hemicerebrum. Kumar et al. stated that glutamate induces LTP by
NMDAR activation and Ca2+ influx. When Glutamate concentration
becomes excess Ca2+ reversibly increases ROS, which leads to in­
hibition of LTP [34].
3.2. Acetylcholine
Acetylcholine (ACh) is a fast-acting, point-to-point neurotransmitter
at the neuromuscular junction and autonomic ganglia. ACh appears to
act as the primary excitatory neurotransmitter in the periphery [53]. It
modulates various physiological functions and is also involved in
mammalian stress reactions. ACh is hydrolyzed by the enzyme known
as Acetylcholinesterase [64]. ChE is involved in cell proliferation, dif­
ferentiation, responses to stress, and amyloid formation. Activation of
ACh in the brain depends on the nature of stress and its duration [16]
and also if the stress is predictable type then I can also increase the
AChE activity in the brain.
3.3. GABA
GABA is a primary inhibitory Neurotransmitter in CNS and it acts as
modulation of anxiety-like behavior [47] and is protective against
oxidative stress [34,55]. During chronic noise exposure, the GABA level
in hemicerebrum was found to be decreased in Sprague-Dawley rats
[14]. Noise increases H2O2 and reduces the GABA level by a) a sus­
tained increase in [Cl-]i, b)Desensitization of GABA receptors c) H2O2
directly or indirectly acts on GABAA [55] and also that Increased NO
inhibits the tonic and phasic GABAergic response in the hippocampus
[34].
3.4. Catecholamines
The relationship between catecholamine and stress is intertwined.
There are three distinct peripheral catecholamine systems, each with
different effectors, regulation, and roles. The three systems are the
sympathetic nervous system, adrenomedullary hormonal system, and
DOPA-dopamine autocrine/paracrine system. Both the peripheral
sympatho-adrenomedullary and central catecholaminergic systems are
activated by various psycho-social and physical stressors [18]. During
the stress activation of sympathoadreno medullary and Hypothalamic
–Pituitary – adrenal axis system [28,75,76], increased the production of
Corticosterone and Catecholamines [28,73]. Adrenal steroids bind with
the neurons by Type I and Type II glucocorticoid receptors [6]. Chronic
exposure of Glucocorticoid receptors in the brain results in the in­
creased release of serotonin and glutamate which may interact pre-or-
post-synaptically and can thereby facilitate the destructive effects in the
brain [51]. Enormous studies revealed that noise stress increased the
corticosterone and catecholamines [5,7,14,32,48,75] and also corti­
costeroids were found to increase catecholaminergic and cholinergic
activity in the brain [19,26]. Norepinephrine is a catecholamine. Nor­
adrenergic neurons project bilaterally from the locus ceruleus along
distinct pathways to many locations, including the cerebral cortex,
limbic system, and spinal cord, forming a neurotransmitter system.
Norepinephrine is released when a host of physiological changes are
activated by a stressful event. The effects of Norepinephrine are alert­
ness and arousal, and influences on the reward system [46]. Noise stress
also exhibited significant elevation of CA in various regions (Table 2). It
may be due to the following factors: 1) Noradrenergic pathways and
adrenergic receptors located from various regions of brain and 2) Ge­
netic manipulation of NE system that increases NE neurotransmission
and protects animals from stress [46].
 A. Arjunan and R. Rajan

Table 2.
Noise and Molecular mechanism in brain.
S.No Model Noise Stress Methods Molecules Regions Remarks Reference

1 Wistar / Male Sub acute stress 100 dB- ELISA TNF-α,IL-2, IF-ɣ Increased in CC, CB, HI neuronal damage [75]
4 h/15 Days
NF-κB Increased in CC, CB, HI
Hsp 70 Increased in CC, CB, HI
IL-4 Decreased in CC, CB, HI
DNA Fragmentation Increased in CC, CB, HI
2 Wistar /Male Chronic stress 100 dB- ELISA Aβ, Aβ1–40, Aβ1–42, APP, β- Increased in HI Aβ accumulation & AD [12]
4 h/28 Days secretase, ɣ- secretase
Western Blot APP, GFAP, IBA1
RT-PCR APP mRNA
ELISA TNF-α & RAGE Increased in HI
Activin A & PDGF-AA Decreased in HI

