Hippocampal cytogenesis abrogation impairs inter-regional communication between the hippocampus and prefrontal cortex and promotes the time-dependent manifestation of emotional and cognitive deficits.

Impaired ability to generate new cells in the adult brain has been linked to deficits in multiple emotional and cognitive behavioral domains. However, the mechanisms by which abrogation of adult neural stem cells (NSCs) impacts on brain function remains controversial. We used a transgenic rat line, the GFAP-Tk, to selectively eliminate NSCs and assess repercussions on different behavioral domains. To assess the functional importance of newborn cells in specific developmental stages, two parallel experimental timeframes were adopted: a short- and a long-term timeline, 1 and 4 weeks after the abrogation protocol, respectively. We conducted in vivo electrophysiology to assess the effects of cytogenesis abrogation on the functional properties of the hippocampus and prefrontal cortex, and on their intercommunication. Adult brain cytogenesis abrogation promoted a time-specific installation of behavioral deficits. While the lack of newborn immature hippocampal neuronal and glial cells elicited a behavioral phenotype restricted to hyperanxiety and cognitive rigidity, specific abrogation of mature new neuronal and glial cells promoted the long-term manifestation of a more complex behavioral profile encompassing alterations in anxiety and hedonic behaviors, along with deficits in multiple cognitive modalities. More so, abrogation of 4 to 7-week-old cells resulted in impaired electrophysiological synchrony of neural theta oscillations between the dorsal hippocampus and the medial prefrontal cortex, which are likely to contribute to the described long-term cognitive alterations. Hence, this work provides insight on how newborn neurons and astrocytes display different functional roles throughout different maturation stages, and establishes common ground to reconcile contrasting results that have marked this field.

Hippocampal NG2+ pericytes in chronically stressed rats and depressed patients: a quantitative study.

OBJECTIVE: The suggested link between major depression disorder (MDD) and blood-brain barrier (BBB) alterations supports an impact on the neurovascular unit in this disease condition. Here we investigate how pericytes, a major component in the neurovascular unit, respond to stress, stress hormones, proinflammatory cytokine and depression. METHOD: Hippocampal sections of chronic unpredictable stressed (CMS) rats, MDD patients and respective controls were immuno-stained against NG2, where the number of NG2+ pericytes in the molecular layer was counted. Proliferation of cultured pericytes after treatment with cortisol and IL-1ß was analyzed using radioactive-labeled thymidine. FINDINGS: The number of NG2+ pericytes was significantly higher in CMS animals than controls. Higher number of NG2+ pericytes was also detected in MDD patients, but the increase did not reach significance. IL-1ß, but not cortisol, induced a significant increase in proliferation of cultured pericytes. CONCLUSION: Our results indicate that exposure to stressful conditions affects the hippocampal pericyte population. These findings add to our knowledge about the impact of stress on the neurovascular unit, which might be relevant for understanding the alterations in BBB found in MDD patients.

Structural and functional brain correlates of suicidal ideation and behaviors in depression: A scoping review of MRI studies.

Identifying and integrating the neural correlates of suicidal ideation and behaviors is crucial to expand the knowledge and develop targeted strategies to prevent suicide. This review aimed to describe the neural correlates of suicidal ideation, behavior and the transition between them, using different magnetic resonance imaging (MRI) modalities, providing an up-to-date overview of the literature. To be included, the observational, experimental, or quasi-experimental studies must include adult patients currently diagnosed with major depressive disorder and investigate the neural correlates of suicidal ideation, behavior and/or the transition using MRI. The searches were conducted on PubMed, ISI Web of Knowledge and Scopus. Fifty articles were included in this review: 22 on suicidal ideation, 26 on suicide behaviors and two on the transition between them. The qualitative analysis of the included studies suggested alterations in the frontal, limbic and temporal lobes in suicidal ideation associated with deficits in emotional processing and regulation, and in the frontal, limbic, parietal lobes, and basal ganglia in suicide behaviors associated with impairments in decision-making. Gaps in the literature and methodological concerns were identified and might be addressed in future studies.

Anticipatory cues in emotional processing shift the activation of a combined salience sensorimotor functional network in drug-naïve depressed patients.

