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Cognitive Dysfunction in Depression: Lessons Learned from Animal Models Gislaine Z. Réus*,1,2, Helena M. Abelaira2, Daniela D. Leffa1 and João Quevedo1,2

1Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA 2Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

Abstract: Major depression is a serious public health problem and one of the most common psychiatric disorders, and it is estimated that millions of people are affected worldwide. In addition, patients having depression present cognitive impairments, which could influence treatment adherence and long-term outcomes. Although, studies have shown that alterations in the hypothalamic–pituitary–adrenal axis, in inflammatory and antioxidant systems, and changes in intracellular pathways are involved in the cognitive impairment verified in depressive patients, it was unclear how these alterations occur. In this context, animal models of psychiatric disorders are revealed as good alternatives for the study of pathophysiology of these and associated factors. Thus, this review will highlight studies with animal models that have helped in understanding the mechanisms involved in cognitive impairment associated with depression, as well as focus on effective treatments that assist in improving both depression and cognition.

Keywords: Animal models, cellular survival pathway, cognition, depression, immune system, neuroendocrine system.

INTRODUCTION

Depression is very common and a severe mental disease [1]. A single occurrence of major depressive disorders (MDD) is described as the presence of minimum five symptoms during the period of two-weeks, as well as persistent depressed mood and anhedonia; Furthermore, negative meaning about life and self, are essential characteristics of depression [2]. Identification and management of MDD have conventionally focused on mood signs; though, neuropsychological dysfunctions are frequently existent and have been shown to subsidize low functional performance [3]. Moreover, cognitive deficit has been showed in subjects with depression and is measured as an essential component of this disease agreeing to the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders criteria [2]. In this context, some evidence suggests a correlation between severe depression and greater cognitive impairments, such as neuropsychological deficits in memory, speech and language, focused and persistent attention, attentiveness and executive functions [4, 5], unlike minor depression which has wispy or no action on mental deficit [6]. Thereby, neuroimaging studies in depressed patients have found changed in the structure and functioning of the brain, such as, (1) reduction in hippocampus, diminished volume of orbitofrontal cortex and increased amygdala volume for negative stimuli and (2) reduction responses in

*Address correspondence to this author at the Department of Psychiatry and Behavioral Sciences, Center for Experimental Models in Psychiatry, Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Tel: 713 486 2653; Fax: 713 486 2553; E-mail: gislainezilli@hotmail.com

anterior cingulated cortex and hippocampus for positive stimuli [1]. Some studies have shown that stress can lead to damage and atrophy of neurons in some brain regions, but more specifically in the hippocampus which is involved with memory and learning process [7, 8]. Furthermore, the hippocampus is involved in connections through the prefrontal cortex and amygdala, regions that are associated with functions, such as cognition and emotion which may be associated with other symptoms of major depression [9]. However, Hamilton and Gotlib [10] demonstrated that patients with depression had an increase in amygdala activity in response to a negative memory. However, the response in the cortical areas of the brain during the execution of a memory task is reduced in major depressive disorder [11], suggesting that biological bases of depression, especially those related to cognitive deficits, are not yet fully known. In the context of functioning in depression, it is important to note that a large number of patients did not respond to the monoaminergic treatment (50% of treated cases achieve full remission), leading to decreased social activities, an impairment in work performance and in well-being [12], suggesting that these patients require additional therapeutic interventions [13]. In fact, depressed patients that present cognitive deficits do not respond to serotonin–norepinephrine reuptake inhibitor, suggesting that these patients require additional therapeutic interventions [14]. In contrast, fluoxetine, a serotonin reuptake inhibitor (SSRI) combined to long-term psychodynamic psychotherapy demonstrated to be effective for specific neurocognitive increases in patients with moderate depression [15]. Thus, suggesting that classic antidepressant join with other treatment can be more effective to treat both depression and cognitive impairment and treatments with new mechanisms

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of action that improve cognition, regardless of their antidepressant activity, can provide a clear therapeutic benefit to these patients [16]. Thus, animal models of psychiatric dysfunction have been described as important tools to investigate the neurobiology of depressive disorder and dysfunction, as well as to help in developing treatments with novel mechanisms of action for this disorder [17]. Thus, this review will instead focus on cognitive disturbances in depression, which are evident in patients who suffer from this disorder. Different deficits will be presented in the light of the existing findings from animal models of depression and how these animal models have helped to understand the mechanisms involved in cognitive deficits in depression.

MATERIAL AND METHODS

We conducted a review of computerized databases (i.e., PubMed) from 1996 to 2014. “MDD” was cross-referenced with the subsequent words: cognitive deficits, cognitive dysfunction, functional outcome and dementia. Cognitive dysfunction was cross-referenced with the subsequent words: depression and oxidative stress, depression and inflammation, depression and neuroendrocrine hypothesis. Bibliographies from identified papers were also verified to detect any other original articles that were associated with the goals of this review.

Evidence to Cognitive Impairment in Depression

Cognitive impairment is any medical condition that affects how the brain processes and stores information, resulting in the impairment of memory, attention, perception, and thinking [18]. Besides, the cognitive performance is related to the ability to regulate emotions, and emotional dysregulation is one of the central features of depression. Thus, individuals with depression can present moderate but significant cognitive deficits [19]. In this sense, studies have shown association among depressive symptoms, cognitive decline and dementia [20, 21]. In fact, Verdelho et al. [22] showed in older individuals that depression is related with an improvement to develop cognitive deficit. In addition, Zheng et al. [23] examined the occurrence of depression in subjects with Parkinson's disease (PD) and detected its characteristics. This work determined that depression is shared in PD and present same medical consequences. Moreover, depression is also present in Alzheimer-type dementia and may share a number of cognitive and affective symptoms, such as amnesia, attention deficit, impaired emotional reactions and a general lack of initiative [24]. The brain outline of cognitive impairment includes executive tasks as scheduling, set unstable, set keeping, problem solving, care and memory function [21, 25]. Memory deficits are categorized by deficiencies in delayed memory, temporal arrangement and conditional combined knowledge [21]. As a result the cognitive dysfunctions lead to poor classroom performance, low self-esteem, as well as academic and psychosocial failure [19; 26]. Wagner et al. [19] found significant deficits in children and adolescents with depression in inhibition capacity, phonemic verbal fluency, sustained attention, verbal memory and planning, as well as in semantic verbal fluency, learning and sustained attention tasks.