4
3 Wistar /Male 100 dB- 4 h/14Days Western Blot PS202, PS396,PS404, and PS422 Increased at 0,3,and 7 days after exposure of noise Decreased at 14th day of noise [14]
in HI
4 Sprague/ Male Acute Noise (100 dB – PCR CRH, CRH-1, CRH-2 Acute – Downregulate CRH-R1 & CRH-R2 Increased CRH mRNA expression [21]
4 h/ 1 day)
Chronic Noise (100 dB- Chroni– Upregualte $pCRH-R1 & downregulate CRH-R2
4 h/30 days)
5 Mice 80 dB-2 h/Day$p1 wk / 3 WB Tau Phosphorylation 1 wk – Increased non-phosphorylated tau at Ser195/198/199/202 & decreased Hyperphosphorylation in HI [10]
wk phophorylated tau at Ser396 epitope in HI$pNo change in AC
3 wk - Increased non-phosphorylated tau at Ser195/198/199/202 & decreased
phophorylated tau at Ser396 epitope in HI & AC
6 Mice/Male 80 dB – 2 h/ six weeks WB SYN, PSD - 95 Reduced expression in CC, HI Impaired Cognition [73]
PCR BDNF mRNA Reduced epression in HI & PFC

dB- decibel, TNF-α – Tumour Necrosis Factor – α, IL −2 – Interleukins 2, IF-ɣ - Interferon- ɣ, NF-κB- nuclear factor kappa-light-chain-enhancer of activated B cells, Hsp 70 – Heat Shock Protein 70, nNOS-, Aβ- Amyloid β,
APP- Amyloid Precursor Protein, GFAP - Glial fibrillary acidic protein, BDNF- Brain-derived neurotrophic factor, PSD-Post Synaptic Density, IBA1- Ionized calcium Binding Adaptor molecule 1,PDGF-AA – Platelet Derived
Growth Factor, CRH – Corticotrophin Releasing Hormone, ELISA –Enzyme Linked Immunosorbent Assay, WB-Western Blot, RT-PCR – Real Time polymerized Chain Reaction.
Physiology & Behavior 227 (2020) 113136
A. Arjunan and R. Rajan Physiology & Behavior 227 (2020) 113136

Fig. 1. When noise reaches the brain via the auditory pathway initiates the secretion of Cotricotrophin Releasing Hormone (CRH) by the Paraventricular Nucleus of
the hypothalamus (PVN). CRH act on corticotrophs cells of the anterior pituitary and its synthesis andrenocorticotrophic normone (ACTH) which enter into cir­
culation, reaches adrenal gland. Adrental cortex synthesizes corticosteroids (CORT). Ehen the CORT level increses it binds to the Type I & Type II glucocorticoid
receptors present in neurons, follows various inflammatory pathways such as TNF-α, NF-κB. Activation of Proinflammatory cytokins, oxidative stress which alerts the
neutrotransmitter synthesis, secretion, and neurotoxicity. Excess free redicals and inflammatory cytokines cause Neurofibrillary tangels formation (NFT), shrinkage
of dendrites in soma, decreased mRNA procduction, DNA methylation, and DNA fragmentation in nucleus leads to impairs Long term potentiation (LTP), cognition
and neurodegeneration.

