Neurobiology and consequences of social isolation ...

Biomedicine & Pharmacotherapy 105 (2018) 1205–1222

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Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha

Neurobiology and consequences of social isolation stress in animal model—A comprehensive review Faiza Mumtaza,b,1, Muhammad Imran Khanc,d,1, Muhammad Zubaire, Ahmad Reza Dehpoura,b,

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a

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran c Department of Pharmacy, Kohat University of Science and Technology, 26000 Kohat, KPK, Pakistan d Drug Detoxification Health Welfare Research Center, Bannu, KPK, Pakistan e Key Laboratory of Integrated Management of Crop Diseases and Pests, College of Plant Protection, Nanjing Agriculture University, Nanjing, 210095, PR China b

A R T I C LE I N FO

A B S T R A C T

Keywords: Social isolation stress (SIS) hypothalamic–pituitary–adrenal (HPA) axis Oxytocin Neurotransmitters Vasopressin N-methyl-D-aspartate (NMDA) Neurotrophicfactors (NTFs) Early growth response transcription factor genes (egr)

The brain is a vital organ, susceptible to alterations under genetic influences and environmental experiences. Social isolation (SI) acts as a stressor which results in alterations in reactivity to stress, social behavior, function of neurochemical and neuroendocrine system, physiological, anatomical and behavioral changes in both animal and humans. During early stages of life, acute or chronic SIS has been proposed to show signs and symptoms of psychiatric and neurological disorders such as anxiety, depression, schizophrenia, epilepsy and memory loss. Exposure to social isolation stress induces a variety of endocrinological changes including the activation of hypothalamic–pituitary–adrenal (HPA) axis, culminating in the release of glucocorticoids (GCs), release of catecholamines, activation of the sympatho-adrenomedullary system, release of Oxytocin and vasopressin. In several regions of the central nervous system (CNS), SIS alters the level of neurotransmitter such as dopamine, serotonin, gamma aminobutyric acid (GABA), glutamate, nitrergic system and adrenaline as well as leads to alteration in receptor sensitivity of N-methyl-D-aspartate (NMDA) and opioid system. A change in the function of oxidative and nitrosative stress (O&NS) mediated mitochondrial dysfunction, inflammatory factors, neurotrophins and neurotrophicfactors (NTFs), early growth response transcription factor genes (Egr) and C-Fos expression are also involved as a pathophysiological consequences of SIS which induce neurological and psychiatric disorders.

1. Introduction The brain is a vital organ, susceptible to alterations under genetic influences and environmental experiences [1–3]. Stress negatively affects the regions of brain which are mainly involved in regulation of emotion including the cortex and hippocampus [4–6]. A number of researchers has been reported that exposure to early life stress experiences (maternal deprivation, social isolation or social defeat in mammals can evidently and adversely affect the normal brain development and respective adult behavior [7–13]. Animal models of stress has been used as helpful tool to investigate the underlying mechanisms through which, stress exerts its detrimental effects on the functions of brain and animal behavior [14,15]. Stress can be physical or psychological, exposure to stress leads to neurochemicals, physiological and pathophysiological alterations, involved in neurophysiological response and pathophysiology of various

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neuronal and psychiatric disorders [16–18]. In the developmental stages of life, exposure to chronic stress caused remarkable neuroplastical alterations, changes in neuroplastical function cause alterations in structure and function of receptors that affect synaptic neurotransmission (excitatory and inhibitory) in several regions of the brain [19,20]. A challenge to the organism that can potentially disrupt homeostasis is defined as stressor, therefore, requires a physiological response. During development (childhood and adolescence) when plastic capacity is maximal, is critical period for the maturation of the neural circuits that control energy homeostasis and stress responses of an organism [21]. To promote a proper neuronal organization in adolescent or neonatal the duration and time of a stressful experience is necessary and these parameters can exacerbate the vulnerability to long term neurochemical and behavioral changes [22].Stressor can be exteroceptive or psychological depending on the organism’s age and gender during s exposure to stress, nature and severity of stressor,

Correspoding author at: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran. E-mail addresses: [email protected], [email protected] (A.R. Dehpour). The first two authors has equally contributed.

https://doi.org/10.1016/j.biopha.2018.05.086 Received 27 December 2017; Received in revised form 10 May 2018; Accepted 18 May 2018 0753-3322/ © 2018 Published by Elsevier Masson SAS.


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depression and anxiety is at its higher level in this periods [51,52]. In adolescence the SI uniquely affects the response to the psychotomimetic drug amphetamine and is detrimental for normal development and may be particularly relevant to the investigation of developmental psychopathology [53]. During adolescence the SIS in nonhuman primates also impaired hippocampal neurogenesis in time-dependent manner [54]. Another study showed that during adulthood the SIS has been shown to delay the proneurogenic effects of exercise in rats [55]. A recent study has been conducted to investigate the influence of isolation stress during adolescence on exercise-induced increases in neurogenesis in sedentary and running conditions. Results of study showed that during adolescence SIS, did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus [56]. Although the underlying mechanisms are still poorly understood, SIS in rats has been proposed to show similar signs and symptoms characteristic of human psychiatric disorders such as anxiety, depression and schizophrenia [57,58].In isolation-reared rats some of behavioural and neurochemical alterations has seen which leads to development of schizophrenia, which has led to SIS being proposed as an animal model of this disorder. There is a consensus view that adult disorders like schizophrenia is developed by number of early environmental factors (physiological, psychological, pharmacological) and among psychological factors SIS is one of leading cause to develop schizophrenia [59,60]. A large number of researchers reported social isolation stress in animal models induced behaviors relevant to depression and anxiety or SIS can produce depression and anxiety co-occurrence [30,61,62]. A number of researchers have reported the SIS as animal model in rodents can induce variety of anxiety like behaviours in a variety of behavioral tests [63]. Isolation reared rats have been believed to show sings characteristic of human anxiogenic profile such as neophobia [58]. Isolation reared rats in the early stages of life have reported Behavioural disturbances including an anxiogenic profile in the elevated plus maze [64,65]. Another study demonstrated that in isolation-reared rats on the elevated plus mazemodest increases in anxiety related behaviours were observed [66]. Moreover, a number of studies revealed thatunder SIS the anxiety-like behaviors increased [67–69]. Furthermore, theisolation reared rats were less sensitive to the anxiolytic effects of diazepam and showed more aggressive behavior in comparison with socially reared rats [70]. Ethnopharmacological relevance Xiaochaihutang (XCHT) exert an antidepressant effect on social isolation (SI)-reared mice demonstrated that it improved depressive/anxiety-like behaviors of SI reared mice by regulating the monoaminergic system, neurogenesis and neurotrophin expression [71]. Studies had reported that the anxiety and depression like behaviours in mice along with a reduction in levels of neuroplasticity genes are maximum under SIS [72,73]. The exposure to social isolation in rodents, recognized to depressive-like behaviours and induce anxiety as reported by many researchers [73,74]. Anxiety-induced anorexia and reductions in body mass was observed in housing hamsters in social isolation selectively in females. The results of study showed that Syrian hamsters tolerate both stable social housing and social isolation in the laboratory [75]. Depression, associated with altered mood and aversion, is among highly prevailing and serious brain disorders that results in decreased concentration during activities, constant sadness, irritability, fatigue, pain, anxiousness and insomnia [76]. Stressful life events, Social isolation, behavioural withdrawal and loss of social contact are considered as major predisposing factors associated with the aetiology of depression [77]. Many important symptoms of depression e.g., feeling of worthlessness, suicidal thinking cannot be modeled in animals whereas, symptoms of Depression resembling core clinical symptoms i.e. depressed mood and anhedonia, are studied in rodent models by using