Furthermore, cognitive deficit in depressed patients have frequently been verified in the areas of thought, learning and memory record, and executive working, defined as set cognitive processing needing the management of numerous cognitive subprocesses to perform a specific objective [27, 28]. The cognitive features related with depression reproduce standards of operation in particular areas of the intellect, such as prefrontal, anterior cingulate, parietal cortices and subcortical regions, which regulate the neurobiology of memory and attention aspects [29-38]. Although it is clear that the presence of cognitive impairment in depression is independent of the clinical remission of psychopathological symptoms, the reasons for poor cognitive performance in depression remains unclear and very little is known around the pathophysiological events linking cognitive deficit and depression [39]. However, depression and cognitive deficit have been linked to a combination of dopaminergic, norepinephrinergic and serotonergic pathways in the limbic system. Thus, dopaminergic treatments, particularly pramipexole, are usually beneficial and lead to a period of restored behavior and mood due to antidepressant effects [40] hypothesized to be governed by dopamine receptor agonism in the limbic system [41]. The serotonin transporter regulates the whole serotonergic system in the brain and stimuli both the dopaminergic and norepinephrinergic process [42]. It has also been hypothesized that well-established antidepressants, such as SSRIs may improve depression in cognitive impairment as serotonergic neurons take up and decarboxylate levodopa, eventually leading to dopamine conversion [43]. Furthermore, studies have shown that target genes potentially play a role in the development of cognitive dysfunction in depression [38, 44]. Involving several favorable candidate genes for depression, the serotonin-transporter-linked polymorphic region SLC6A4 gene and the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) genes are widely studied for depressive illnesses all around the world [45]. Serotonin (5-HT) is known as a monoamine neurotransmitter that plays a major role in neural plasticity. The 5-HT system can be manipulated by different types of drugs like antidepressant agents, which cause alterations in 5-HT levels and thereby influence many brain regulated functions such as mood, cognition, perception, sleep and appetite [46]. In recent years, it has been well established that 5-HT not only influences brain functioning as a monoamine neurotransmitter but also affects brain development as a neurotrophic factor [46]. The BDNF is expressed in the brain and several tissues and has been proposed as a biomarker of depression [45, 47]. Studies show that the presence of low BDNF levels in the peripheral blood and postmortem brain of subjects with depressive symptons and that antidepressant administration enhances BDNF levels [48, 49]. Another gene involved in depression is glycogen synthase kinase-3 (GSK3) rs6782799, which is coded by GSK3A and GSK3B genes. These ubiquitous serine/threonine protein kinases acts in several cellular via covering neurodevelopment [50], and alterations in the modulation of GSK3B enzyme function have been shown as a risk condition of bipolar depression [51]. In addition, these genetic polymorphisms and negative life events have been correlated with emotional and cognitive control and some of the above mentioned brain alterations [39, 45, 52, 53].

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Moreover genetic polymorphisms, the epigenetic events in genes that act in the brain have been related with a variety of neurobiological functions comprising the central nervous system growth, memory, cognition and neurodegeneration [54]. In fact, DNA hypomethylation leads to enhanced gene expression, and to hypermethylation-induced silencing of the gene encoding [55, 56]. Thus, decreased expression of BDNF and SLC6A4 seen in chronic stress status may be related to the cognitive deficits associated with depression [38, 45]. In addition, the increase expression of GSK3 may partially contribute to depression or behaviors associated with depression [57]. Furthermore, neurodegenerative changes in depression may be caused by inflammation associated with neurotoxic actions of inflammatory cytokines, neurotoxic effects of glucocorticoids, reduced levels of polyunsaturated fatty acids, and oxidative and nitrosative stress [44, 58]. All these elements lead to the damage of fatty acids, protein and DNA in the brain cells [44]. In addition, Lindqvist et al. [59] measured inflammatory biomarkers in the cerebrospinal fluid biological samples from PD subjects and a control group to examine associations between non-motor conditions and inflammation. This work found that non-motor symptoms of patients with fatigue, depression, and cognitive deficit are related with greater cerebrospinal fluid levels of inflammatory biomarkers. The compilations of the data discussed in this study provide help to the idea of discrepancy factors that are involved in cerebral impairment clinically showed as cognitive deficit and depression. Indeed, more studies are needed to clarify the mechanisms by which cognitive deficit influences the development of depression and vice versa.

Preclinical Studies Relating the Interaction Between Depression and Cognition Impairment

Cognitive Dysfunction in Depression: Neuroendrocrine Hypothesis

It is well established that depression state can influence cognitive processes. However, the key point involved in the onset of cognitive impairment caused by psychiatric disorders is still the question of studies. In line with this, animals, such as rats and mice have long been on the front lines of research. It is remarkable that all animal models of depression have contributed to a better understanding of the neurobiology of this disorder, as well as associated symptoms [17]. In addition, cognitive components of emotional processing may be a powerful tool to identify unequivocal measures of emotion in animals and may serve as a translational tool in the study of affective dysfunction [60], thus, helping to enhance our knowledge of human mood disorders and to find implications pertaining therapy. The chronic mild stress is an animal model based on environmental manipulations, which induce anhedonia, one of the major symptoms of depression in humans [61-63]. Moreover, chronic mild stress induces in rodents, physiological alterations, similar to those found in individuals suffering from depression. For example, changes on hypothalamic–pituitary–adrenal (HPA) axis [62-64]. Interestingly, hyperactivity within the HPA axis is supposed

to be involved in the pathogenesis of stress-induced cognitive deficits [65, 66]. In fact, Lee et al. [66] reported that repeated administration of the exogenous stress hormone corticosterone (CORT) lead to progressive memory deficits in rats subjected to classical tests to evaluate memory that include passive avoidance and Morris water maze tests; however, treatment with Baicalin extracted from Scutellaria baicalensis and that possesses antioxidant and anti-inflammatory activities was able to attenuate exogenous CORT-induced destruction, as indicated by improved cognitive functioning during behavioral tests. Besides, Baicalin increased the expression of neurotrophin BDNF and transcription factor cAMP-response-element-bindingprotein (CREB) and normalized HPA axis (at least a reduction in CORT levels) (Table 1). The CORT was also pointed to be critically involved in mediating the harmful effects of stress on cognitive functions involving prefrontal cortex and hippocampus interplay [67]. The glucocorticoid secretion is known to activate specific brain areas, such as hippocampus, amygdala, and prefrontal cortex, which are enriched mineralocorticoid and glucocorticoid receptors, and these effects are responsible for encoding, processing, and retaining the information of emotional events [68, 69]. Glucocorticoids in dentate gyrus (DG) subregion of the hippocampus are profoundly affected by chronic restraint stress; stress further affects the expression of numerous genes associated with chromatin structure and epigenetic processes, such as Asf1, Ash1l, Hist1h3f, and Tp63 [70]. Rats exposed to chronic CORT also present gene alteration in the lateral nucleus amygdala. In fact, Monsey et al. [71] in a study on rats chronically exposed to CORT (50 mg/ml) showed an increase in the expression of the memory-related immediate early genes Arc/Arg3.1 and Egr-1 in the lateral nucleus amygdala, and an enhancement in consolidation of fear memory and long-term memory; on the other hand, treatment with fluoxetine (a SSRI) reversed persistent CORT-related increases in memory-related immediate early genes expression in the lateral nucleus amygdala and the CORT-related improvement memory consolidation of fear (Table 1). In a mouse model of depression based on a chronic (4 weeks) administration of CORT, it was demonstrated that cognitive deficits evaluated in different memory tests, for example, CORT-treated mice showed a decrease in time exploring the novel object during the test session and a lower discrimination index compared to the control mice, a characteristic of recognition memory impairment (Table 1) [72]. Moreover, associative memory was also impaired, as observed with a decrease in freezing duration in CORT-treated mice in one-trial contextual fear conditioning, thus pointing out the cognitive alterations in this model, beyond the alteration in spatial learning performance and short-term spatial memory (Table 1) [72]. Post-traumatic stress disorder, which is known to induce symptoms including hyperarousal, intrusive memories and abnormalities in fear responses, may be also involved in HPA axis dysregulation. In fact, in animal model, post-traumatic stress disorder was related to an impaired extinction retention concomitant with increased glucocorticoid receptor (GR) expression in the medial prefrontal cortex and dorsal hippocampus (Table 1); nevertheless, antiepileptic phenytoin administration prevented the development of extinction retention deficits