4. Noise on molecular level in brain
Various studies have enumerated that stress can delimitate the
molecular level in a living organism. This review explains how noise
can alter the molecular mechanism in the brain. Limited studies denote
that noise disrupts the neuronal cell function by molecular level
(Fig. 1).
Wankhar et al. reported that sub-acute noise significantly increased
pro-inflammatory cytokines such as Interleukin-2 (IL-2), Interferon- γ
(IF-γ), Tumor necrosis factor- α (TNF- α), decreased anti-inflammatory
IL-4 cytokine, and increased Nuclear factor - κB (NF-KB), Heat shock
protein 70 (HSP 70) secretion in the cerebral cortex, cerebellum and
hippocampus [75]. TNFα is considered to be a “master regulator” of
pro-inflammatory cytokine production and can be synthesized in the
microglia, astrocytes, and by some populations of neurons [41,50].
Activation of TNF signaling through TNFR1 and TNFR2 can activate the
number of intracellular signaling pathways including nuclear factor
kappa –B (NF-κB), p38, C-jun N-terminal kinase (JNK) and the cer­
amide/sphingomyelinase signaling pathway, resulting in various re­
sponses including inflammation, proliferation, cell migration, apop­
tosis, necrosis [41], inhibition of long term potentiation, accumulation
of Aβ and decreased two neuroprotective cytokines such as activin A
and Platelet derived growth factor (PDGF-AA) during chronic noise in
the hippocampus [12].
Activin βA, a member of the TGF-β superfamily regulates the late-
long term potentiation (L-LTP) induction, morphology of dendritic
spines, and neurogenesis. It also has a neuroprotective function [1].
Activation of PDGF indirectly inhibits N-methyl-D-aspartate (NMDA)
[12]. During Noise, a low level of PDGF expression can cause Glutamate
excitotoxicity and neurodegeneration. Glial fibrillary acidic protein
(GFAP), an astrocyte marker, can help astrocytes maintain their me­
chanical strength and shape and participates in processes linked to cell
movement and structure and plays a vital role in astrocyte-neuron
communication [17]. Ionized calcium-binding adapter molecule 1 (Iba-
1) is involved in the membrane ruffling and phagocytosis and are ex­
pressed centrally by microglia and infiltrating macrophage [8].
HSPs are a family of functionally-related proteins, these are in­
volved in the cellular repair by re-folding the proteins to act as mole­
cular chaperones in physiological processes [75]. The stress activation
of the Hypothalamo pituitary adrenal (HPA) axis and sympathoadreno
medullary system leads to increased Catecholamine levels which ele­
vate the immunosuppressive hormones glucocorticoids and activation
of inflammatory cytokines [75]. Altered cytokine secretion increases
the inflammatory cytokine on exposure to noise which can result in the
neuroinflammation with reactive oxygen/nitrogen species (RONS)
playing a major role in eliciting neuronal DNA smear pattern in the
brain [76]. Gai et al. reported that the long-term noise exposure causes
significant and persistent abnormalities in the corticotropin-releasing
factor (CRF) signaling system and the hyperphosphorylation of tau in
the hippocampus [23]. The CRF system plays a major role in the co­
ordination of neuroendocrine and neuropsychiatric responses to stress.
It consists of CRF and its receptors, CRFR1 and CRFR2. CRF and its
receptors are found in the hippocampus and prefrontal cortex, and the
dysregulation of the CRF system in these regions cause alterations in
Alzheimer's disease (AD) -like pathology in animals [9]. Chronic noise
exposure causes significant and persistent hyperphosphorylation of tau
and formation of pathological Neurofibrillary tangles (NFT) tau (PS202,
PS396, PS404, and PS422) in the hippocampus and the prefrontal
cortex, which may lead to cognitive impairment and neurodegenerative
diseases like AD [14]. Glutamate and the proinflammatory cytokine,
TNFα, have been suggested to contribute to increasing β -amyloid
peptide (Aβ) generation and also elevates the level of Receptor for
Advanced Glycation Endproducts (RAGE) in the hippocampus. Accu­
mulation of Aβ, neuroinflammation, and prominent tau pathology in
the hippocampus are important pathological features of AD. Aβ pep­
tides are generated as a product of APP sequential degradation by the
APP-cleaving enzyme. An imbalance between the production, clear­
ance, and aggregation of these peptides causes Aβ to accumulate and is
thought to be the initiating factor in AD. These processes can ultimately
lead to neuronal metabolic failure and synaptic dysfunction [12].
Chronic exposure to corticosterone in rats reduces the mRNA expres­
sion of BDNF and NT-3 in the hippocampus [6].