BACKGROUND: Major depressive disorder is characterized by a large-scale brain network dysfunction, contributing to impairments in cognitive and affective functioning. Core regions of default mode, limbic and salience networks are also impaired in emotional processing and anticipation. This study aimed to explore default mode, salience, and limbic networks modulation during the processing of emotional stimuli with and without anticipatory cues in depression, and further investigate how these networks were functionally coupled with the rest of the brain. METHODS: Twenty-one drug-naïve depressed patients and 15 matched controls were included in the study. All participants completed a psychological assessment and the affective pictures paradigm during an fMRI acquisition. Group independent component analysis and psychophysiological interactions analyses were performed. RESULTS: A significant interaction between Cue, Valence and Group was found for the salience/sensorimotor network. When processing uncued emotional stimuli, patients showed increased activation of this network for negative vs. neutral pictures, whereas when anticipatory cues were displayed previously to the picture presentation, they invert this pattern of activation (hyperactivating the salience/sensorimotor network for positive vs. neutral pictures). Patients showed increased functional connectivity between the salience/sensorimotor network and the left amygdala as well as the right inferior parietal lobule compared to controls when processing uncued negative pictures. LIMITATIONS: The sample size was modest, and the salience/sensorimotor network included regions not typically identified as part of salience network. Thus, this study should be replicated to further interpret the results. CONCLUSIONS: Anticipatory cues shift the pattern of activation of the salience/sensorimotor network in drug-naïve depressed patients.

StressMatic: A Novel Automated System to Induce Depressive- and Anxiety-like Phenotype in Rats.

Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research.

Treatment-Resistant Depression in Portugal: Perspective From Psychiatry Experts.

Guidance about treatment-resistant depression (TRD) in Portugal is very limited, even though depression prevalence is among the highest in European countries. A questionnaire was conducted, followed by two advisory boards with seven Portuguese psychiatry experts, to characterize and discuss MDD and TRD epidemiology, diagnosis, patient journey, treatment options, and unmet clinical needs. Consensus was reached on the main issues. In daily practice, TRD can be defined as moderate to severe MDD episodes with insufficient clinical improvement after two antidepressant treatments, taken in adequate doses and duration. TRD diagnosis and treatment are mostly decided by psychiatrists at public hospitals. Treatment type and duration must be adjusted to characteristics of the patient and the depressive episode, including symptoms, number of previous episodes, comorbidities, and previous treatment response and side effects. The most relevant objectives of TRD treatment are reaching response and remission, prevention of suicide, and improvement of quality of life, functionality, and wellbeing. Regarding pharmacotherapy, antidepressant switch occurs more frequently with non-response, while optimization, combination, and augmentation are considered for patients with partial response. Psychotherapy should be considered in parallel to pharmacological treatment. Brain stimulation techniques are underused. Lifelong treatment is required for recurrent or more chronic TRD episodes, but patient adherence is also poorer in these cases. In Portugal, TRD management is limited by lack of access to specialist care and to many treatment options. These aspects highlight that conventional pharmacotherapy does not lead to remission in many patients and that optimization strategies are frequently necessary to achieve satisfactory treatment outcomes.

Beyond New Neurons in the Adult Hippocampus: Imipramine Acts as a Pro-Astrogliogenic Factor and Rescues Cognitive Impairments Induced by Stress Exposure.

Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance of depressive-like behaviors upon astrocytic dysfunctions in animal models. However, little is known about the importance of de novo generated astrocytes in the mammalian brain and in particular its possible involvement in the precipitation of depression and in the therapeutic actions of current antidepressants (ADs). Therefore, we studied the modulation of astrocytes and adult astrogliogenesis in the hippocampal dentate gyrus (DG) of rats exposed to an unpredictable chronic mild stress (uCMS) protocol, untreated and treated for two weeks with antidepressants-fluoxetine and imipramine. Our results show that adult astrogliogenesis in the DG is modulated by stress and imipramine. This study reveals that distinct classes of ADs impact differently in the astrogliogenic process, showing different cellular mechanisms relevant to the recovery from behavioral deficits induced by chronic stress exposure. As such, in addition to those resident, the newborn astrocytes in the hippocampal DG might also be promising therapeutic targets for future therapies in the neuropsychiatric field.

Suicidal Ideation Is Associated With Reduced Functional Connectivity and White Matter Integrity in Drug-Naïve Patients With Major Depression.