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and upregulation of GR [73]. Phenytoin exerts inhibitory effects on voltage-gated sodium channels and decreases excitatory neural transmission via glutamate antagonism [73]. Thus, alteration in both the glutamate neurotransmission and the HPA axis appears to be involved in cognitive deficits associated with mood disorders. In fact, abnormal GR levels are linked with both stress and memory impairment [74]. Maternal deprivation represents a good animal model for the research of depression. Furthermore, basic studies have provided direct evidence that early life stress leads to heightened responsiveness to stress and alterations in the HPA system throughout the lifespan [75, 76]. In addition, stress in early life has been linked with memory impairment. In fact, rats that experienced maternal deprivation showed a

depressive behavior in adulthood that was elevated HPA axis activity due stressors, elevated corticotropin releasing factor mRNA in the brain, and learning impairments in both Morris water maze and in the novel object recognition test [77]. Interestingly, mifepristone (an antagonist of glucocorticoid receptor) and propranolol (an antagonist of β-adrenoceptor) were able to reverse depressive-like behavior and memory deficits [77]. Cognitive deficits owing HPA alterarion induced by maternal deprivation were also completely reversed by SB271046, a selective 5-HT6 receptor antagonist (Table 1) [78]. 5-HT6 antagonists were also observed to regulate gamma-aminobutyric acid and glutamatergic systems, which are involved in both depression and cognition and could explain the relationship of both. In fact, 5-HT6 antagonists are able to reduce

Table 1. Relation between stress, cognitive dysfunction, biological alterations and therapeutic targets from animal model studies.

Animal Model Cognitive Dysfunction Biological Effect Treatment Effect Ref.

Stress by CORT Memory impairment ↑ HPA axis, ↓ BDNF and CREB Baicalin reverses [66]

Stress by CORT Increase in fear memory consolidation

Memory-related gene dysfunction Fluoxetine reverses [71]

Stress by CORT Recognition memory and spatial impairments - - [72]

Post-traumatic stress Extinction retention impairment ↑ GR expression Phenytoin reverses [73]

Maternal deprivation in pups Learning impairment ↑ HPA axis Mifepristone, propranolol and

SB271046 reverse [78]

CCR6−/− and CCR7−/− Learning and spatial memory impairments - [86]

AβOs infusion Memory impairment ↑ IL-1β, TNF-α and glial cells Fluoxetine reverses [89]

Obesity Memory impairment ↑ Pro-inflammatory cytokines and IDO - [90]

Chronic psychosocial stress Learning impairment ↑ Oxidative stress Theanine reverses [97]

Chronic stress Cognitive impairment - Vitamins E and C reverse [98]

Chronic stress Memory impairment Oxidative and mitochondrial damage Curcumin reverses [101]

Chronic stress Cognitive impairment ↑ TNF-α, CORT and oxidative/ nitrergic stress American ginseng reverses [102]

Maternal deprivation in pups Recognition memory impairment

↓ BDNF and PSD95; ↑ GFAP

- [111]

Maternal deprivation in dam Memory capability impairment

↓Cell proliferation and 5-HT ↑ apoptosis

- [112]

Chronic stress Auditory trace and contextual fear conditioning ↓ Growth hormone Growth hormone reverses [117]

BDNF(+/Met) Working memory impairment ↑ HPA axis - [122]

Transgenic mouse model of Alzheimer Recognition memory impairment - TrkB agonist reverses [123]

Social stress Long-term memory impairment ↑ ERK1/2 and IL-6; ↓ CREB and BDNF

Curcumin reverses [126]

Chronic stress Spatial memory impairment ↓ BDNF Enriched environment, aripiprazole and olanzapine reverse [127]

Maternal deprivation Memory impairment ↑ CRH and histone H3 acetylation; ↓ cytosine

methylation

CRHR1 (blockade) and enriched environment reverse [137]

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gamma-aminobutyric acid release that in turn results in elevated glutamate release, and consequent increase in gene expression of specific protein involved in learning and memory, such as PSA-NCAM [79]. So, it seems that agent modulators of endocrine, glutamatergic and monoaminergic systems appear to be involved in the improvement of cognitive deficits related with depression.

Cognitive Dysfunction in Depression: Oxidative Stress and Inflammation Hypothesis

Studies show that in both stress and depression are correlated to alteration in immune system. In fact, high levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-12, IL-1β, interferon-γ and tumor necrosis factor- α (TNF-α) have already been related to the patients with depression [80, 81]. Moreover, in the CNS, the microglia plays an important role in synapses, signaling and neurotransmission control and also systemically regulate normal functions of the immune systems [82]. Still, IL-1β is also involved in the regulation of HPA axis activity in the brain [83], suggesting that the integration of the immune system and inflammation may contribute together to alterations in the nervous system related to psychiatric disorders. In fact, recently, Farooq et al. [84] demonstrated that rodents exposed to chronic mild stress presented microglial activation in the infralimbic, nucleus accumbens, caudate putamen, amygdala and hippocampus. Rats deprived maternally in adulthood also presented increase in TNF-α and IL-1 levels in the periphery, and on the other hand, treatment with a classic antidepressant, imipramine was able to reverse both depressive-like behavior and cytokines alterations [85]. Jaehne and Baune [86] using knockout mice to chemokine receptors (CCR6−/− and CCR7−/−) showed that both mice presented depressive-like behavior and impairment in learning and spatial memory (Table 1), suggesting that chemokine receptors may play a role in cognition and learning behavior. In addition, evidence suggested that alterations in the immune system may be a commonality between depression and associated cognitive deficits. In fact, blocking IL-6 reverses memory deficit in stressed and control rodents, suggesting that basal IL-6 signaling in the neurons (for example, in the nonexistence of stress or inflammation), and somewhere inflammation is not outstanding, enriching IL-6 and/or JAK2-STAT3 signaling may recover executive function [87]. Additionally, treatment with aspirin and ascorbic acid (nonselective cyclooxygenase inhibitor) was able to improve the spatial learning performance of rats, beyond decreasing oxidative stress parameters and increasing the expressions of several receptors related to learning and memory process [88]. Recently, Ledo et al. [89] related that amyloid-β peptide (AβOs) that are reported to be accumulated in the brain of Alzheimer’s disease patients, injected as intracerebroventricular dose in mice induced depressive-like behavior and memory impairment reported at 24h and 8 days after a single injection, and on the other hand, treatment with fluoxetine antidepressant reversed depressive behavior and cognitive deficits. Additionally, AβO-injected rodents showed an increase in IL-1β and TNF-α in the brain tissue, beyond an elevation in glial cell, which were blocked by fluoxetine treatment [89], thus establishing that AβOs and inflammation can be linked with memory impairment and