chronicity of the stressor and subjectively recognized threat [23]. In animals, the model of social isolation (SI) rearing is commonly considered as an early life stressor [24]. Social isolation is considered as potent stressors in both humans and animals [25,26]. Social isolation stress (SIS) was evolved in 1960 s when researchers reported social isolation as hyper emotional and abnormally reactive to handling [27]. It can alter the behavioural responses to subsequent stress, early life isolation of laboratory rats from social interaction leads to stressful experience [28]. The concept of SIS in adolescencecan result in alterations in reactivity to stress, social behavior, neurochemical, physiological, anatomical and alteration in function of neuroendocrine system in both animal andhumans that may remain during adulthood [12,29,30]. Furthermore, the SIS is a miserable social condition which contributes to fatigue, modification in a variety of behaviours and the responsitivity to psychotropic drugs and predisposes individuals to various diseases [31,32]. The degree and intensity of SIS induced effects are variable among species depending upon social organization of respective species [33–35]. The maintenance of mental and physical health and human well-being depends on social interaction and lack of social contact is associated with higher risk of cognitive deterioration and neuronal disorders. The SIS induced studied on neuronal disorders generated new knowledge in various research fields including pharmacology, behavior and neurobiology [23,36,37]. The major long lasting symptoms caused by social isolation stress (SIS) in rodent studies have been observed in number of behavioral disorders especially in anxiety and depression [30,38,39]. In mice SIS is also able to induce learning deficits [40]. The SIS has marked effect on cell proliferation and neurogenesis as reprted by many researchers [35,41,42]. The release of neurotransmitter including dopamine, serotonin and glutamate is affected by SIS induced changes in brain activity [43]. In mice housed in isolation for one month, the disrupted brain connectivity from post-natal day 35 onwards, prominently affecting the dorsolateral orbitofrontal cortex by using, neuroimaging methods [44]. During the critical period the experience of social isolation streee may result in immature neural circuitry between pre frontal cortex and subcortical targets [45]. A previous study reported the reduced fractional anisotropy in the uncinate fasciculus [46]. In another study, in male rats reared in isolation for 15 weeks after weaning an increased size of the lateral but not third ventricles together with a decrease in brain size and body weight was observed [47]. Controlled studies on the effect of severe social isolation in humans are rare due to the ethical implications. The result of a follow-up study of children reared in orphanages showed smaller cortical white matter volumes in institutionalized children [48]. This review will examine the impact of social isolation stress on brain development and discuss its potential correlations with symptoms of neuropsychological disorders in particular to anxiety, depression, schizophrenia, Obesity and epilepsy. This review will also focus on the effects of social isolation stress on endocrine functions in animal models of rat or mice, with particular attention being given to the role of the neurotransmitters in brain dysfunction associated with early social isolation and provide insight into the etiology and the major signaling mechanisms underlying some symptoms of major depressive disorder (Fig. 1). 2. Prognosis of SIS as underlying cause in etiology of various nervous disorders During early stages of life, acute or chronic stress can promote the onset of emotional and affective disorders, such as depression and anxiety [49]. The plasticity-driven organization of neural circuits in the hippocampus, prefrontal cortex and amygdala is associated with adolescence [50]. The susceptibility to stress is maximum in adolescence and the emergence of neurobiological disorders such as schizophrenia, 1206


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Fig. 1. Social isolation stress and its consequences on hippocampus.

3. Molecular/Biochemical aspects of SIS

forced swimtest,tail suspension testand the sucrose preference test [78]. Moreover, the behavioral and neurochemical changes in Juvenile social isolation stress (SIS) showed reminiscent of various symptoms observed in depressed patients [30,57]. Previous clinical and preclinical data have shown have shown increased risk of seizure susceptibility due to social isolation stress in both human and rodents [16,79–81]. In epileptic patients chronic social isolation stress is a determinant psychosocial factor which has prominent effects on the quality of life, severity of disease and social functioning [82]. Psychosocial stressors (e.g. SIS) are accompanied by high severity and morbidity of epilepsy but the underlying mechanisms by which chronic stress increases risk and occurrence of seizure is poorly understood by researchers [19,83]. Previous studies have demonstrated that SIS induced negative changes in various neurotransmission systems in brain including both nitrergic and glutamatergic systems increased seizure susceptibility [84]. Furthermore, under SIS the misplacement of NMDA receptors in the limbic area induced epileptogenesis and excitatory state in animals [85]. A study reported that in mice, exposure to long-term social isolation for seven weeks increased seizure susceptibility to picrotoxin [80]. Another research showed that SIS has a proconvulsant effect on socially isolated animals which resulted to conclude the proconvulsant effect of SIS on rodents [79]. Under SIS Hypoalgesiawas observed in isolates [86] while, a study revealed no change in pain response in the tail flick test of heat sensitivity [66]. Conflicting results have also been found, social isolation appeared to increase the oral response to a mild tail pinch, striatal dopaminergic activity is involved in this type of behaviour without causing any difference in sensitivity in response to formalin injection [87]. Opioid system which plays a crucial role in juvenile social behaviors in rodents underwent significant changes such as alteration in nociception and reduced sensitivity to pain [88,89]. Studies showed that social isolation associated with age-related cognitive decline and dementia and high risk factor of lower level of cognition at baseline and during follow-up with more rapid cognitive decline [90]. In elderly people social isolation is a powerful risk factor for Alzheimer’s disease (AD) and cognitive decline as a longitudinal study revealed that the risk of AD was more than doubled in lonely persons [91]. A study has showed there was impaired novel object discrimination observed under SIS [92]. Social recognition memory is a type of memory associated with social relationships [93], is mediated by a dedicated brain neuronal network, and regulated by specific type of molecules which are only involve to modulate memory [94–96] (Fig. 2)

As a psychosocial stressor experiencing juvenile SIS (as a valid animal model of chronic stress) has been extensively reported to negatively induce diversity of long lasting behavioral, neuroendo-crinological, neuro-chemical and immunological alterations in animals [97]. 3.1. Electrophysiology/Electro-physiochemical aspects The ion channels have an important role in the release of neurotransmitters and stimulate the post synaptic neurons in CNS by increasing the intracellular concentration of Na + and Ca2+ ions in presynaptic neurons [98]. In socially isolated rats the alteration in the electrophysiological properties of some neurons has observed [99] (Table 1). 3.2. Endocrinal changes associated with SIS Many researchers demonstrated in their studies that dysregulation of neuroimmune-endocrine system is one of the fundamental mechanisms that cause neuronal disorders [102]. Exposure to social isolation stress induces a variety of endocrinological changes including the activation of hypothalamic–pituitary–adrenal (HPA) axis, release of catecholamines, culminating in the release of glucocorticoids (GCs) and activation of the sympatho-adrenomedullary system however, among different studies the effects of social isolation on the HPA axis in rats are not consistent [103]. In adulthood the chronic SI leads to changes in corticosterone levels, increases baseline and drug-induced locomotor activity [104]. Anxiety and depressive-like behaviors dure to disruption in the HypothalamicPituitary-Adrenal (HPA) axis under chronic SIS, resulting in but cycling estrogens could modify these behaviors. A study was conducted to determine the relationship between ovarian hormones during the normal cycle could interact with social isolation to alter anxiety and depressivelike behaviors. Results showed a decrease in anxiety behaviors in females in the estrus stage accompanied by a decrease in GR expression in hippocampal DG and CA3 [105]. The social isolation in social species like geese, is an ecologically relevant and acts as a stressor [106]. Stress is not only immunosuppressive, but can also have no effect or can even be immunoenhancing. Therefore, the effects of social isolation on immune function can be ambiguous [107]. In recent studies, the researchers investigated that loneliness and SIS were associated with activation of the sympathetic nervous system and hypothalamic pituitary– adrenocortical axis and chronic social stress leads to enhanced myelopoiesis, glucocorticoid resistance, upregulatedproinflammatory gene 1207


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Fig. 2. Social isolation stress and its concequencws on various brain regions.

oxytocin are necessary whereas, by several lines of evidence equivalent conclusion could be draw for vasopressin. In a study researcher suggests the involvement of oxytocin-dependent synaptic plasticity in the MeA in long social recognition memory whereas, in adult rats oxytocin-dependent synaptic plasticity is abolished when isolated for seven days [146]. Study shows the lack of short-term social recognition memory observed in that mice in which the gene encoding oxytocin (Oxt) was knocked-out (Oxt-KO mice) by using the social habituation-dishabituation paradigm [142]. Similar results in another study demonstrated the loss of short-term social recognition memory due to the Oxtr gene encoding the oxytocin receptor was knocked out in mice [147,148]. Furthermore, oxytocin cannot be released from nerve terminals in CD38-KO mice leads to lack of social recognition memory but not for other types of memory [149]. Study shows impairment in social recognition memory was observed in Brattleboro rats, which cannot synthetize biologically active vasopressin as result of a spontaneous mutation in the corresponding gene [150,151]. The result of another research data shows social recognition memory is impaired by antagonists of vasopressin while it is facilitated by its agonists in male rats [152–155]. Further to support the involvement of vasopressin, in mice Social recognition memory was found to be impaired either one of the two vasopressin receptors expressed in the brain, Avpr1a and Avpr1b [156]. Altogether, the results of previous studies showed the significant involvement of unique oxytocin and vasopressin dependent underlying mechanisms in social recognition memory. As, previous studies unraveling the underlying processes mediating the damaging effects of partial or perceived social isolation by using animal models, would facilitate clinical trials with various interventions, such as to compensate for the damaging effects of social isolation the intranasal delivery of vasopressin and oxytocin [157,158].