Depression is a highly prevalent psychiatric disorder affecting millions of people worldwide. Depression is characterized by decreased mood or loss of interest in daily activities, changes in feeding and circadian rhythms and significant impairments in cognitive and executive function. In addition, the occurrence of recurrent thoughts of death and suicidal ideation confers depressed patients a higher risk of suicide than the general population. With this study, we aimed to explore the neural correlates of suicidal ideation in drug-naïve patients diagnosed with depression. Twenty-five patients were scanned using two-different magnetic resonance imaging (MRI) modalities, resting state functional MRI (fMRI) and diffusion tensor imaging (DTI). Resting state allowed the exploration of connectivity patterns in the absence of a specific stimulus and DTI allowed a detailed analysis of structural white matter integrity with measures like fractional anisotropy (FA). Probabilistic independent component analysis (PICA), network-based statistics and tract-based spatial statistics (TBSS) were applied to analyze resting-state fMRI and DTI data, respectively. Our results showed that, in our sample of drug-naïve patients, suicidal ideation was negatively associated with resting-state functional connectivity in the visual networks and with FA in the genu of corpus callosum and in the right anterior corona radiata. In addition, a significant association was identified between suicidal ideation and a functional connectivity network that included connections between regions in the superior and orbitofrontal cortex, the cerebellum, the cingulate gyrus as well as temporal and occipital regions. In conclusion, this work has expanded our knowledge about the possible functional and structural neuronal correlates of suicidal ideation in drug-naïve patients with depression, paving the way for future personalized therapeutic approaches.

White Matter Microstructure Alterations Associated With Paroxetine Treatment Response in Major Depression.

More than one-third of depressive patients do not achieve remission after the first antidepressant treatment. The "watch and wait" approach used to find the most effective antidepressant leads to an increased personal, social, and economic burden in society. In order to overcome this challenge, there has been a focus on studying neural biomarkers associated with antidepressant response. Diffusion tensor imaging measures have shown a promising role as predictors of antidepressant response by pointing to pretreatment differences in the white matter microstructural integrity between future responders and non-responders to different pharmacotherapies. Therefore, the aim of the present study was to explore whether response to paroxetine treatment was associated with differences in the white matter microstructure at baseline. Twenty drug-naive patients diagnosed with major depressive disorder followed a 6- to 12-week treatment with paroxetine. All patients completed magnetic resonance brain imaging and a clinical assessment at baseline and 6-12 weeks after treatment. Whole-brain tract-based spatial statistics was used to explore differences in white matter microstructural properties estimated from diffusion magnetic resonance imaging. Voxel-wise statistical analysis revealed a significant increase in fractional anisotropy and a decrease in radial diffusivity in forceps minor and superior longitudinal fasciculus in responders compared to non-responders. Thus, alterations in white matter integrity, specifically in forceps minor and the superior longitudinal fasciculus, are associated with paroxetine treatment response. These findings pave the way for personalized treatment strategies in major depression.

Adult neurogenic process in the subventricular zone-olfactory bulb system is regulated by Tau protein under prolonged stress.

OBJECTIVES: The area of the subventricular zone (SVZ) in the adult brain exhibits the highest number of proliferative cells, which, together with the olfactory bulb (OB), maintains constant brain plasticity through the generation, migration and integration of newly born neurons. Despite Tau and its malfunction is increasingly related to deficits of adult hippocampal neurogenesis and brain plasticity under pathological conditions [e.g. in Alzheimer's disease (AD)], it remains unknown whether Tau plays a role in the neurogenic process of the SVZ and OB system under conditions of chronic stress, a well-known sculptor of brain and risk factor for AD. MATERIALS AND METHODS: Different types of newly born cells in SVZ and OB were analysed in animals that lack Tau gene (Tau-KO) and their wild-type littermates (WT) under control or chronic stress conditions. RESULTS: We demonstrate that chronic stress reduced the number of proliferating cells and neuroblasts in the SVZ leading to decreased number of newborn neurons in the OB of adult WT, but not Tau-KO, mice. Interestingly, while stress-evoked changes were not detected in OB granular cell layer, Tau-KO exhibited increased number of mature neurons in this layer indicating altered neuronal migration due to Tau loss. CONCLUSIONS: Our findings suggest the critical involvement of Tau in the neurogenesis suppression of SVZ and OB neurogenic niche under stressful conditions highlighting the role of Tau protein as an essential regulator of stress-driven plasticity deficits.