depressive-like behavior in rodents. In an obese animal, depressive-like behavior, memory impairment, and exacerbated hippocampal and hypothalamic pro-inflammatory cytokines expression and brain tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) activation were demonstrated (Table 1) [90], suggesting that obesity, and obesity-associated inflammatory may characterize a susceptibility state to immune-mediated depressive symptoms. In fact, diseases related to obesity, such as diabetes is correlated with both inflammation and depression [91, 92]. It is well known that inflammatory cytokines may be activated by oxidative stress, which is constituted by an impairment or inability to balance antioxidant production with reactive oxygen and nitrogen species levels, and both situations are likely to be involved in brain diseases [93, 94]. Still, Gioroni et al. [95] reported that the memory deficits in patients with Alzheimer’s disease were associated with increased oxidative stress. In addition, in the plasma of patients with depression, increased levels of thiol protein groups were found which, through oxidation, reflect the loss of compensatory capacity of antioxidative mechanisms. Also the elevated concentration of thiol protein groups in plasma was associated with a decrease in efficiency of declarative-memory, working memory and verbal fluency [96]. Thus, it is suggested that oxidative stress, as well as inflammation could be important factors associated with the initiation of cognitive deficits and depression. In fact, the treatment with antioxidants has shown effects in both depression and memory. For example, treatment with theanine (γ-glutamylethylamide), an amino acid in tea reversed brain atrophy, learning deficiency, behavioral depression and oxidative damage in the DNA brain of mice subjected to chronic psychosocial stress [97]. In addition, both vitamins E and C prevented cognitive impairment induced by chronic stress in rats [98]. Still, curcumin, a polyphenol extracted from the plant Curcuma longa presented antidepressant properties and anti-inflammatory action [99, 100]. It was also reported that curcumin improved memory performance, reversed anhedonia and restored oxidative and mitochondrial damage in chronically stressed mice [101]. American ginseng treatment significantly improved cognitive impairment; reduced TNF-α, acetylcholinesterase, and CORT levels; and attenuated oxidative–nitrergic stress induced by chronic mild stress, and these effects modulated nitrergic signaling cascade [102]. Multi-targeted experimental diet attenuated cognitive, cellular, and immune changes in a manner that was largely comparable to memantine (an antagonist of N-methyl-D-aspartate (NMDA) receptor used to treatment of Alzheimer disease) in rats subjected to the olfactory bulbectomized rat, model of depression [103].

Cognitive Dysfunction in Depression: Neuroplasticity Hypothesis

The signaling pathways and mechanisms that control the formation of synapses and neuroplasticity have been studied in models of learning and memory [104, 105], as well as have a significant role in both pathophysiology and treatment of depression [85, 106, 107]. Thus, it is possible that central protein responsible for the control of neuroplasticity may be a common point in association between depression and

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cognitive deficits. The hippocampus is one of the main regions affected by stress and is very important in memory circuit; moreover, both stress and glucocorticoids impairs neurogenesis in the hippocampus [68, 108]. In fact, the inhibition of WNR signaling in the DG, which plays an important role in the generation of newborn neurons, reduced neurogenesis, and the effects prejudiced the performance of rats subjected to object recognition test [108]. Also, maternal deprivation by 24 hours on postnatal day 3 induced lesser cell number and cell density in the dentate gyrus granule cell layer and dendritic rearrangement of DG neurons, without affecting hippocampal neurogenesis [109]. In line with this, Krugers et al. [110], using the same protocol, showed that 24 h of maternal deprivation on postnatal day 3 did not affect dendritic complexity of pyramidal and stellate cells in the basolateral amygdala of adult male and female rats, suggesting that other cellular substrates for learning and memory, for example, at synaptic or cellular level, trigger the higher expression of fear memories after early life stress experience. In fact, Marco et al. [111] investigated the effects of early maternal deprivation by 24 h at postnatal day 9 and related an impairment in recognition memory only in females, but a general reduction in neuronal cells density and in the markers of synaptic plasticity (BDNF, postsynaptic density (PSD95)), and in adolescent male and female rats, and an enhance in hippocampal glial fibrillar acidic protein (GFAP) expression only in adolescent males (Table 1). The maternal deprivation is able to affect not only pups, but also the dam. Infact, depressed-like state induced by repeated separation of pups affected the memory ability in inhibitory avoidance task of the maternal rodents, beyond a decreased cell proliferation and 5-HT expression, and enhanced apoptosis in the hippocampus (Table 1) [112]. Interestingly, growth hormone (GH), which is produced by pituitary and hippocampus [113, 114] leads to synaptic plasticity and facilitates the hippocampal neurotransmission [115, 116]. Vander Weele et al. [117] showed that chronic stress in rats induced a profound and lasting down regulation of GH in the dorsal hippocampus. In addition, rats that experienced chronic stress also exhibited significant impairment on two hippocampus-dependent tasks (auditory trace fear contextual fear conditionings); on the other hand, repair of hippocampal GH in the dorsal hippocampus via viral-mediated gene transfer prevented stress-related damage [117], suggesting that damage of hippocampal GH contributes to hippocampal deficits after prolonged stress and reestablishing hippocampal GH levels after stress can stimulate stress resilience. Among intracellular survival cascades, one of the most important is the signaling BDNF signaling and associated cascades. In fact, BDNF is important in activity-dependent synaptic plasticity in the hippocampus [118]. BDNF is produced from a precursor molecule proBDNF and is converted to its mature form (mBDNF); mBDNF influences neuronal function by binding to TrkB [119]. Interestingly, cognitive impairment has been appointed to be caused by decreased neurogenesis in the brain areas that is considered an important pathogenic factor in mood disorders, such as depression. In fact, a decrease in the BDNF serum levels was linked with worse neurocognitive performance in patients with major depression [120]. BDNF polymorphism are

related to stress vulnerability and memory impairment, Yu et al. [121] demonstrated that heterozygous BDNF (+/Met) mice exhibited HPA axis hyper-reactivity, increased depressive/anxiety-like behaviors, and impaired working memory after restraint stress. Moreover, BDNF(+/Met) mice showed more changes in the levels of BDNF and apical dendritic spine density in the brain following stress, which are associated with working memory deficits and anxiety-like behaviors. In another way, intrahippocampal injection of BDNF was able to protect against the protein Aβ-induced long-term potentiation impairment [122]. Furthermore, 7,8-dihydroxyflavone (7,8-DHF), a selective TrkB agonist improved object memory formation in the object recognition task in both healthy rats and in a transgenic mouse model of Alzheimer’s disease (APPswe/PS1dE9 mice) [123]. BDNF is regulated by a series of proteins and associated cascades incluiding Akt; and interestingly, Akt2 knockout mice (Akt(-/-)) displayed anxiety and depressant-like behavior, but not presented cognitive deficits, compared to Akt(+/+) mice [124]. Thus it is possible that other pathways involved in BDNF activation could be related to cognitive impairment in depression, for example, brain extracellular signal-regulated kinase-1/2 (ERK1/2) and CREB. In fact, socially defeated (a social stress) rats had more errors in memory tests and induced anxiety and depressive-like behavior, besides ERK1/2 and IL-6 were activated, while the protein levels of calcium/calmodulin-dependent protein kinase type (CAMK)-IV, CREB, glyoxalase (GLO)-1, BDNF and glutathione reductase (GSR)-1 were significantly less in the hippocampus of socially defeated rats, suggesting that these alterations could be responsible for anxiety-depression-like behaviors and as well as memory impairment in rats [125]. Moreover, chronic administration with curcumin was able to reverse the behavioral and cognitive deficits induced by stress, and chronic stress decreased hippocampal ERK and BDNF levels; however, curcumin was able to reverse these changes [126]. Enriched environment, and antipsychotic drugs, aripiprazole and olanzapine improved spatial memory and also had an antidepressant-like effect on prenatally stressed rats; also chronic treatment with aripiprazole and olanzapine increased BDNF levels in the hippocampus of stressed rats (Table 1) [127]. In line with this, Gusmulu et al. [128] related that the treatment with olanzapine and antidepressant tianeptine reversed the memory impairment in chronic mild stress-exposed mice, beyond both drugs increased BDNF and CREB expression in the hippocampus of stressed rodents. Kaixin San, a traditional Chinese medicine, also reversed depressive-like behavior and improved performance in Morris water maze test of rats exposed to chronic stress, and these effects were correlated to an increase in 5-HT and dopamine (DA), noradrenergic (NE), Ach, and BDNF protein and a decrease in the level of acetyl cholinesterase in the stressed-induced rats [129]. Panax ginseng used in Korean traditional herbal medicines, administrated chronically to rats submitted to repeated immobilization stress displayed a reversion in depressive-like behavior and cognitive impairment in active avoidance conditioning test; and blocked the enhance in tyrosine hydroxylase expression in the locus coeruleus and the decrease in BDNF mRNA expression in the hippocampus [130]. Still, N-acetylserotonin, one of the methoxyindole derivatives of tryptophan, exerted antidepressant-like and