expression, and oxidative stress [108]. According to a research, baseline corticosterone and immune parameters were not affected by mine-exposure but after social isolation, in comparison with control goslings the mine goslings tended to show decreased haemagglutination [109]. A study conducted recently to evaluate if social isolation would induce further emotional or anxiety-like behavior disturbance and suppress neurogenesis in an experimental model that was repeatedly treated with cortisol by using sprague-dawley rats. The results suggested that the condition of hypercortisolemia is associated with behavioral and neurological effect of social isolation which can also augment the signs and symptoms of depressed patients with potential alteration in neurogenesis [110] (Table 2). 3.2.1. Role of SIS in social recognition memory (SRM) Social recognition memory is a type of memory associated with social relationships is mediated by a dedicated brain neuronal network [93] (Table 3). 3.2.2. Oxytocin and vasopressin in SRM Oxytocin and vasopressin are produced mainly in non-overlapping populations of neurons in the same three hypothalamic nuclei, are twin’’ 9-amino acid peptides. The hypothalamic nuclei, the supraoptic nucleus (SON), the accessory nucleus (AN) and the paraventricular nucleus (PVN) project their axons to the posterior pituitary gland (neurohypophysis), where they release vasopressin and oxytocin into the blood [141]. Interestingly, it was clearly shown by multiple studies, expression of oxytocin was high in medial nucleus of the amygdala (MeA), is a brain region where oxytocin action is necessary for formation of social recognition memory [142]. Furthermore, the area where vasopressin activity is most critical to this memory form is lateral septum (LS) along with olfactory bulb (OB) where, its activity was also shown to be important [143–145]. Studies showed, specifically for social recognition memory, Table 1 Electro-physiological aspects of Social Isolation Stress (SIS). Property

Stressor

Effect

Reference

Electro-physiology

Social Isolation Stress (SIS)

Reduced action potential height and increased action potential threshold in hippocampal pyramidal neurons. No change in resting membrane potential was observed LTP in the CA1 to subiculum pathway reduced which leads to altered long term potentiation Short hyperpolarization and abnormal firing of Pyramidal neurons in PFC

[99]

1208

[100] [101]


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Table 2 Endocrinal changes associated with Social Isolation Stress (SIS). Endocrine System

Effect

Reference

HPA-axis

HPA axis function was increase due to SIS No change in HPA axis function studied by SIS SIS leads to hyperactivity of HPA axis allow the normal release of ACTH and CORT levels indicates that HPA axis is able to react normally in potentially dangerous situations. In male rats high basal HPA activity and high responsiveness to endocrine system and behavior Clinical and preclinical studies have shown the dysregulation and inability of HPA axis to manage the response to acute stress, causes enhanced response to acute stress due to massive release of CORT High or low HPA axis activity is responsible for inappropriate SI-induced forms of aggression The responsiveness of HPA axis to acute stressors is enhanced by SIS is accompanied by inflammatory responses in mammals Studies demonstrated that SIS during adolescence correlates with HPA axis hyper responsiveness in hippocampus (HIPP) and pre-frontal cortex (PFC), are brain regions to manage mood and behavior In socially deprived rats, glucocorticoid stress responses to and immobilization stress and open-field exposure become decreased By socially isolation aggression-induced glucocorticoid responses becomes double Glucocorticoid stress responses was enhanced by SIS in startle whereas, no effect of isolation on hippocampal glucocorticoid Increased level of GCs leads to increase the generation of reactive oxygen species (ROS) Levels of ACTH may be elevated

[111] [28] [12]

Glucocorticoids (GCs)

ACTH

Corticosterone (CORT)

In socially deprived subjects conflicting findings shows decreased level of basal ACTH By post-weaning social isolation Immobilization induced basal plasma level of ACTH responses remained unaltered Basal plazma concentration of ACTH was reduced in isolated rats due to social isolation Isolation-reared rats have lower plasma corticosterone After a 10 min open-field test Basal CORT level are not affected by SIS Investigated increased basal CORT levels SIS leads to decreased levels of basal CORT levels SIS increase the aggression-induced corticosterone stress response Elevated level of basal CORT observed by SIS when animals housed in wire floor cages If the animals are housed in standard cages basal corticosterone levels remains unaffected by SIS SIS caused increased corticosterone levels in depressive like behavior The dexamethasone induced suppression of corticosterone secretion blunted by SIS Basal plasma corticosterone remain unaffected by SIS Hypertrophy of the adrenal gland cortex along with decreased decrease serum corticosterone level Levels of serum corticosteroneupregulated, hippocampal GR in single-housed animals decreased Enhanced corticosterone levels by twelve hours of social isolation

[39] [112] [113] [102,113,114,115,116] [86,117] [118,119] [12] [120] [121] [12] [117,122] [123] [115] [86] [28,124,125,126] [111,127] [128] [119] [129] [123] [130] [115] [131] [132] [133] [134]

[169–171]. Basal DA turnover by atypical antipsychotics was increased in amgydala due to isolation rearing while DA turnover in medial PFC and mesocortical area was decreased interestingly [129]. Clozapine and olanzapine-induced DA release in medial PCF of isolates was increased [172]. Some researchers reported unchanged basal DA in medial PCF [173]. Microdialysis studies have revealed that there was a greater dopamine elevation in the NAc under SIS after systemic cocaine and amphetamine injections [43,166,174,175]. Due to SIS Cocaine-induced DA efflux in NAcc is potentiated, for uptake inhibition the potency of cocain was not different between rearing conditions [176]. Furthermore, by isolation rearing enhanced DA release in the NAcc in some areas of the striatum and PFC due to reduction in NMDAR1 A mRNA expression by in situ hybridization [177]. Isolation induced PPI deficits are reversed by DA depletion in NAcc [178]. Studies showed the enhanced presynaptic DA release seen in NAcc due to a deficit in glutamatergic innervation of the NAcc [179]. SI-induced increased release and uptake of dopamine terminal activity

3.3. Neurotransmitters In several regions of the central nervous system (CNS), SIS alters the level of neurotransmitters as well as receptor sensitivity as demonstrated by many researchers [43,159,160]. Furthermore, a number of studies have shown that interruption or impairment in neurotransmitter systems plays a major role in development of neuronal disorders in socially isolated rodents [69,161,162]. 3.3.1. Dopamine In male isolation-reared mice the increased levels of prefrontal DA and 5-HT release are consider as the neurochemical basis for induction of abnormal behaviors [163].The increased release of dopamine in response to salient events via phasic burst firing in SI induced animals [164].Many studies reported SI has been shown to suggest increases in extracellular dopamine levels and changes in dopamine function [129,165–168]. By contrast, some microdialysis studies have shown there was no increase in extracellular dopamine levels after SIS Table 3 Effects of SIS on social recognition memory (SRM). Effect of SIS Memory (SRM)

Reference

Acute (short term) social isolation was sufficient to induce rapid severe impairment of long-term memory in adult mice and rats which seems to be specific to social memory, is induced within one day of solitary-housing, and is reversed following several days in group-housing as well as caused impairment of short term social recognition memory In the isolated animals interestingly, researcher found the restoration of the long-term social memory due to odor-enriched housing Only long-term social recognition memory was impaired by social isolation when tested 30 min after the first encounter. By following acute social isolation, impaired synaptic plasticity in the MeA as well as reduced adult neurogenesis in the dentate gyrus and olfactory bulb was shown to be involved in longterm social recognition memory. A number of studies confirmed that long-term social recognition memory requires cAMP responsive element binding protein (CREB) activity and requires protein synthesis and is hippocampal-dependent in group-housed mice