Astrocytic plasticity at the dorsal dentate gyrus on an animal model of recurrent depression.

Astrocytes are now known to play crucial roles in the central nervous system, supporting and closely interacting with neurons and therefore able to modulate brain function. Both human postmortem studies in brain samples from patients diagnosed with Major Depressive Disorder and from animal models of depression reported numerical and morphological astrocytic changes specifically in the hippocampus. In particular, these studies revealed significant reductions in glial cell density denoted by a decreased number of S100B-positive cells and a decrease in GFAP expression in several brain regions including the hippocampus. To reveal plastic astrocytic changes in the context of recurrent depression, we longitudinally assessed dynamic astrocytic alterations (gene expression, cell densities and morphologic variations) in the hippocampal dentate gyrus under repeated exposure to unpredictable chronic mild stress (uCMS) and upon treatment with two antidepressants, fluoxetine and imipramine. Both antidepressants decreased astrocytic complexity immediately after stress exposure. Moreover, we show that astrocytic alterations, particularly an increased number of S100B-positive cells, are observed after recurrent stress exposure. Interestingly, these alterations were prevented at the long-term by either fluoxetine or imipramine treatment.

Btbd3 expression regulates compulsive-like and exploratory behaviors in mice.

BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We tested Btbd3 wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests. Btbd3 heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering in Btbd3 wild-type and heterozygous, but not knockout mice. In contrast, Btbd3 expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of high Btbd3 expression. Surprisingly, Btbd3 knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked down Btbd3 expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampal Btbd3 knockdown recapitulated Btbd3 knockout phenotypes. Our findings reveal that hippocampal Btbd3 expression selectively modulates compulsive-like and exploratory behavior.

Metabolism and adult neurogenesis: Towards an understanding of the role of lipocalin-2 and iron-related oxidative stress.

The process of generating new functional neurons in the adult mammalian brain occurs from the local neural stem and progenitor cells and requires tight control of the progenitor cell's activity. Several signaling pathways and intrinsic/extrinsic factors have been well studied over the last years, but recent attention has been given to the critical role of cellular metabolism in determining the functional properties of progenitor cells. Here, we review recent advances in the current understanding of when and how metabolism affects neural stem cell (NSC) behavior and subsequent neuronal differentiation and highlight the role of lipocalin-2 (LCN2), a protein involved in the control of oxidative stress, as a recently emerged regulator of NSC activity and neuronal differentiation.

Chronic stress targets adult neurogenesis preferentially in the suprapyramidal blade of the rat dorsal dentate gyrus.

The continuous generation of new neurons and glial cells in the adult hippocampal dentate gyrus (DG) represents an important form of adult neuroplasticity, involved in normal brain function and behavior but also associated with the etiopathogenesis and treatment of psychiatric disorders. Despite the large number of studies addressing cell genesis along the septotemporal axis, data on the anatomical gradients of cytogenesis along the DG transverse axis is scarce, especially after exposure to stress. As such, in this study we characterized both basal proliferation and survival of adult-born neural cells along the transverse axis of the rat dorsal DG, and after stress exposure. In basal conditions, both proliferating cells and newborn neurons and glial cells were preferentially located at the subgranular zone and suprapyramidal blade. Exposure to chronic stress induced an overall decrease in the generation of adult-born neural cells and, more specifically, produced a regional-specific decrease in the survival of adult-born neurons at the suprapyramidal blade. No particular region-specific alterations were observed on surviving adult-born glial cells. This work reveals, for the first time, a distinct survival profile of adult-born neural cells, neurons and glial cells, among the transverse axis of the DG, in both basal and stress conditions. Our results unveil that adult-born neurons are preferentially located in the suprapyramidal blade and suggest a regional-specific impact of chronic stress in this blade with potential repercussions for its functional significance.

Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors.

Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 microg/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

Induction of a hyperanxious state by antenatal dexamethasone: a case for less detrimental natural corticosteroids.