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cognition-enhancing effects, and these results were correlated to theactivation of TrkB receptors, and anti-inflammatory and anti-oxidative effects [131]. Pudell et al. [132] demonstrated that female rats treated with fish oil supplementation during lactation, mating, habituation and gestation, lead to a reversion in anxiety/depressive-like behaviors and deficits in the object location task in their pups subjected to olfactory bulbectomy in adult life; additionally, fish oil augmented levels 5-HT and BDNF in the hippocampus of stressed rats. Agomelatine, a novel antidepressant and melatonin reversed stress-induced deficit in visual memory in the novel object recognition test and blocked spatial learning and memory deficit in the stressed rats in the Morris water maze test, and both agomelatine and melatonin upregulated the levels of BDNF and CREB gene expression alterations induced by stress in BALB/c mice [133]. Interestingly, stressed mice treated with cotinine (a predominant metabolite of nicotine) exhibited improved performance than control cohorts on the working memory task, and the antidepressant effects by cotinine were concomitant with a growth in the synaptophysin expression in the brain of restrained rodents, by the inhibition of the GSK3β in the hippocampus and prefrontal cortex [134]. In fact, transgenic mice overexpressing GSK3β demonstrated deficits in memory tests and atrophy in the dorsal hippocampal [135]. Histones are the major proteins that make up chromatin. They act as a matrix in which the DNA winds and plays a key role in gene regulation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are enzymes that influence transcription by adding (acetylation) or removing (deacetylation) acetyl groups from a ε-N-acetyl lysine amino acid in histones. The histone acetylation is linked to transcriptional activity, while deacetylation is linked to inactivation of gene transcription. The deregulation and aberrant activity of HAT and HDAC - ex. gene overexpression, mutation, translocation and amplification - have been implicated in oncogenesis, even in the central nervous system [136]. Moreover, epigenetic regulation of marked genes involved in stress may be related to memory impairment in depression. Wang et al. [137] observed an increased hippocampal corticotropin-releasing hormone (CRH) and histone H3 acetylation, and reduced cytosine methylation in CRH promoter region in the adulthood rodents following postnatal maternal separation. In addition, the block of CRHR1 signaling and enriched the environment, decreasing the hippocampal synaptic damage and memory impairment in the maternal deprived rats [137]. Furthermore, increase in histone acetylation, via genetic or pharmacological inhibition of HDACs or by targeting HATs has been pointed to augment fear extinction and to generate a long-term extinction memory that can protect from return of fear phenomena [138]. Recently, studies have highlighted the role of microRNAs (miRNAs) in the pathophysiology of depression [139, 140] that are new regulators of gene expression of genes involved in depression, such as GSK-3 and BDNF, and are also important in neurogenesis regulation. O'Connor et al. [141] demonstrated that electroconvulsive shock therapy and ketamine, an antagonist of NMDA receptor, presented antidepressant effects in many studies, were able to reverse changes in the hippocampal miRNA expression

induced by chronic stress in rats. Collectively, these studies suggest that agents including modulator of the signaling cascades involved in cellular survival, as well as epigenetic mechanisms and gene expression may be important therapeutic targets for depression and associated cognitive impairment.

CONCLUSION

Cognitive dysfunction in patients with depression has been reported for many years, however, the pathological mechanisms involved in these alterations are still not fully elucidated. In this sense, animal models of depression, which are known to induce behavioral and biochemical alterations in rodents similar to those found in humans with depression, have aided in the understanding of neurobiological alterations linking cognitive impairment in depression. In this way, disturbances in HPA function that may lead to inflammatory and antioxidant system alterations, beyond alterations in proteins involved in signaling pathways, mainly, BDNF, GSK3β, CREB, and gene regulation, have been recognized to have an important role in cognitive dysfunction in depression. In addition, depression animal models have played an essential role in providing new pharmacological targets for the treatment of both depression and cognitive impairment. The therapeutic aims have been based principally on modulator agents which may decrease the activation of the HPA axis, pro-inflammatory cytokines and oxidative stress, in addition to the regulation of genes that promote cell survival and enhance the ability of synaptic neurons of brain regions involved in the regulation of mood and memory formation.

LIST OF ABBREVIATIONS

5-HT = Serotonin AβOs = Amyloid-β Peptide BDNF = Brain-Derived Neurotrophic Factor CORT = Corticosterone CREB = cAMP-Response-Element-Bindingprotein CRH = Corticotropin-Releasing Hormone DG = Dentate Gyrus ERK = Signal-Regulated Kinase GFAP = Gamma-Aminobutyric Acid; Glial Fibrillar Acidic Protein GH = Growth Hormone GR = Glucocorticoid Receptor GSK3 = Glycogen Synthase Kinase-3 HAT = Histone Acetyltransferase HDAC = Histone Deacetylase HPA = Hypothalamic–Pituitary–Adrenal IDO = Indoleamine 2,3-Dioxygenase IL = Interleukin MDD = Major Depressive Disorders

8 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 10 Réus et al.

NMDA = N-Methyl-D-Aspartate PD = Parkinson's Disease PSD95 = Postsynaptic Density SSRI = Serotonin Reuptake Inhibitor TNF-α = Factor-α

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Laboratory of Neurosciences (Brazil) is a center within the National Institute for Translational Medicine (INCT-TM) and is also a member of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (JQ and GZR), FAPESC (JQ), Instituto Cérebro e Mente, UNESC (JQ), and L´Oréal/UNESCO/ABC Brazil Fellowship for Women in Science 2011 (GZR). JQ is a CNPq Research Fellow. HMA has CAPES studentship. Center for Experimental Models in Psychiatry (USA) is funded by the Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston.

REFERENCES

[1] Yu T, Guo M, Garza J, et al. Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction. Int J Neuropsychopharmacol 2011; 14: 303-17.

[2] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington VA: American Psychiatric Publishing 2013.

[3] Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res 2006; 145: 39-48.

[4] Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry 2001; 178: 200-6.

[5] McDermott LM, Ebmeier KP. A meta-analysis of depression severity and cognitive function. J Affect Disord 2009; 119: 1-8.

[6] Airaksinen E, Larsson M, Lundberg I, Forsell Y. Cognitive functions in depressive disorders: evidence from a population-based study. Psychol Med 2004; 34: 83-91.

[7] Sapolsky R. Glucocorticoids and atrophy of the human hippocampus. Science 1996; 273: 749-50.

[8] Duman R. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 2004; 5: 11-25.

[9] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59: 1116-27.

[10] Hamilton JP, Gotlib IH. Neural substrates of increased memory sensitivity for negative stimuli in major depression. Biol Psychiatry 2008; 63: 1155-62.

[11] Elliott R, Sahakian BJ, Herrod JJ, Robbins TW, Paykel ES. Abnormal response to negative feedback in unipolar depression: evidence for a diagnosis specific impairment. J Neurol Neurosurg Psychiatry1997; 63: 74-82.

[12] Zajecka J. Treating depression to remission. Journal of Clinical Psychiatry 2003; 64: 7-12.

[13] Herrera-Guzmán I, Gudayol-Ferré E, Lira-Mandujano J, et al. Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res 2008; 160: 72-82.