[135]

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[136] [137]

[135,138,139,140]


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potassium, measured by using in vivo microdialysis [195]. The socially isolated rat tends to attenuate the normal elevation in 5-HT release induced by systemic amphetamine in PFC [196]. In isolation the release of 5-HT from the medial NAcc is increased with exposure to inescapable foot shock, measured by microdialysis [197]. Studies reported the direct interaction of 5-HT3 receptors with NMDA receptor, mediate response in pyramidal cells of the rat cortex [198]. The co-administration of subeffective doses of 5-HT3 receptors and NMDA receptors antagonists synergistically produced antidepressant effects correlate the direct interaction of 5-HT3 receptors with NMDA receptor [199]. Social deprivation induced inappropriate forms of aggression and depression have also been associated with Serotonin (5HT) which is considered as central neuromodulator of the induction of depression and aggression [112]. Social isolation is used as depression model in rodents and major depression and obsessive compulsive disorder can be caused by hypofunction of the serotonergic system. Researcher reported that social isolation stress inhibit the serotonin release in a frequency-dependent manner by chronic selective serotonin reuptake inhibitors (SSRIs) treatment [200]. A study reported that the effect of chronic social isolation (lasting 90 days) on anxiety-related behaviors. The result showed long-term social deprivation surprisingly decreased anxietyrelated behavious and decreased level of serotonin but levels of dopamine and metabolites of these neurotransmitters 5HIAA and DOPAC, respectively, remained unchanged [201]. The chronic SI-induced aggressive behavior is regulated by a selective 5-HT reuptake inhibitor (SSRI),Flouoxetine, in chronic SI mice [202]. On the elevated plus maze isolation rearing caused an increased anxiogenic response to the 5-HT agonist,meta-chlorophenylpiperazine (mCPP) which has been attributed to increased responsiveness of 5HT2Creceptor in the hippocampus [159].The chronic SI-induced aggressive behavior the effects of 5-HT3 agonists remain unclear, although ineffectivity of 5-HT3 antagonists is approved against SI-induced aggressive behavior [203,204]. Antidepressant-like effects of 5HT3 receptors stimulation demonstrated by behavioral tests of rodents, indicated the contribution of the 5-HT3 receptor in inducing emotional changes, such as those associated with depressive moods and aggression [205]. However another study suggests, chronic SI-induced depressive-like behavior could not be induced by 5-HT3 receptor [206]. Tropisetron, a 5-HT3 receptor antagonist was investigated to evaluate its role in adolescence SIS which is associated with the development of depression. The results of study showed the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence by mitochondrial dysfunction caused by tropisetron by decreasing the nitrergic system activity in the cerebral cortex [74] (Table 5).

Table 4 Effects of SIS on Dopamine Receptors. Effecct Dopamine (DA) Receptor

Reference

In the mesolimbic or nigrostriatal systems no change in either the density or affinity of either DA D1or D2receptors Higher levels of basal extracellular dopamine in the stratum specifically functional down-regulation of DA D2receptors in striatum in isolates In the dorsal/ventral striatumnochange in either the number, density, efficacy or affinity of either DA D1or D2receptors following 30 days isolation of Sprague–Dawley rats. A selective elevation in DA D2but not D1receptor binding observed in the NAcc and amygdala of isolation reared In isolation rearing there is an increased ratio of high: low affinity states of the DA D2 receptors

[189] [166]

[190]

[191] [192]

in the dorsal and increased uptake of dopamine in ventral striatum, including the nucleus accumbens core (NAc) in rats was demonstrated [24]. In SI rats the increase in reinforcement of psychostimulants is observed [68,168,180,181]. Many studies reported reinforcement of psychostimulants following early life SIS on striatal dopamine terminals, increased uptake rate of dopamine release in the NAc and robust inhibition of dopamine uptake in DMS was observed by the psychostimulants but different effects on release [69,182–186]. Some researchers demonstrated that in the prefrontal cortex of intruder male isolationreared mice the extracellular DA and 5-HT levels did not affected by anesthetized to pentobarbital or to a novel object while during or after an aggressive encounter prefrontal DA levels were higher [187,188] (Table 4). 3.3.2. Serotonin (5 hydroxytryptamine) Studies shows that 5-hydroxytryptamine3 (5-HT3) receptors as ligand gated ion channels are involved in formation of the inhibitory networks during maturation of brain.It is also involved in the pathophysioliogy of anxiety and mood disorders that mice exhibit reduced anxiety-like behaviors with lacking these receprors [193]. Early SIS disrupts the maturation of neurotransmission systems such as serotonergic system that regulates the mood and behavior,any change in this system influenced by SIS is reported by different regions of the brain including limbic area [39]. In social bot not isolated rats the release of 5-HT in dorsal hippocampus increase by Parachloroamphetamine and footshock,shows a marked deficit in serotonergic function in the hippocampus of isolates [194]. In the hippocampus and cortical of isolation reared rats have shown reduced 5-HT release evoked by either elevated plus maze exposure or Table 5 Effects of SIS on5-HT Receptors. Effecct Serotonin/ 5-HT Receptors

Reference

In isolation reared rats the aggressive behavior is associated with decreased activity of brain 5-hydroxytryptamine (5 H T) receptors In Lister hooded rats30 days isolation rearing elicited back muscle contractions and elevated the wet-dog shakes by systemic administration of a 5HT2Areceptor agonist and increased 5-HT1Areceptor mediated flat body posture and reciprocal forepaw treading Under SIS, in cortex and hippocampus reduced levels of 5-HT release or postmortem amount have been observed after different isolation periods confirming SIS not only impair turnover of 5-HT but also its biosynthesis A decreased turnover of 5-HT in basal NAcc is shown by SIS Isolation rearing has been shown the turnover of 5-HT remains unaffected in NAcc Isolation rearing has been shown the turnover of 5-HT remains unaffected in the PFC or caudate putamen Presysnaptic 5-HT1B receptors is altered by SIS whereas, post-synaptic hippocampal 5-HT1Areceptors remains unaffected In-vivo hippocampal post-synaptic 5-HT1 A receptor function not changed by electrophysiology but release of endogenous 5-HT mediated by 5-HT1B decreased, consistent with impaired presynaptic 5-HT function in hippocampus In the prelimbic, motor and cingulate cortex, SIS significantly increased 5-HT2Areceptor binding, whereas 5-HT1Areceptor binding in the prelimbic cortex was reduced and increased in the motor cortex and hippocampus 5-HT1Abinding is increased by Isolation-rearing in mice In the dorsal raphe nucleus of isolation-reared mice the function of 5-HT1A measured by GTPgammaS binding is increase

[207] [65]

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[170,195,208,209] [129] [176] [196] [210] [194,210] [211] [212] [213]


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mGluR5 levels in the dorsal PFC was reported by rearing Sprague–Dawley rats in isolation from whereas, no change was monitored in the ventral PFC or striatum, hence in the dorsal PFC decreased mGluR1 and mGluR5 protein [179]. In another study, under chronic social isolation stress have reported reduced levels of glutamate receptors in cortex and hippocampus [233,234]. To explain the SI-induced behavioral outcomes a study was conducted and result of study showed the decreased glutamate and glutamine may suggest the neuron-glial integrity was implicated by chronic SI by neurochemical and biochemical changes which leads to SI-induced behavioral abnormalities.The concentrations of glutamate and glutamine in the dorsal hippocampus was significantly decreased by chronic SIS but remains same in the cerebral cortex as oxidative stress is more severe in the hippocampus than in cortex in terms of the changes in antioxidant enzymes [235]. According to previous studies, postweaning social isolation leads to alters various behavioral patterns including hippocampus dependent activities. The result of this study reported that after postweaning social isolation caused an increased expression of several N-methyl-D-aspartate andkainate receptors (for example, Grin2a in CA1, Grik4 in CA3) in contrast to decreased expression of GABAA receptor subunit genes, and Gabra1, Gabra2, Gabra4, Gabra5, Gabrb2, Gabrg1, and Gabrg2 under postweaning social isolation [236]. The adolescent SI increased the expression of glutamate markers in the adult mPFC but not adult [53].