BACKGROUND: Synthetic glucocorticoids are commonly prescribed during pregnancy, despite a lack of systematic investigations of their potential impact on the developing brain and neurological and behavioral performance. METHODS: Neuroendocrine parameters and behavior in the adult offspring of pregnant Wistar rats treated antenatally with either dexamethasone (DEX) or corticosterone (CORT) were monitored; DEX (.1 mg/kg and 1 mg/kg) and CORT (25 mg/kg) were given to pregnant rat dams on gestation days 18 and 19. RESULTS: Despite normal basal levels of corticosterone, the adult offspring of mothers given DEX or CORT displayed abnormal responses in the dexamethasone-suppression test. Neither treatment influenced spatial memory performance, but both DEX and CORT facilitated development of depression-like behavior following chronic stress. The latter finding demonstrates that high-dose antenatal corticotherapy can impair the organism's resilience to stress in adulthood. Interestingly, comparison of the progeny of CORT-treated and DEX-treated mothers revealed that the latter were more anxious. CONCLUSIONS: Since DEX and CORT differ in their affinity for glucocorticoid and mineralocorticoid receptors and corticosteroid-binding globulin, our findings emphasize the need to consider the pharmacologic properties of antenatal corticotherapies and demonstrate the potential long-term benefits of ligands that can bind to both receptors.

Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus.

Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.

The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition.

There is accumulating evidence that adult neurogenesis and dendritic plasticity in the hippocampus are neuroplastic phenomena, highly sensitive to the effects of chronic stress and treatment with most classes of antidepressant drugs, being involved in the onset and recovery from depression. However, the effects of antidepressants that act through the selective inhibition of monoamine oxidase subtype A (MAO-A) in these phenomena are still largely unknown. In the present study, adult neurogenesis and neuronal morphology were examined in the hippocampus of rats exposed to chronic mild stress (CMS) and treated with the selective reversible MAO-A inhibitor (RIMA) drug, pirlindole and the selective serotonin reuptake inhibitor (SSRI), fluoxetine. The results provide the first demonstration that selective MAO-A inhibition with pirlindole is able to revert the behavioural effects of stress exposure while promoting hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons.

The Sweet Drive Test: refining phenotypic characterization of anhedonic behavior in rodents.

Measuring anhedonic behavior in rodents is a challenging task as current methods display only moderate sensitivity to detect anhedonic phenotype and, consequently, results from different labs are frequently incongruent. Herein we present a newly-developed test, the Sweet Drive Test (SDT), which integrates food preference measurement in a non-aversive environment, with ultrasonic vocalizations (USVs) recording. Animals were placed in a soundproofed black arena, under red light illumination, and allowed to choose between regular and sweet food pellets. During the test trials, 50 KHz USVs, previously described to be associated with positive experiences, were recorded. In a first experimental approach, we demonstrate the ability of SDT to accurately characterize anhedonic behavior in animals chronically exposed to stress. In a subsequent set of experiments, we show that this paradigm has high sensitivity to detect mood-improving effects of antidepressants. The combined analysis of both food preference and the number of 50 KHz vocalizations in the SDT provides also a valuable tool to discriminate animals that responded to treatment from non-responder animals.

A trans-dimensional approach to the behavioral aspects of depression.

Depression, a complex mood disorder, displays high comorbidity with anxiety and cognitive disorders. To establish the extent of inter-dependence between these behavioral domains, we here undertook a systematic analysis to establish interactions between mood [assessed with the forced-swimming (FST) and sucrose consumption tests (SCT)], anxiety [elevated-plus maze (EPM) and novelty suppressed feeding (NSF) tests] and cognition (spatial memory and behavioral flexibility tests) in rats exposed to unpredictable chronic-mild-stress (uCMS). Expectedly, uCMS induced depressive-like behavior, a hyperanxious phenotype and cognitive impairment; with the exception of the measure of anxiety in the EPM, these effects were attenuated by antidepressants (imipramine, fluoxetine). Measures of mood by the FST and SCT were strongly correlated, whereas no significant correlations were found between the different measures of anxiety (EPM and NSF); likewise, measures of cognition by spatial memory and behavioral flexibility tests were poorly correlated. Inter-domain analysis revealed significant correlations between mood (FST and SCT) and anxiety-like behavior (NSF, but not EPM). Furthermore, significant correlations were found between cognitive performance (reverse learning task) and mood (FST and SCT) and anxiety-like behavior (NSF). These results demonstrate interactions between different behavioral domains that crosscut the disciplines of psychiatry and neurology.