[14] Herrera-Guzmán I, Gudayol-Ferré E, Lira-Mandujano J, et al. Cognitive predictors of treatment response to bupropion and

cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res 2008; 160: 72-82.

[15] Bastos AG1, Guimarães LS, Trentini CM. Neurocognitive changes in depressed patients in psychodynamic psychotherapy, therapy with fluoxetine and combination therapy. J Affect Disord 2013; 151: 1066-75.

[16] Clark L, Chamberlain SR, Sahakian BJ. Neurocognitive mechanisms in depression: implications for treatment. Annu Rev Neurosci 2009; 32: 57-74.

[17] Abelaira HM, Réus GZ, Quevedo J. Animal models as tools to study the pathophysiology of depression. Rev Bras Psiquiatr 2013; 35: 112-20.

[18] Bakkour N, Samp J, Akhras K, et al. Systematic review of appropriate cognitive assessment instruments used in clinical trials of schizophrenia, major depressive disorder and bipolar disorder. Psychiatry Res 2014; 216: 291-302.

[19] Wagner S, Müller C, Helmreich I, Huss M, Tadić A. A meta-analysis of cognitive functions in children and adolescents with major depressive disorder. Eur Child Adolesc Psychiatry 2014; in press.

[20] Korczyn AD. Mild cognitive impairment in Parkinson's disease. J Neural Transm 2013; 120: 517-21.

[21] Tachibana H. Cognitive impairment in Parkinson's disease. Seishin Shinkeigaku Zasshi 2013; 115: 1142-9.

[22] Verdelho A, Madureira S, Moleiro C, et al. Depressive symptoms predict cognitive decline and dementia in older people independently of cerebral white matter changes: the LADIS study. J Neurol Neurosurg Psychiatry 2013; 84: 1250-4.

[23] Zheng J, Sun S, Qiao X, Liu Y. Depression in patients with Parkinson's disease and the associated features. J Huazhong Univ Sci Technolog Med Sci 2009; 29: 725-8.

[24] Bystad M, Pettersen K, Grønli OK. Depression or Alzheimer-type dementia? Tidsskr Nor Laegeforen 2014; 134: 525-8.

[25] Gyurak A, Goodkind MS, Kramer JH, Miller BL, Levenson RW. Executive functions and the down-regulation and up-regulation of emotion. Cogn Emot 2012; 26: 103-18.

[26] Lundy SM, Silva GE, Kaemingk KL, Goodwin JL, Quan SF. Cognitive Functioning and Academic Performance in Elementary School Children with Anxious/Depressed and Withdrawn Symptoms. Open Pediatr Med J 2010; 4: 1-9.

[27] Lawrence C1, Roy A, Harikrishnan V, Yu S, Dabbous O. Association between severity of depression and self-perceived cognitive difficulties among full-time employees. Prim Care Companion CNS Disord 2013; 15: 1-9.

[28] Trivedi MH, Greer TL. Cognitive dysfunction in unipolar depression: implications for treatment. J Affect Disord 2014; 152-4.

[29] Levin RL, Heller W, Mohanty A, Herrington JD, Miller GA. Cognitive Deficits in Depression and Functional Specificity of Regional Brain Activity. Cognit Ther Res 2007; 31: 211-33.

[30] Jurado MB, Rosselli M. The elusive nature of executive functions: a review of our current understanding. Neuropsychol Rev 2007; 17: 213-33.

[31] McIntosh S, Howell L, Hemby SE. Dopaminergic dysregulation in prefrontal cortex of rhesus monkeys following cocaine self-administration. Front Psychiatry 2013; 4: 88.

[32] Foerde K, Shohamy D. The role of the basal ganglia in learning and memory: insight from Parkinson's disease. Neurobiol Learn Mem 2011; 96: 624-36.

[33] Zanto TP, Rubens MT, Thangavel A, Gazzaley A. Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory. Nat Neurosci 2011; 14: 656-61.

[34] Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 2009; 10: 410-22.

[35] Ritchey M, Wing EA, LaBar KS, Cabeza R. Neural similarity between encoding and retrieval is related to memory via hippocampal interactions. Cereb Cortex 2013; 23: 2818-28.

[36] Duvarci S, Pare D. Amygdala Microcircuits Controlling Learned Fear. Neuron 2014; 82: 966-80.

[37] Doya K. Complementary roles of basal ganglia and cerebellum in learning and motor control. Curr Opin Neurobiol 2000; 10: 732-9.

[38] Millan MJ, Agid Y, Brüne M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 2012; 11: 141-68.

[39] Papazacharias A, Nardini M. The relationship between depression and cognitive deficits. Psychiatr Danub 2012; 24: S179-82.

Depression and Cognition in Animal Models CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 10 9

[40] Rodriguez-Oroz MC, Jahanshahi M, Krack P, et al. Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms. Lancet Neurol 2009; 8: 1128-39.

[41] Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL. Comparison of pramiprexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 2000; 11: 58-65.

[42] Bearer EL, Zhang X, Janvelyan D, Boulat B, Jacobs RE. Reward circuitry is perturbed in the absence of the serotonin transporter. Neuroimage 2009; 46: 1091-104.

[43] Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009; 8: 464-74.

[44] Talarowska M, Bobińska K, Zajączkowska M, et al. Impact of oxidative/nitrosative stress and inflammation on cognitive functions in patients with recurrent depressive disorders. Med Sci Monit 2014; 20: 110-5.

[45] Lee KY, Jeong SH, Kim SH, et al. Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder. Psychiatry Investig 2014; 11: 192-9.

[46] Kepser LJ, Homberg JR. The neurodevelopmental effects of serotonin: A behavioural perspective. Behav Brain Res 2014; in press.

[47] Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64: 238-58.

[48] Duman RS. Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry. 2002; 3: 306-10.

[49] Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 2010; 7: 231-5.

[50] Hur EM, Zhou FQ. GSK3 signalling in neural development. Nat Rev Neurosci 2010; 11: 539-51.

[51] Ronai Z, Kovacs-Nagy R, Szantai E, et al. Glycogen synthase kinase 3 beta gene structural variants as possible risk factors of bipolar depression. Am J Med Genet B Neuropsychiatr Genet 2014; 165B: 217-22.

[52] Beaver KM, Vaughn MG, Wright JP, Delisi M. An interaction between perceived stress and 5HTTLPR genotype in the prediction of stable depressive symptomatology. Am J Orthopsychiatry 2012; 82: 260-6.

[53] Yang C, Xu Y, Sun N, et al. The combined effects of the BDNF and GSK3B genes modulate the relationship between negative life events and major depressive disorder. Brain Res 2010; 1355: 1-6.

[54] Pidsley R, Mill J. Epigenetic studies of psychosis: current findings, methodological approaches, and implications for postmortem research. Biol Psychiatry 2011; 69: 146-56.

[55] Fass DM, Schroeder FA, Perlis RH, Haggarty SJ. Epigenetic mechanisms in mood disorders: targeting neuroplasticity. Neuroscience 2014; 264: 112-30.

[56] Kato T, Iwamoto K. Comprehensive DNA methylation and hydroxymethylation analysis in the human brain and its implication in mental disorders. Neuropharmacology 2014; 80: 133-9.

[57] Jope RS, Roh MS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 2006; 7: 1421-34.

[58] Pessoa Rocha N, Reis HJ, Berghe PV, Cirillo C. Depression and cognitive impairment in Parkinson's disease: a role for inflammation and immunomodulation? Neuroimmunomodulation 2014; 21: 88-94.