3.3.3. Gamma aminobutyric acid (GABA) The gene expression is regulated by neuroactive progesterone metabolites and thereby the function of GABAA receptors during social isolation, the increased neuronal excitability consequent to the reduction of GABAergic tone elicited by social isolation. The 5-HT3 receptor is a ligand-gated ion channels that is permeable to Na+, K+, and Ca2+ ions, expressed on GABAergic neurons in the DMN among hypothalamic region, the release of GABA is increased when the 5-HT3 receptor expressed on GABAergic neurons to suppress neuronal excitation caused decreased SI time by GABA antagonists [214]. Experimental data demonstrate that GABAB antagonist has antidepressantlike activity, the involvement of GABAB receptors in the pathophysiology of depression and GABAB receptor knockout elevated anxious behavior in mice [215–217]. It is believed that the effects of GABAA receptor agonist are antagonized by SIS [218]. Applying social isolation for 7 weeks alters GABAergic system in adolescent mice leads to a decrease in seizure threshold [80]. Social isolation of 3 months leads to 70% increase in flunitrazepam binding affinity in hippocampal tissue might be due to alteration in endogenous levels of allosteric modulators of the GABA receptor in wistar rats [219]. Social isolation is characterized by low level of neuroactive steroids leads to an upregulation of GABAA receptors subtype (containing of α and δ subunits combination) due to overexpression of α and δ subunits [220]. Marked reduction in the basal cerebrocortical and plasma concentrations of progesterone was observed by mild chronic stress due to social isolation of rats for 30 days [160]. The increased susceptibility to picrotoxin (GABA antagonist) and a reduced affinity for allopregnanolone (modulator of GABA) observe in social isolates during seizure episodes [80]. In SIS rats, a reduce number of parvalbumin and calbindin positive in GABAergic interneurons of hippocampus [221,222]. Chronic SI-induced aggressive behavior in mice have been suggested to be associated with the down-regulation of 5-HT3 receptor protein levels in the hypothalamic regions, because most of 5-HT3 receptor is expressed on GABAergic neurons in hypothalamus leads to decrease in release of GABA, contributing to the enhancement of aggression level in chronic SI mice due to hyper-activation of neurons [206].

3.3.5. AMPA receptor It was demonstrated that by the activity of the AMPA receptor in the amygdala exerts anxiety and depression like behaviors [237]. Moreover, the up-regulation of AMPA receptor protein levels in amygdala of chronic SI-induced mice have been suggested to be associated with depressive like symptoms confirmed by measuring the protein levels of AMPA receptor subunits GluR1 and GluR2 [206]. Previous studies shown, SIS mice were deficient for the GluR1 subunit-containing AMPA receptors exerted a reduced inter-male aggression which shows the involvement of AMPA-type glutamate receptors in the management of social behavior [238]. By contrast in mice with chronic mild stress the increased function of AMPA receptor induced an antidepressant like effect [239] and Ketamin which is a NMDA receptor antagonist exerted its antidepressant activity by enhancing activation of AMPA receptor [240] whereas, Ketamin abolished SIS induced chronic stress [241].

3.3.4. Glutamate It has been well documented that excitatory synaptic transmission such as glutamate is increased by SIS and leads to disturb the expression and function of receptors in the CNS [84,223]. It has been evaluated that stress-induced increase in neurotransmission of glutamatergic system leads to excitotoxicity, causes brain injury through activation of NMDA receptors [224,225]. In the PFC of isolates, there was no change in basal glutamaterelease, measured by micro dialysis [179]. It has been well documented that isolation rearing causes long-term organizational and functional changes to the hippocampus and cortex, leads to reduced glutamate function [43]. The isolation-induced locomotor hyperactivity tends to enhance by sub-chronic administration of phencyclidine which is anon-competitive NMDA receptor antagonist. An altered function of glutamate and acetylcholine release leads to cognitive disruption, it is important to understand the various tonic mechanisms that regulate function of glutamate [43,226]. In the PFC and hippocampus of mice the binding activity of the group II metabotropic glutamate receptor (mGluR2/3) is increased by SIS [227]. It is well documented that in socially isolated animal’s metabotropic glutamate receptors (mGluRs) undergo functional changes [227]. Isolation-rearing induced abnormal behaviors are reversed by 5-HT1 A receptor agonists and metabotropic glutamate 2/3 (mGlu2/3) receptor agonists [228–231]. It was reported in a study that by following 26 days isolation of Sprague–Dawley rats by using microarray analysis,observed an increase in mGluR6 and AMPA3 inotropic glutamate receptor subunits in the medial PFC [232]. A specific decrease in mGluR1 and

3.3.6. Noradrenaline Previous studies reported an increase in noradrenaline turnover was observed in the hippocampus, cortex and cerebellumof isolation-reared Wistar rats [121]. Furthermore, social deprivation increases aggressioninduced adrenaline stress responses [119]. Under Social isolation stress isolates show improved retention in the water maze due to increased level of NA, normalized by NA depletion [175]. In SIS the noradrenergic function is reduced in response to stress as exemplified by the reduced release of noradrenaline confirmed from five minute tail pinch test [242]. In isolated animals stress-induced reduction of NE in basal levels as well as in ventral striatum [243–245]. In isolates hippocampus clonidine-induced hypoactivity increased but post-synaptic α2 adreno-receptor activity remained unaltered due to enhanced presynaptic α2 function with increased α2 receptors [246]. In isolates hippocampus, Idazoxan-induced NA release was greater due to altered sensitivity of presynaptic α2 autoreceptors [247]. Previous studies shows no effect of SIS on basal but K+-induced dorsal hippocampal NA release increased might be due to the enhances presynaptic α2 autoreceptor function of NA nerve terminals in isolates [247]. Moreover, a decrease in number of α-2 adrenoreceptors and supersensitive α-1 in striatum of isolated ratsdemonstrated that striatal NE tone could be reduced by isolation stress [169]. 3.3.7. Opioid system In regulation of stress induced behaviors opioid system plays a key 1211


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results of a study indicated the altered endocannabinoid system in ananimal model of aspects of schizophrenia which implies that socially isolated rats under different housing conditions may provide newinsight into the role of the endocannabinoid system in the development of psychoses [279]. SIS in Adolescent result in profound perturbations in adult behavior, the social isolation mediated behavioral deficits by adolescent in rats can be ameliorated by chronic administration of a cannabinoid CB1 receptor antagonist or by blocking dopamine D2 receptors in the prefrontal cortex. The influence of SIS by the adolescence on the mature expression and/or surface distribution of D2 and CB1 receptors were investigated. The result of study showed that SIS leads to selectively decreased dendritic D2 immunogold labeling in the PFC which was only evident in dendrites that were not contacted by axon terminals containing CB1 while there was no apparent change in the expression of CB1 or D2 receptors in presynaptic terminals [280]. During an investigation to evaluate the relation between cannabinoid system and SIS in depressive-like behavior and anxiety like behavior researcher found that behavioral abnormality followed by SIS was mitigated after administration of WIN55, 212-2 (non-selective cannabinoid receptor agonist). By administration of AM-251 (cannabinoid receptor type 1 antagonist) and AM-630 (cannabinoid receptor type 2 antagonist) depressive-like effects induced by SIS were significantly increased. Upon co-administration of AM-251 and AM-630, the antidepressant effect of WIN55, 212-2 was significantly reversed in IC animals which leads to suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS [281].

role [248,249]. At the endocrinological,behavioural, and neuronal levels the stressors induce activation of opioid networks [250,251]. In addition, it has been shown that the opioid system is known to affect mood and emotional responses, mediates some antinociception like effects of fluoxetine, and has role in modulation of a variety of functions like seizure susceptibility,pain,addiction and neurotransmission [252–255]. Large body of evidence has documented the influence of postweaning SIS to alter the opioid system regulation due to which seizure susceptibility may be aggravated [119,256]. The negative consequences of post-weaning SIS are associated with opioid system as during social isolation in adult ratsfor seven days increased the mPFC opioid binding [257]. It has been reported that in post weaning SIS opioidergic and GABAergic system may be involved in the proconvulsant effect [80,248]. Past studies have shown that endogenous opioids induce their effects by acting on their receptors including mu opioid receptors (MORs), delta opioid receptors (DORs) and kappa opioid receptors (KORs).Each of opioids receptor show a certain cellular response, distinctly regulate the emotional responses and their expression in the brain elevate after stress experience [258–261]. Opioid peptides play a key role in early social interactions, are involved in parental bonding and play behavior in juvenile [257,262,263]. The peptides have different selectivity towards the opioid receptors, distinct neurobiological functions and regulate stress response in the brain. Stress response in the brain is regulated through effects on different receptor system, Metenkephalin-Arg6Phe7 (MEAP) on δ and μ opioid receptors, dynorphin B (DYNB) on κ opioid receptors and nociceptin/orphanin FQ (N/OFQ) NOP receptors [250,251] (Table 6).