5

Table 3.
Noise on morphology of brain.
S.No Model
1 Wistar/Male
2 Wistar/Male
3 Wistar/Male
6
4 Sprague–Dawley /Male
5 C57BL/6NJ
Mice
6 Wistar /Female
9 Mice/Male
A. Arjunan and R. Rajan
Noise Stress Methods Brain regions Expression Remarks Reference
Sub acute stress (100dB- Immunohistochemistry CB Increased number of nNOS positive cell in Purkinji Increased free radical [76]
4 Hrs / 15 D cells generation
Decreased number of Purkinji cells/50,000µm2per
area
Chronic stress camera Lucida drawings mPFC Dendrite retraction and disbranching Impairment of spatial memory [40]
100 dB-4 h/1,15,30
D
HI Dentritic count (3rd& 4th order Neurons)
reduced.Atrophy of pyramidal neurons
Chronic stress Protein array Imaging HI Increased expression of GFAP, IBA1 neuroinflammation [12]
100 dB- 4 h/28 D
Chronic stress Nissel staining HI Reduced MOD in CA1 and DG regions. Excitotoxicity in HI [13]
100 dB – 4 h / 30 Days No significant change in CA3 region
Immunohistochemistry Decreased NR2B expression in CA1, CA3, and DG Internalization of NR2B
regions
< 85 dB – 8 h/1 D Coronal section from each hemisphere – measured Cortical thickness and Reduced cortical thickness and shrunken brain Impairs Cognition [29]
by NanoZoomer Brain volume volume
Densitometry mPFC area and Neuronal No difference in right/left hemisphere mPFC area
density Reduced neuronal density
Volumetric analysis HI, Reduced HI volume and Neuroal density
Densitometry DG Density
PMC section - NanoZoomer Amygdala Cortical area Reduced
198 dB −1.7 ± Immunohistochemistry c-Fos,c-Myc,β-APP Increased expression of c-Fos,c-Myc,β-APP cerebral Loss of metabolic and growth [56]
Cortex, Thalamus, Hippocampus.
80 dB – 2 h/ 6 Wks Nissl's staining HI, CX shrunken, irregularly arranged, and weakly stained Impaired Cognition [10]
in CA1 & PFC
Physiology & Behavior 227 (2020) 113136
 Table 4.
A. Arjunan and R. Rajan

Noise on neurobehaviour.
S.No Model Noise Stress assessment Behavior Remarks Reference

1 Wistar albino/Male Sub acute stress (100 dB- 4 h / Rota Rod Decreased time spent in Rota Rod Decreased Motor coordination [67,76]
15 Days)
Narrow Beam Increased in Time taken to cross in seconds & number of slips Decreased Balance & Motor
coordination
Elevated Plus Maze Time spent and entry in open arm decreased Increased Anxiety Behaviour [67]
2 Rheus Mild Noise (100–110 dB – Delayed Response Task Delayed working memory Impaired Cognition [3]
Monkey/ Female & Male 30 min)
Visual Discrimination Task Decreased Visual Discrmination
3 C57BL/6NJ < 85 dB – 8 h/ 1 Days Novel Object Recognition Task Increased time spent with old object Impaired PFC cognitive function [29]
Mice
Elevated Plus Maze Increased Time spent in the closed arms
Rota Rod Increased shorter time
Morris Water Maze Increased swim latency and lower swim distance
Balance Beam Test Increasedtime (sec) to pass across the beam & number of falls and turns
4 Wistar albino Sub acute stress Open Field Test Day 1- Decreased ambulation peripheral square, central square, Increased Anxiety Behaviour [74]
/Male (100 dB- 4 h / 15 Days) grooming, increased rearing, fecal bolus &immobilization
Day 15 –Decreased ambulation in central squares, Increased
immobilization & fecal bolus

7
Elevated Plus Maze Decreased number of open arm entry & Percentage of open arm entry
5 Sprague–Dawley /Male 55–95 dB – 20 min/1 to 15 Days Eating Behaviuor Less food intake in beginning of Stress period and becone normalize Alters eating behavior [33]
course of further stress sessions.
Longer latency
Decreased duration, speed of food intake, defecation & Exploration
6 Sprague– 90 dB- 15 min/ 6 Session Eating Behaviuor by Tailpinch Increased Eating Stress induced eating behavior [77]
Dawley /Male experience
7 Holtzman male rats 90,100,110 dB - 20 min / 5 Days Feeding Beaviour No significance change in three groups Inibitory effect of feeding is lesser and [54]
shorter
8 Wistar albino /Male 15 min - 30 Days Food Intake Decreased food intake Reduced Body Weight [2]
9 Sprague–/Female (Virigin& 114 dB- 10 min – on 5th day of Endocrine Virigin-Increase total activity,grooming and rearing Lactaing rats showed normal behavior [78]
Lactating) Surgery Behavioural Lactating - higher than the virgin but directed towards to the pups. reactivity due to prolactin
Response
10 Wistar albino Sub acute stress Open Field Test Decreased ambulation in central squares, peripheral squares, rearing, Increased anxiety, fear and altered [67]
/Male (100 dB- 4 h / 15 Days grooming and fecal bolus &Increased immobilization locomotor activity.
11 Wistar albino/ Male Chronic stress Radial Arm Maze Increased number of reference memory error, working memeory error Spatial memory impairment [40]
100 dB-4 h/1,15,30 Days and time taken to visit all baited arms.
12 Sprague–Dawley /Male Chronic stress Morris Water Maze Increased escape latency, Decreased time spent in target quardarnt Spatial learning and memory [13]
100 dB – 4 h / 30 Days
13 Sprague–Dawley /Male Acute (100 dB – 4 h/ 1 Days) Defensive withdrawal test Decreased time spent in open field Anxiety behavior [21]
Chronic -(100 dB- 4 h/30 Days) No signifacant Decreased Anxiety
14 Mice 80 dB- Open Field Test Decreased number of crossing & Rearing impaired spatial learning [10]
/Male 2 h/ 6 Wks.
Morris Water maze increased escape latency
Physiology & Behavior 227 (2020) 113136
A. Arjunan and R. Rajan Physiology & Behavior 227 (2020) 113136