[59] Lindqvist D, Hall S, Surova Y, et al. Cerebrospinal fluid inflammatory markers in Parkinson's disease--associations with depression, fatigue, and cognitive impairment. Brain Behav Immun 2013; 33: 183-9.

[60] Richter SH, Schick A, Hoyer C, et al. A glass full of optimism: enrichment effects on cognitive bias in a rat model of depression. Cogn Affect Behav Neurosci 2012; 12: 527-42.

[61] Arent CO, Réus GZ, Abelaira HM, et al. Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats. Neurochem Int 2012; 61: 1072-80.

[62] Fortunato JJ, Réus GZ, Kirsch TR, et al. Effects of beta-carboline harmine on behavioral and physiological parameters observed in thechronic mild stress model: further evidence of antidepressant properties. Brain Res Bull 2010; 81: 491-6.

[63] Réus GZ, Abelaira HM, Stringari RB, Fries GR, Kapczinski F, Quevedo J. Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal

cortex induced by chronic mild stress in rats. Metab Brain Dis 2012; 27: 175-82.

[64] Garcia LS, Comim CM, Valvassori SS, et al. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mildstress in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 450-5.

[65] Plaschke K, Feindt J, Djuric Z, et al. Chronic corticosterone-induced deterioration in rat behaviour is not paralleled by changes in hippocampal NF-kappaB-activation. Stress 2006; 9: 97-106.

[66] Lee B, Sur B, Shim I, Lee H, Hahm DH. Baicalin improves chronic corticosterone-induced learning and memory deficits via the enhancement of impairedhippocampal brain-derived neurotrophic factor and cAMP response element-binding protein expression in the rat. J Nat Med 2014; 68: 132-43.

[67] Dominguez G, Faucher P, Henkous N, et al. Stress induced a shift from dorsal hippocampus to prefrontal cortex dependent memory retrieval: role of regional corticosterone. Front Behav Neurosci 2014; 8: 166.

[68] Broadbent NJ, Squire LR, Clark RE. Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci USA 2004; 101: 14515-20.

[69] Miller DB, O’Callaghan JP. Neuroendocrine aspects of the response to stress. Metabolism 2002; 51: 5-10.

[70] Datson NA, van den Oever JM, Korobko OB, et al. Previous history of chronic stress changes the transcriptional response to glucocorticoid challenge in the dentate gyrus region of the male rat hippocampus. Endocrinology 2013; 154: 3261-72.

[71] Monsey MS, Boyle LM, Zhang ML, et al. Chronic corticosterone exposure persistently elevates the expression of memory-related genes in the lateralamygdala and enhances the consolidation of a Pavlovian fear memory. PLoS One 2014; 9: e91530.

[72] Darcet F, Mendez-David I, Tritschler L, et al. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression. Front Behav Neurosci 2014; 8: 136.

[73] George SA, Rodriguez-Santiago M, Riley J, Rodriguez E, Liberzon I. The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficitsand glucocorticoid upregulation in the rat medial prefrontal cortex. Psychopharmacology 2014; in press.

[74] Turner JD, Alt SR, Cao L, et al. Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. Biochem Pharmacol 2010; 80: 1860-8.

[75] Heim C, Nemeroff CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 2001; 49: 1023-39.

[76] Réus GZ, Stringari RB, Ribeiro KF, et al. Maternal deprivation induces depressive-like behaviour and alters neurotrophin levels in the rat brain. Neurochem Res 2011; 36: 460-6.

[77] Aisa B, Tordera R, Lasheras B, Del Río J, Ramírez MJ. Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats. Psychoneuroendocrinology 2007; 32: 256-66.

[78] Marco B, Aisa B, Ramírez MJ. Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: cognitive implications. Neuropharmacology 2008; 54: 708-14.

[79] Upton N1, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics 2008; 5: 458-69.

[80] Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24-31.

[81] Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 201-17.

[82] Marin I, Kipnis J. Learning and memory and the immune system. Learn Mem 2013; 19; 20: 601-6.

[83] Goshen I, Yirmiya R. Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocrinol 2009; 30: 30-45.

[84] Farooq RK, Isingrini E, Tanti A, et al. Is unpredictable chronic mild stress (UCMS) a reliable model to study depression-induced neuroinflammation? Behav Brain Res 2012; 231: 130-7.

[85] Réus GZ, Dos Santos MA, Abelaira HM, et al. Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats. Behav Brain Res 2013; 242: 40-6.

10 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 10 Réus et al.

[86] Jaehne EJ, Baune BT. Effects of chemokine receptor signalling on cognition-like, emotion-like and sociability behaviours of CCR6 and CCR7 knockout mice. Behav Brain Res 2014; 261: 31-9.

[87] Donegan JJ, Girotti M, Weinberg MS, Morilak DA. A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex. J Neurosci 2014; 34: 953-62.

[88] Kara Y, Doguc DK, Kulac E, Gultekin F. Acetylsalicylic acid and ascorbic acid combination improves cognition; Via antioxidant effect or increasedexpression of NMDARs and nAChRs? Environ Toxicol Pharmacol 2014; 37: 916-27.

[89] Ledo JH, Azevedo EP, Clarke JR, et al. Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice. Mol Psychiatry 2013; 18: 1053-4.

[90] André C, Dinel AL, Ferreira G, Layé S, Castanon N. Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induceddepressive-like behavior: Focus on brain indoleamine 2,3-dioxygenase activation. Brain Behav Immun 2014; in press.

[91] Ceretta LB, Réus GZ, Stringari RB, et al. Imipramine treatment reverses depressive-like behavior in alloxan-diabetic rats. Diabetes Metab Res Rev 2012; 28: 139-44.

[92] Laake JP, Stahl D, Amiel SA, et al. The association between depressive symptoms and systemic inflammation in people with type 2 diabetes: findings from the south London diabetes study. Diabetes Care 2014; in press.

[93] Vida C, Gonzalez EM, Fuente MD. Increase of Oxidation and Inflammation in Nervous and Immune Systems with Aging and Anxiety. Curr Pharm Des 2014; in press.

[94] Hsieh HL, Yang CM. Role of redox signaling in neuroinflammation and neurodegenerative diseases. Biomed Res Int 2013; 2013: 484613.

[95] Gironi M, Bianchi A, Russo A, et al. Oxidative imbalance in different neurodegenerative diseases with memory impairment. Neurodegener Dis 2011; 8: 129-37.

[96] Gałecki P, Talarowska M, Bobińska K, et al. Thiol protein groups correlate with cognitive impairment in patients with recurrent depressive disorder. Neuro Endocrinol Lett 2013; 34: 780-6.

[97] Unno K, Fujitani K, Takamori N, et al. Theanine intake improves the shortened lifespan, cognitive dysfunction and behavioural depression that are induced by chronic psychosocial stress in mice. Free Radic Res 2011; 45: 966-74.

[98] Tagliari B, Scherer EB, Machado FR, et al. Antioxidants prevent memory deficits provoked by chronic variable stress in rats. Neurochem Res 2011; 36: 2373-80.

[99] Jiang H, Wang Z, Wang Y, et al. Antidepressant-like effects of curcumin in chronic mild stress of rats: involvement of its anti-inflammatory action. Prog Neuropsychopharmacol Biol Psychiatry 2013; 47: 33-9.

[100] Zhang L, Luo J, Zhang M, et al. Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behaviour and structural plasticity in the lateral amygdala of rats. Int J Neuropsychopharmacol 2014; 17: 793-806.

[101] Rinwa P, Kumar A. Piperine potentiates the protective effects of curcumin against chronic unpredictable stress-induced cognitive impairment and oxidative damage in mice. Brain Res 2012; 1488: 38-50.