3.3.9. N-methyl-D-aspartate (NMDA) receptor N-methyl-D-aspartate (NMDA) receptors have attained special attention because of their involvement in the pathophysiology of a vast number of nervous disorders such as depression, epilepsy, schizophrenia, and anxiety [240,282,283]. Previous data showed that in both human and animal studies blockade of NMDA receptors is not only able to reduce detrimental impacts of stress but also exerts anxiolytic, anticonvulsant, antidepressant properties [284–286]. Another research has shown that SIS increases NMDA receptor binding capacity in the frontal cortex [287]. In cortico-limbic areas juvenile SIS has been reported to change excito-inhibitory balance by alteringthe regulation of NMDA receptors and nitrergicsystem [81,288,289]. In adolescence SIS induced depression like behavioral effect in the FST and splash test is reversed due to NMDA receptor blockade by administration of sub-effective doses of NMDA receptor antagonists including ketamine (1 mg/kg), MK-801 (0.05 mg/kg), and magnesium sulfate (10 mg/kg) whereas, failed to alter anxiety-like behaviors of SIS [290]. Recent studies have shown the involvement of NMDA receptor subunits NR2 A and NR2B in the pathophysiology of depression and anxiety [291]. Other studies indicate that NR2B subunit of NMDA receptor is potently involved in various pathophysiological processes such as epilepsy and developmental plasticity [85,292,293]. Recent studies revealed the involvement of NR2 A in mediating the anxietylike behaviors [294]

3.3.8. Cannabinoid system The cannabinoid systems consist of the CB1 and CB2 cannabinoid receptors and are considered as an important neuromodulator in the central nervous system [272]. Recent studies demonstrated that the different pathways including the modulation of HPA axis are involved in the antidepressant effects of cannabinoid system [273]. The modulation of neuroinflammation and regulation of release of neurotransmitters is also exerted through activation of HPA axis [274,275]. Previous studies have shown that,in different regions of the brain such as amygdala, nucleus accumbens (NAc), hippocampus, and pre-frontal cortex (PFC), the expression of the CB1R is altered by fear, stress, and emotions [276]. Studies showed the involvement of cannabinoid receptors in depression, little is known about the relation between cannabinoid system and SIS as there is no evidence showing that cannabinoid agonists have beneficial effects in depression following SIS paradigm [223,277]. Previously data demonstrated that the 9-tetrahydrocannabinol (9-THC) which is a major psychoactive constituent of Cannabis sativa is involved in disruptions in sensorimotor gating in socially isolated rats [278]. The SIS has been shown to produce behavioral and neurochemical alterations in schizophrenia and a dysregulation in both the endocannabinoid and dopaminergic systems has been observed in schizophrenia. These Table 6 Effects of SIS on Opioid system. Effect Opiate Receptors

Reference

Increases the density of mu receptors by 58% in basolateral amygdala (BLA) and33% in the bed nucleus of striaterminalis (BNST) shown by SI Under stress condition an enhancement in expression and release of β-endorphin due to interaction between β-endorphin and the mu opioid receptor agonist The effect of tramadol, as a μ-opioid receptor activator was studied on serotonin and norepinephrine transporters, shows 5-HT reuptake inhibited by tramadol Under acute SIS an association between elevated corticosterone and central N/OFQ Short single housing leads to acute SIS leads to increased levels of IR-N/OFQ in amygdala and a similar trend in hypothalamus Low levels of endogenous opioid peptides observe in SIS Disruption of social interactions early in life have little effect on basal levels of immune-reactive DYNB Single housing cause SIS, short single housing cause elevated immune-reactive (IR) corticosterone accompanied by increased levels of N/OFQlevels, whereas changes in MEAP were only found after 7 days(long single housing) and DYNB was not affected at all

[119] [258,259,264] [265] [266,267] [268] [269] [270] [271]

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the involvement of mitochondrial dysfunction [318,319]. Under stressful conditions, oxidative damage occurs due to excessive amounts of reactive oxygen species (ROS) generated by mitochondria which correlates with glutathione (GSH) and ATP depletion [320–322]. Furthermore, clinical studies revealed that SIS-induced O&NS contributes to neurochemical and behavioral alterations in rodents [323,324]. The increase in the level of O&NS caused by increase level of NO leads to cell injury and mitochondrial dysfunction [325]. In addition evidence reported that impairments in the oxidant/antioxidant equilibrium is due to boosting the generation of ROS and NO in the specific brain regions such as hippocampus under effect of psychosocial stressors [326]. Another study shows that cellular oxidative stress leads to SIinduced behavioral outcomes due to 6–8 weeks induced oxidative damage in the brain by SIS caused increased levels of nitric oxide and depleting brain endogenous antioxidant and glutathione content [327]. Impaired mitochondrial energy production is associated with decresed levels of N-acetyl-l-aspartate (NAA) [328]. SIS induced reduction in levels of NAA and phosphorylcholine (PCr) in the hippocampus indicated a deficit in energy metabolism in brain cells (Patel TB, Clark, 1979).The increased production of reactive oxygen species (ROS) and decreased antioxidant capacity of neural tissue leads to inhibit mitochondrial oxidative metabolism and interrupting mitochondrial energy production thus impairing neuronal viability and neuron-glial integrity, confirming the decreased activity of mitochondrial enzymes containing redox-sensitive active sites (aconitase, succinate dehydrogenase, and CK) by chronic SIS [329]. Chronic SI inhibits the activities of catalase and glutathione peroxidase (GPx) in the hippocampus [132]. Furthermore,the activities of the antioxidant enzymes catalase, GPx, and SOD decreased by SIS of 8 weeks in the rat hippocampus and increased the concentration of H2O2 in same area of brain.The mechanism for the SIS induced oxidative imbalance in the hippocampus is due to decrease in the antioxidant capacity of brain tissue and increase in production of ROS including H2O2 causes a poor systemic energy conditions set by SIS [235]. Evidence reported that mood disorders with mitochondrial disorders are of most prevalent symptoms observed in children and adolescents [330,331]. The anxiety-like behaviors of socially isolated animals were attenuated by tropisetron through correcting the mitochondrial dysfunction and moderating the nitrergic system in hippocampus [332]. Mitochondrial performance and O&NS were reported as underlying mechanisms involved in pathogenesis of anxiety disorders, anxiogenic effect of early SIS was partly mediated by NOinduced O&NS along with impaired mitochondrial function. Mitochondrial function negatively upsets by early SIS due to by massive production of ROS and NO as well as a significant decrease in ATP and GSH levels along with impaired mitochondrial function [62,332]. The disruption of mitochondrial dysfunction impacts oligodendrocytes in the prefrontal cortex, and results in impaired myelination due to increased oxidative stress [333,334]. A number of studies reported that the social isolation stress after weaning display mitochondrial dysfunction and increased oxidative stress in cortical areas of mice [74,335]. The disruption in oxidation-reduction (redox) homeostasis by both impairing antioxidant defences and promoting free radical formation in the hippocampus and prefrontal cortex was observed by psychosocial stress [336]. A study reported that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex while there was no significant interaction between social isolation stress and glutathione deficiency. The neurochemical alterations caused by SIS leads to impaired glutathione synthesis in mouse model [337].