5. Noise on morphology of brain
Many studies have evidenced that the vulnerability may emerge
from stress effects on higher cortical and limbic structures [3,42].
Table 4 describes various types of noise stress which causes neuroa­
natomical changes in experimental animals. The cumulative exposure
to glucocorticoid results in the disruption of the hippocampus by the
following mechanism: 1) inhibition of energy metabolism, 2) involution
of the dendrite process 3) Inhibition of long term potentiating and
paradigms 4) inhibition of primed burst potentiation 5) Presence of
NMDA receptors of glucocorticoid [3, 79] 6) alteration in synaptic
terminal structures and 7) Inhibition of neuronal regeneration in CA3
regions [65].
Table 3 reports that noise stress significantly increased Dopamine
levels in the brain [57,75,76]. Excess dopamine in the cytosol is easily
metabolized by monoamine oxidase (MAO) to produce hydrogen per­
oxide or by autoxidation to synthesize quinine. Autoxidation of dopa­
mine or L-dopa via quinone formation generates free radicals such as
superoxide radicals and hydrogen peroxide. This increases free radicals
generation which could have initiated a cascade of free radical-medi­
ated changes in the cerebellar Purkinje cells morphology [76]. Stress
elicits excessive DA release which can be normalized by DA receptor
stimulation impairing the PFC function, high levels of Norepinephrine
release impairs the PFC working memory abilities via α1-receptor
mechanism and catecholamines may interact to take the PFC “Off-line”
[3,79].
Saljo et al. reported that 198 dB of short lasting impulse noise in­
creases the expression of c-Fos,c-Myc,β-APP cerebral Cortex, Thalamus,
Hippocampus [56]. The proto-oncogene c-Myc activates caspases,
which mediate the apoptotic process and regulate genes, for iron
homeostasis. Increased expression of c-Myc indicates a loss of metabolic
and growth control associated with the transformation of a normal cell
[37].
6. Noise and behavior
There is increasing evidence that noise stress impairs cognition
[73], motor coordination, eating, and lactational behavior in experi­
mental animals (Table 5). The adverse effect of noise includes meta­
bolic and anatomical changes in neurons, reduced dendritic count,
impaired memory, cognition, and locomotor activity [75].
6.1. Cognition
Fink defined cognition as “a healthy brain is one that can perform
all the mental processes that are collectively known as cognition, in­
cluding the ability to learn new things, intuition, judgment, language,
and remembering.” Impaired cognition is often associated with con­
siderable socioeconomic burden, adding to the public health imperative
[22]. Table 5 shows that animals exposed to noise have impaired cog­
nition. Memory is defined as the process of “information acquisition,
storage, and retrieval”. There are several dichotomies of memory (i.e.,
explicit and implicit, short and long-term, semantic, and episodic.
Neurotransmitter systems and BDNF are involved in learning and
memory processes, synaptic plasticity and a substantial part of learning
and memory impairment are due to changes in neurotransmission and
BDNF [79]. The brain is a major target organ for corticosteroids
[42]. Increased oxidative stress, neurotransmitter alteration may induce
changes in Long-term Potential and the synaptic plasticity leads to
learning and memory impairment in noise-induced animals.
6.2. Motor coordination
CNS controls motor coordination by the activation of the motor
cortex, cerebellum, and basal ganglia. The dopaminergic system is a
major neurotransmitter involved in movement and locomotion via the
basal ganglia. The cerebellum is known to contribute to motor control
and coordination activity by integrating the motor output with ongoing
sensory feedback. Noise increases dopamine which facilitates free ra­
dical damage in Cerebellum leading to impaired motor coordination.
And also Cerebellar Purkinje cells release inhibitory neurotransmitter
GABA which reduces the transmission of impulses. Due to the reduction
of glutamatergic and GABAergic neurotransmission systems which
differently activate altering the motor coordination [76].
6.3. Feeding behaviour
Feeding is essential. Table 5 described that various levels of noise
alter feeding behaviors’. Acute stress activates sympathetic arousal and
GC release supports behavioral, automatic, and endocrinological
changes that promote energy mobilization such as increased cardiac
output, blood pressure, gluconeogenesis, triglyceride levels, and re­
direction of blood flow to fuel the muscles, heart and the brain. Chronic
exposures of stress can dysregulate the HPA axis, which affects energy
metabolism and feeding behavior [80].
6.4. Fear and anxiety
The bed nucleus of the stria terminalis and amygdala receive pro­
jections from the basolateral amygdala and project, in turn, to