[102] Rinwa P, Kumar A. Modulation of nitrergic signalling pathway by American ginseng attenuates chronic unpredictable stress-induced cognitive impairment, neuroinflammation, and biochemical alterations. Naunyn Schmiedebergs Arch Pharmacol 2014; 38: 129-41.

[103] Borre YE, Panagaki T, Koelink PJ, et al. Neuroprotective and cognitive enhancing effects of a multi-targeted food intervention in an animal model ofneurodegeneration and depression. Neuropharmacology 2014; 79: 738-49.

[104] Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci 2009; 10: 647-58.

[105] Yoshihara Y, De Roo M, Muller D. Dendritic spine formation and stabilization. Curr Opin Neurobiol 2009; 19: 146-53.

[106] Réus GZ, Vieira FG, Abelaira HM, et al. MAPK signaling correlates with the antidepressant effects of ketamine. J Psychiatr Res 2014; 55: 15-21.

[107] Gururajan A, Hill R, van den Buuse M. Long-term differential effects of chronic young-adult corticosterone exposure on anxiety

anddepression-like behavior in BDNF heterozygous rats depend on the experimental paradigm used. Neurosci Lett 2014; S0304-3940.

[108] Jessberger S, Clark RE, Broadbent NJ, et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem 2009; 16: 147-54.

[109] Oomen CA, Soeters H, Audureau N, et al. Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats. Psychopharmacology 2011; 214: 249-60.

[110] Krugers HJ, Oomen CA, Gumbs M, et al. Maternal deprivation and dendritic complexity in the basolateral amygdala. Neuropharmacology 2012; 62: 534-7.

[111] Marco EM, Valero M, de la Serna O, et al. Maternal deprivation effects on brain plasticity and recognition memory in adolescent male and female rats. Neuropharmacology 2013; 68: 223-31.

[112] Sung YH, Shin MS, Cho S, et al. Depression-like state in maternal rats induced by repeated separation of pups is accompanied by a decrease ofcell proliferation and an increase of apoptosis in the hippocampus. Neurosci Lett 2010; 470: 86-90.

[113] Nyberg F, Burman P. Growth hormone and its receptors in the central nervous system location and functional significance. Horm Res 1996; 45: 18-22.

[114] Sun LY, Al-Regaiey K, Masternak MM, Wang J, Bartke A. LocalexpressionofGHand IGF-1inthehippocampusofGH-deficientlong-livedmice. Neurobiol Aging 2005; 26: 929-37.

[115] Zearfoss NR, Alarcon JM, Trifilieff P, Kandel E, Richter JD. Amolecularcircuit composedofCPEB-1andc-Jun controlsgrowthhormone-mediated synapticplasticityinthemouse hippocampus. J Neurosci 2008; 28: 8502-9.

[116] Molina DP, Ariwodola OJ, Linville C, et al. Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats. Neurobiol Aging 2012; 33: 1938-49.

[117] Vander Weele CM, Saenz C, Yao J, Correia SS, Goosens KA. Restoration of hippocampal growth hormone reverses stress-induced hippocampal impairment. Front Behav Neurosci 2013; 7: 66.

[118] Korte M, Carroll P, Wolf E, et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA 1995; 92: 8856-60.

[119] Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 2012; 18: 82-97.

[120] Oral E, Canpolat S, Yildirim S, et al. Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder. Brain Res Bull 2012; 88: 454-9.

[121] Yu H, Wang DD, Wang Y, et al. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J Neurosci 2012; 32: 4092-101.

[122] Li QS, Yang W, Pan YF, et al. Brain-derived neurotrophic factor prevents against amyloid beta protein-induced impairment of hippocampal in vivo long-term potentiation in rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2012; 28: 425-9.

[123] Bollen E, Vanmierlo T, Akkerman S, et al. 7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice. Behav Brain Res 2013; 257: 8-12.

[124] Leibrock C, Ackermann TF, Hierlmeier M, et al. Akt2 deficiency is associated with anxiety and depressive behavior in mice. Cell Physiol Biochem 2013; 32: 766-77.

[125] Patki G, Solanki N, Atrooz F, Allam F, Salim S. Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress andinflammation in a rat model of social stress. Brain Res 2013; 1539: 73-86.

[126] Liu D, Wang Z, Gao Z, et al. Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed tochronic unpredictable stress. Behav Brain Res 2014; S0166-4328.

[127] Nowakowska E, Kus K, Ratajczak P, Cichocki M, Woźniak A. The influence of aripiprazole, olanzapine and enriched environment on depressant-like behavior, spatial memorydysfunction and hippocampal level of BDNF in prenatally stressed rats. Pharmacol Rep 2014; 66: 404-11.

[128] Gumuslu E, Mutlu O, Sunnetci D, et al. The effects of tianeptine, olanzapine and fluoxetine on the cognitive behaviors of unpredictable chronic mild stress-exposed mice. Drug Res 2013; 63: 532-9.

Depression and Cognition in Animal Models CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 10 11

[129] Liu M, Yan J, Zhou X, Hu Y, Liu P. Effect of Kaixin San on learning and memory in chronic stress depression model rats. Zhongguo Zhong Yao Za Zhi 2012; 37: 2439-43.

[130] Lee B, Shim I, Lee H, Hahm DH. Effect of ginsenoside Re on depression-and anxiety-like behaviors and cognition memory deficit induced byrepeated immobilization in rats. J Microbiol Biotechnol 2012; 22: 708-20.

[131] Oxenkrug G, Ratner R. N-acetylserotonin and aging-associated cognitive impairment and depression. Aging Dis 2012; 3: 330-8.

[132] Pudell C, Vicente BA, Delattre AM, et al. Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats. Eur J Neurosci 2014; 39: 266-74.

[133] Gumuslu E, Mutlu O, Sunnetci D, et al. The Antidepressant Agomelatine Improves Memory Deterioration and Upregulates CREB and BDNF GeneExpression Levels in Unpredictable Chronic Mild Stress (UCMS)-Exposed Mice. Drug Target Insights 2014; 8: 11-21.

[134] Grizzell JA, Iarkov A, Holmes R, Mori T, Echeverria V. Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronicstress in mice. Behav Brain Res 2014; 268: 55-65.

[135] Fuster-Matanzo A, Llorens-Martín M, de Barreda EG, Ávila J, Hernández F. Different susceptibility to neurodegeneration of

dorsal and ventral hippocampal dentate gyrus: a study with transgenic mice overexpressing GSK3β. PLoS One 2011; 6: e27262.

[136] Drummond DC, Noble CO, Kirpotin DB, et al. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 2005: 45; 495-528.

[137] Wang A, Nie W, Li H, et al. Epigenetic upregulation of corticotrophin-releasing hormone mediates postnatal maternal separation-inducedmemory deficiency. PLoS One 2014; 9: e94394.

[138] Whittle N, Singewald N. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand? Biochem Soc Trans 2014; 42: 569-81.

[139] Dwivedi Y. Evidence demonstrating role of microRNAs in the etiopathology of major depression. J Chem Neuroanat 2011; 42: 142-56.

[140] Mouillet-Richard S, Baudry A, Launay JM, Kellermann O. MicroRNAs and depression. Neurobiol Dis 2012; 46: 272-8.

[141] O'Connor RM1, Grenham S, Dinan TG, Cryan JF. microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. Int J Neuropsychopharmacol 2013; 16: 1885-92.

Received: August 11, 2014 Revised: September 25, 2014 Accepted: September 25, 2014 DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 25470404