whereas, administration of selective NR2B antagonists exert antidepressant effects [291]. Previous study demonstrated the involvement of post-weaning social isolation stress via altering the expression of specific genes induces a variety of behavioral deficits. Regarding this impact of gene expression, SIS selectively increases the expression of 5hydroxytryptamine-2C (5-HT2C) and NR2 A in different regions of brain, the expression of NR2 A was upregulated in prefrontal cortex of brain [159]. In isolation-reared rats mRNA of the Nmethyl-d-aspartate (NMDA) receptor subunit NR1 A was decreased in the hippocampus as shown by a situ hybridization study [177]. It has been well documented that NR2B is responsible for massive influx of calcium into postsynaptic hippocampal neurons that leads to hyper-excitability and activation of variety of biological pathways including nitrergic system [295]. SIS is able to alter NMDA receptor activity as reported by previous animal studies. SI induced upregulation of NR2 A expression in the prefrontal cortex (PFC) of rats was observed by researchers [296]. Also, SIS caused increased mRNA expression of NR2 A and NR2B in the hippocampus [84]. In another study, increased binding of NMDA receptor in frontal cortex was observed [287]. Studies indicated in IC mice the involvement of NR2B NMDA receptor subunit in the proconvulsant effect of juvenile SIS [297]. Another study reported that in mice the social isolation results in an altered response to a ketamine (NMDA receptor antagonist), in the prefrontalcortex resulted in an increased ketamine-induced glutamine increase and a reduction of GABA concentration [298]. The higher synaptosomal NR2 A and NR2B levels in the hippocampus were observed in SI mice due to social isolation-induced increased expression of NMDA receptors in the hippocampus which caused stress exacerbation of aggressive behaviors [299]. 3.3.10. Nitrergic system (nitric oxide -neurotransmitter and second messenger molecule) Nitric oxide (NO) which is a neuromodulator, a neurotransmitter,highly reactive second messenger molecule, with proconvulsive or anticonvulsive properties and considered as an important neuronal messenger in the CNS [300]. NO contributes to a variety of physiological and pathophysiological processes by acting as biological molecule which initiate a vast and complex signaling processes in the hippocampus (HIPP), within the brain and periphery including learning, memory, Pruritis, pain modulation, synaptic plasticity, seizure susceptibility, stress, and depression [284,301–305]. In brain NO is synthesized from L-arginine by nitric oxide synthase (NOS), consisting of three isoforms, iNOS (inducible), eNOS (endothelial) and nNOS (neuronal), exert its biological activities by the soluble enzyme guanylylcyclase (sGC), followed by rise in second messenger cyclic guanosine monophosphate (cGMP) contents, are the key pathways for NO actions in the brain [306]. In response to stressful stimuli in thehippocampus,iNOS and nNOS have been reported to increase the NO levels [307,308]. NO system plays an important role in many neurodegenerative disorders such as neuronal damage induced by brain ischemia, Parkinson's and Huntington's diseases and Epilepsy [309]. Juvenile SIS enhances susceptibility to pentylenetetrazole (PTZ)induced seizures in mice by enhancing the nitrergic system activity in the hippocampus of brain [310] In adolescent mice, SIS is associated with an increased seizure susceptibility to pentylenetetrazole [16]. Another study showed that SIS in adolescence caused a variety of behavioral deficits and results showed that lithium exerts a protective influence against the proconvulsant effect of adolescent SIS. This effect was exerted by nitrergic system that includes activation of neuronal NOS in the hippocampus [311] (Table 7).

3.3.12. Inflammatory factors/Cytokine hypothesis Important cytokines according to a modern classification, involved in neuro-inflammatory processes (IL-6, TNF-α) are member of neurokines upper family belongs to NTFs [338]. A vast amount of evidence

3.3.11. Oxidative and Nitrosative Stress (O&NS) mediated mitochondrial dysfunction A number of studies revealed in etiology of psychiatric disorders, 1213


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Table 7 Effects of SIS on Nitrergic system. Effect Nitric oxide (NO)

Reference

Exposure to chronic stress such as SIS results in NO overproduction due to overexpression of nNOS in the hippocampus through glutamate excitotoxicity In socially isolated animals the increased activity of NOS or NO levels in the HIPP are correlated with seizure vulnerability changes In various studies SIS leads to increased expression of NOS isoforms or elevated levels of NO metabolites in the limbic areas In mediating the depressive and anxiogenic effects of SIS there is marked role of overproduction of cortical NO via activity of iNOS in the cortex SIS increased the NO levels in the HIPP due to the upregulation of nNOS but not iNOS Underlying mechanisms by which SIS primes seizure vulnerability in the adolescence has correlated with activation of nitrergic system in the hippocampus and enhanced seizure susceptibility in the PTZ seizure model, additionally proconvulsant properties of SIS were modulated by subeffective doses of L-NAME and 7-NI while proconvulsant effect of SIS was aggravated by L-arg administration In recent studies in adult mice following SIS, demonstrated that nitrergic system and NMDA receptors contribute to development of proconvulsant effect and depression like behaviors

[312] [313] [289,314] [225,289,315] [316] [16]

in this process [353]. A recent study evaluated that the effects of a prolonged corticosterone administration differ between adolescent and adult rats because Hippocampal expression of BDNF was but increased in the adolescent rats while it decreased in the adult rats. In contrast, SIS seems to decrease hippocampal BDNF irrespective of age at which the animals were isolated [354]. The chronic social isolation impairs antioxidant defenses and disrupts redox homeostasis in the brain as demonstrated by number of researchers [336,355]. To produce oxidative and nitrosative status, BDNF transcription factors NF-κB and AP-1 are sensitive and active [356]. These transcription factors NF-κB and AP-1 have been implicated to play a role in the pathogenesis of neuropsychiatric disorders, including schizophrenia and depression [357]. A study revealed the involvement of BDNF in the pathogenesis of stress-related mental illness instead of the fact that the mechanisms linking chronic social isolation, BDNF expression and the elicited behavioral. However, an altered expression of BDNF in the brain of rats reared or housed in social isolation was checked and result of study showed a decreased expression of BDNF in the hippocampus and this downregulation of BDNF seems to be associated with increased anxietylike symptoms [358] (Table 9).

Table 8 Effects of SIS on Inflammatory factors and Cytokines. Effect Inflammatory factors

Reference

After contextual fear conditioning, Social isolation for 1 or 3 hour cause an increase in IL-1 β protein in the cerebral cortex and hippocampus In depression model of chronic mild SIS, the decrease in the levels of IL-2↓, IL-4↓ and showed higher basal corticosterone in isolated mice In rats by social isolationleads to increase the balance of versusantiinflammatory cytokine and alteration in kynurenine metabolism with a decrease in neuroprotective ratio whereas,increase in levels of TNF-α↑ and IFNɤ↑ Under chronic SIS exposure disruption of the HPA axis activity is result of NO overproductions and inflammatory cytokines, including IL-1β.In socially isolated animals previous research demonstrated the up-regulation of IL-1β gene was observed in both HIPP and PFC of IC mice.

[130,340]

[290,317]

[341]

[342]

[343]

indicates that the system of inflammatory cytokines regulate maintenance, development, survival and the demise of neurons and glial cells as well as the alterations in levels of cytokines, NTFs and their receptors can modify normal neuronal function [339] (Table 8).

3.4.2. Early growth response transcription factor genes (Egr-1 toEgr-4) Some aspects of synaptic plasticity-related cognitive performance is regulated by early growth response transcription factor genes (Egr-1Egr-4), synaptic activity-inducible immediate early genes [373]. AmongEgr family Egr-1 is important molecule for triggering activitydependent modifications in the visual cortex and a useful marker of sensory input and for the consolidation of the memory [374]. The social isolation stress down-regulate the expression of Egr-1 protein and its gene in an isolation-period dependent manner in the cerebral cortex but not in the striatum whereas, Egr-2, -3 and -4 protein levels is not affected by social isolation stress [375]. In schizophrenic patients the expression level of Egr-1 gene is decrease in the postmortem brain [376]. In socially isolated mice the expression levels of Egr-1 is decrease in the cortical neurons plays at least a role in the onset of cognitive impairment due to SIS [375]. It was reported in the frontal cortex that down-regulation of Egr-1 mRNA is occurred as early as 7 days after starting social isolation housing leads to induce the similar behavioral changes induced by SIS such as impaired prepulse inhibition, enhanced aggressiveness, and reduced susceptibility to pentobarbital anesthesia [230,377]. Neurochemical changes associated with down-regulation of Egr-1 mRNA in the frontal cortex included down-regulation of type I 5reductase, a key enzyme involved in neurosteroid synthesis in the frontal cortex, which is responsible for major behavioral changes of SIS [81,378–380]. Result of a study reported that SI stress causes epigenetic changes of neurodevelopmental disorder-related protein expression, and in rat hippocampal neurons Egr-1 was also increased by epigenetic regulation [104].