Table 5.
Noise stress and neurotransmitter modulation.
S.No Model Noise Stress Methods Neurotransmitters Brain Regions Reference

1 Wistar albino/Male Acute (100dB- 30 mins / 1 Day) Spectrophotometer Acetylcholine Decreased in CC, CS, HY, HI [61]
Acetylcholinesterase Increased in CC, CS, HY, HI
2 Wistar albino/Male Sub acute stress HPLC Norepinephrine Increased in HY [75]
(100 dB- 4 h / 15 Days Dopamine
Sertonin
3 Wistar albino/Male Sub acute stress HPLC Norepinephrine Increased in CB, CS [76]
(100 dB- 4 h / 15 Days Dopamine
Sertonin
4 Sprague–Dawley /Male Chronic stress HPLC-EC System Glutamate Increased in Hemicerebrum [13]
100 dB – 4 h / 30 Days
GABA Decreased in Hemicerebrum
Asp, Gly No significant channge
5 Sprague–Dawley /Male 100 dB – 15, 30, 90 and 240 mins Lowry's Method [3H]5-HT Decreased in HY, HI, CC [43]
6 Wistar albino/Male Sub acute stress HPLC Norepinephrine Increased in CC, CB, CS, HY, HI, P [57]
(100 dB- 4 h / 15 Days Epinephrine
Dopamine Increased in CC, CB, HY, HI
5-HT Increased in CC, HY, P, CS

HPLC - High Performance Liquid Chromatography, HPLC-EC - High Performance Liquid Chromatography- Electrochemical Detection, P-Pons.

8
A. Arjunan and R. Rajan
downstream target areas that mediate many of the behavioral, auto­
nomic, and electrophysiological consequences of fear and anxiety.
Enormous studies denoted that noise increases anxiety-like behavior.
High level of glucocorticoids increases the excitation of amygdala
neurons by decreasing the GABA level and also increases the cytosolic
calcium which triggers cytoarchitectural changes in BLA neurons [44].
7. Epigenetics and noise
Epigenetics is considered to be a link between environmental ex­
posure and human diseases. Epigenetics refers to changes that alter
gene transcription in the absence of direct alterations to the genetic
sequence. Limited studies explained the several environmental pollu­
tants such as toxic metals, pesticides, noise can induce aberrant DNA
methylation and histone modification in gene expression regulation
[68]. Chronic exposure to stress leads to alteration of the expression of
longevity genes such as sirtuin-1, p53, thioredoxin-interacting protein,
HSP 70 in the rat hippocampus [58]. Guo et al. report that exposure of
noise stress (70–75 dB) for short term and long term in Wistar rats is
associated with aberrant DNA methylation of Comt (Inferior colliculus),
Mc2r (hippocampus), BDNF and LINE-1 (Medulla oblongata) [25].
8. Discussion
Stress is a fundamental perception that discerns both life and evo­
lution. In life, stress affects social, psychological, and physiological
environments which can simultaneously impinge on wellbeing [35].
Especially social factors may threaten the homeostasis. Selye also sup­
ported and proposed the theory that various external stimuli might
generate undifferentiated physiological as well as psychological well­
being [60]. All creatures face threats to homeostasis, which are met
with adaptive responses. And also when an individual is exposed to
acute stress adaptive strategies can be adopted which typically do not
impose a health burden. In contrast, if stressors are chronic, it may lead
to diseases [59].
Exposure of stress is thought to precipitate or exacerbate several
psychiatric disorders, including schizophrenia, depression, and post-
traumatic stress disorders [3,75]. In this review, we have documented
the associations between Noise stress and brain and have described how
noise deteriorates the brain functions. Exposure to continuous noise of
85–90 dBA, chronic in industrial settings, can lead to loss of hearing,
with an increase in the threshold of hearing sensitivity, and can also
cause non-auditory health effects [69]. Oxidation-reduction (redox)
homeostasis, like pH control, is central to life. Redox processes pervade
practically all fundamental processes; from bioenergetics to metabolism
and life functions [62]. A balance between free radicals and anti­
oxidants is necessary for proper physiological function. If free radicals
exceed in range it can adversely alter lipids, proteins, and DNA and
trigger several human diseases such as cardiovascular, inflammatory
disease, cataract, cancer, and neurodegenerative diseases. Antioxidants
prevent free radical-induced tissue damage by preventing the formation
of radicals, scavenging them, or by promoting their decomposition
[36].
From Table 1, studies denote that noise above 100 dB (acute, sub­
acute, and chronic) increased the oxidative stress and decreased the
antioxidant level in various regions of the brain. The increased oxida­
tive stress is due to peroxidation of membrane lipids which affects a
variety of functions resulting in increased membrane rigidity, decreased
activity of membrane-bound enzymes (e.g., sodium pump), impairment
of membrane receptors and altered permeability damage to phospho­
lipids, radicals also can directly attack membrane proteins and induce
lipid-protein and protein-protein cross-linking, all of which contribute
to altered membrane integrity [71].
Stress activates the hypothalamic-pituitary-adrenal axis, secretion
of corticosterone in adrenal glands which crosses the blood-brain bar­
rier and interacts with the neurons and neuroglial cells which alters the
9
Physiology & Behavior 227 (2020) 113136
neuroanatomical and neurophysiological functions in Brain [45].
Table 2 shows the increased acetylcholine and glutamate level in
hemicerebrum during the noise. Due to altered neurotransmitter levels
in PFC, it undergoes neurochemical changes and morphological
changes including reduced dendrite density and branches.
Studies in various animals have reported that noise stress results in
the damage to the hippocampus, a brain area involved in cognition
[73]. The Hippocampus is well known as the “cognitive arm” of the
limbic system [20] and also for declarative or explicit memory espe­
cially in the conscious or voluntary recollection of information [6].
Chronic exposure to a high level of CORT down-regulates the GLUCORT
receptors and increases the sensitivity of HPA axis – temporal, spatial
aspects of skill movement, posture, balance coordination, affect neu­
ronal metabolism, cell survival, physiology, neuronal morphology. The
hippocampus, mPFC, the amygdala is an essential component of the
neuronal circuit mediating stress. The amygdale provides a primary link
between subcortical areas that responsible for fear and cerebral cortical
receiving sensory information about the external environment [29].
Joseph et al. reported that chronic exposure of the limbic system in the
brain to the adrenal steroids has been correlated with neuropsychiatric,
neurophysiologic, neurotransmitter, and neuroanatomical changes [6].
9. Conclusion
Stress is an unavoidable circumstance in our life. Due to urbaniza­
tion and modern lifestyle noise pollution/ stress has increased tre­
mendously in our day to day life. Noise becomes a hazard to the phy­
sical, mental, and social wellbeing of an individual who works in a
noisy environment or to those who are vulnerable to exposure to noise.
Various studies have reported that chronic exposure to noise deterio­
rates brain function and may lead to neurodegenerative disease.
Reduction of the impact of noise on health can be done by using various
preventive measures such as earplugs, planting trees, regular main­
tenance of vehicles, and development of a therapeutic intervention for
noise-induced neurodegenerative diseases
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