3.4. Neuroplasticity-related signaling pathways 3.4.1. Involvement of Neurotrophins/ Neurotrophicfactors (NTFs) The development and integrity of the noradrenergic, serotonergic, dopaminergic, cholinergic and glutamatergic systems is affected by Neurotrophicfactors (NTFs). The balance between support and dysfunction of NTFs leads to the base of the link between neurodegeneration and inflammation [338]. BDNF is a member of the neurotrophin family of growth factors and it probably being importantly involved in various neuropsychiatric diseases [344,345]. Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal plasticity, strongly affects synaptogenesis,neuronalsurvival,spineformation,long-termpotentiation,neuronalexcitabilityand adult hippocampal neurogenesis [346–350]. In a depression model of social isolation, 6 h period of social isolation immediately after contextual fear conditioning impaired memory for context fear measured 48 h later and decreased level of neurotrophins especially BDNF mRNA in the dentate gyrus and the CA3 region of the hippocampus assessed immediately after the isolation [130]. Recent studies indicated that it may create an important link between stress and mental illnes as the reduced BDNF levels in the peripheral blood are observed in mental disorders [15,351]. Studies showed the involvement of serotoninergic system in mediating the effects of social isolation on BDNF expression. As number of studies has reported that SIS exerted multiple effects on the serotoninergic system and as a result, serotonin can affect BDNF chromatin remodeling [13,30,352]. In chronic social isolation there is reduced transcription of the BDNF gene and glucocorticoids play a central role 1214


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Table 9 Effects of SIS on Neurotrophicfactors. Property

Effect

Reference

BDNF

Hippocampal BDNF was decrease in rats adult when socially isolated Studies shows as an upstream transcriptional activator of BDNF, CREB expression in hippocampus is decreased under influence to specific type of stressor Post weaning SIS for 4.3 weeks leads to decreased BDNF protein expression in the hippocampus Postweaning for 2 and next 3 weeks of social housing leads to decresed BDNF mRNA and protein expression in the hippocampus and increased BDNF mRNA and protein expression in mPFC Postweaning for 5.7 weeks leads to decreased BDNF protein expression in th central amygdala and the hippocampus Postweaning for 8 weeks decreased BDNF protein level in thestriatum In Adolescent social isolation for 9 weeks leads to decreased BDNF protein levels in the hippocampus In Adolescent social isolation for 2 for next 2 weeks of social housing) weeks leads to increased BDNF protein levels in mPFC In Adults social isolation for 3 weeks leads to decreased BDNF mRNA expression in the hippocampus and increased BDNF mRNA expression in PFC In Adults social isolation for 6 weeks leads to decreased BDNF protein levels in the hippocampus In Adults social isolation for 8 weeks leads to decreased BDNF expression in the dorsal hippocampus In the temporal cortex of isolated rats the level of N-acetyl aspartic acid (NAA), a marker of neuronal integrity is reduce indicating possible neuronal loss or dysfunction whereas,no similar change has been reported in the frontal cortex, hippocampus or striatum Synaptophysin is a synapsespecific protein associated with presynatic release of neurotransmitters at the synapses and as a marker of synaptic activity, after 8 weeks of isolation in Lister hooded rats the level of Synaptophysin was reduced in the molecular layer of the dentate gyrus The expression of synaptophysin is decreased by SIS in hippocampus

[131] [359]

N-acetyle Aspartate Synaptophysin

[360] [361] [362] [363] [364] [365] [366] [367] [368] [369] [370,371] [372]

phosphorylation in limbic area is altered by SIS leads to neuro-degeneration, altered mood state and altered neurotransmitter synthesis [396]. Furthermore, SIS causes a decrease in the expression of hippocampal pCREB due to decrease in the expression of synaptophysin which is a protein downstream to pCREB, regulate neurotransmitter packaging in the presynaptic knob leads to reduced apical dendritic arborization in hippocampus [372].

A recent study reported that week 2 after commencement of SI, in relevant to symptoms of developmental disorders such as ADHD,Sansonintoat doses of 800 and 2400 mg/kg/day ameliorated SIinduced behavioral abnormality. The result showed that Sansonintoameliorate SI-induced behavioral abnormality by down regulating the expression of Egr-1 by SIS [381]. 3.4.3. Cell proliferation By various manipulations of the social environment adult neurogenesis is affected a lot in established proliferative zones which are subventricular zone of the lateral ventricle and dentate gyrus (DG) of the hippocampus [157,382,383]. The measure of survival or cell proliferation can be increased [41,384] decreased(Schoenfeld et al 2012).There might be no change under influence of social isolation and is effected by isolation paradigm, with brain region (DG or SVZ), species and, sex [42]. A number of studies reported that environmental or social stressors tend to decrease neurogenesis [136,385,386]. Social isolation in rats for 15 days leads to increase in the number of adult generated hippocampal cells expressing a neuronal phenotype [41]. A study revealed that in adult P. californicusmice,social isolation increases adult cellular proliferation and cell survival in DG of the hippocampus, confirms that social isolation should have particularly acute effects on neurogenesis in highly social species of mice i.e. Peromyscuscalifornicus [387].

4. Conclusion The Neurobiology of Social Isolation Stress has provided an overview of recent advances in the role of Neurotransmitters and chemical mediators which are involve in pathogenesis of social isolation stress because less focus has been given to the molecular mechanisms involve as underlying cause of disease. We have especially focused on the dysregulation in the balance of neurotransmitters in brain either on level of presynaptic or postsynaptic release leads to cause stress if animals kept socially isolated as reported by many researchers in field of psychiatric and brain disorders. Along with the changes in level of neurotransmitters, exposure of social isolation stress on endocrine function in animal models of rat or mice leads to change in the level of number of hormones which induce a change in the function of endocrine system. It showed the potential correlations with symptoms of neuropsychological disorders due to its growing impact on the brain signaling by interrupting the levels of different neurotransmitters. Elucidation of acute of chronic social isolation stress in early stage of life could be used as diagnostic tool or indicator of different type of neurological and psychiatric disorders like schizophrenia, epilepsy, anxiety, depression or memory loss. After identification of the most key regulators, chemical mediators and neurochemicals which are involve in molecular mechanism of social isolation stress, a new area of research has emerged. This review gives insights into the role of a number of neurobiological compounds involved as underlying cause of social isolation induced psychiatric and neurological disorders and their prognosis which will help researchers to elucidate the major signaling mechanisms underlying some symptoms of major depressive disorder.

3.4.4. C-Fos Expression A significant elevation in c-fos mRNA protein is a useful and frequently used method to elucidate neural circuitry and induced a variety of psychological and physiological challenges as shown by previous studies [388,389]. It has been reported in the prefrontal cortex, dorsal raphe nucleus, and ventral tegmental area of male isolation-reared mice show increased encounter-induced c-Fos expression [163]. Many other studies demonstrated in the nucleus accumbens shell of group- and isolation reared mice, encounter stimulation increased c-Fos expression to a similar degree [390–392]. In SIS induced brain immunoreactivity for c-Fos revealed the activation of the medial and basolateral amygdala the hypothalamic para-ventricular nucleus (PVN) and hypothalamic attack area were involved in aggressive behavior towards an intruder [393].

Availability of data and materials

3.4.5. CREB Expression In synaptic plasticity the altered expression of CREB in hippocampus plays a regulatory role that could induce functional deformity in brain and leads to phenotypic abnormalities [394,395]. CREB

All the materials in drafting this manuscript is already published and is available in public domain.

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Ethics approval and consent to participate [24]

Not applicable.

[25]

Competing interests All the authors declare no competing interests.

[26]

Funding

[27]

This work was supported by a grant (96002757) from Iran National Science Foundation (INSF) and Drug Detoxification Health Welfare Research Center, KPK, Pakistan.

[28]

Author’s contribution

[30]

Faiza Mumtaz and Muhammad Imran Khan prepared the draft of manuscript. Muhammad Zubair prepared the tables and figures while Ahmad Reza Dehpour reviewed, outlined and revised this manuscript.

[31]

Acknowledgements

[33]

We would like to aknowledge the valuable suggestion and comments of late professor Sattar Ostadhadi in organizing tables.

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