Pathophysiology Of Affective Disorders Research Articles

Steroid-induced mania in a patient with previously well-controlled organic bipolar 1-like affective disorder secondary to acquired brain injury: case report and literature review

Steroid-induced neuropsychiatric sequelae are common, and pose significant risks to people usually receiving glucocorticoids in the context of physical illness. Steroid-induced mania and hypomania are the most common of the acute complications, yet despite great progress in understandings in neurophysiology there are no recent studies which review the factors which might predict who will experience this severe complication, nor are there consensus guidelines on management. We report the unusual case of a woman in her 50s admitted to a psychiatric unit with steroid-induced mania despite compliance with two mood stabilisers, several days after the administration of a Dexamethasone and Docetaxel chemotherapy regime adjunctive to lumpectomy for breast cancer. She had previously been diagnosed with an organic affective disorder (with classical bipolar 1 pattern) following severe ventriculitis related to ventricular drain insertion for obstructive hydrocephalus secondary to a colloid cyst. She had no psychiatric illness before this brain injury, but has a maternal history of idiopathic bipolar 1 affective disorder. Her episode of steroid-induced mania resolved following use of sedative medications, continuation of her existing mood stabilisers, and reductions of the steroid dosing in collaboration with her oncology team, which also protected her from further manic relapses during continued chemotherapy. Established mental illness, a family history, and acquired brain injury may reflect risk factors for steroid-induced mania through currently unclear pathways. Future epidemiological studies could better confirm these observations, and basic neuroscience may look to further explore the role of extrinsic glucocorticoids in the pathophysiology of affective disorders.

Molecular changes in hippocampal energy metabolism in mice selectively bred for extremes in stress reactivity: relevance of mitochondrial dysfunction for affective disorders.

Affective disorders, such as major depression, are frequently associated with metabolic disturbances involving mitochondria. Although dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is known to alter energy metabolism, the precise mechanisms linking stress and metabolic disturbances are not sufficiently understood. We used a mouse model of affective disorders to investigate the impact of a genetic predisposition for extremes in stress reactivity on behavioural and metabolic phenotypes as well as energy metabolism. Adult males of three independent mouse lines selectively bred for high, intermediate or low HPA axis reactivity were tested for exploratory and locomotor activity as well as stress-coping behaviour. Additionally, basal and stress-induced plasma corticosterone levels, body weight, food intake and body composition were measured. At the molecular level, the hippocampal transcriptome was analysed using microarray, serial analysis of gene expression and qRT-PCR. Finally, mitochondrial DNA copy number, damages and mitochondrial respiration were assessed. We found clear effects of the differential stress reactivity on the behavioural, morphometric and metabolic measures. Remarkably, the hyperactive behavioural and neuroendocrine stress-coping style of High Reactivity mice was associated with significant changes in the expression of an extended list of genes involved in energy metabolism and several mitochondrial functions. Yet, only minor changes were found in mitochondrial DNA copy number, damages and respiration. Thus, our findings support a prominent role of glucocorticoids in shaping the major endophenotypes of the stress reactivity mouse model and contribute towards understanding the important role of HPA axis dysregulation and changes in energy metabolism in the pathophysiology of affective disorders.

Physical Activity Alters Functional Connectivity of Orbitofrontal Cortex Subdivisions in Healthy Young Adults: A Longitudinal fMRI Study.

Physical activity (PA) plays an important role in affect processing. Studies describe the orbitofrontal cortex (OFC) as a major hub for emotion processing and the pathophysiology of affective disorders. Subregions of the OFC show diverse functional connectivity (FC) topographies, but the effect of chronic PA on subregional OFC FC still lacks scientific understanding. Therefore, we aimed at investigating the effects of regular PA on the FC topographies of OFC subregions in healthy individuals within a longitudinal randomized controlled exercise study. Participants (age: 18-35 years) were randomly assigned to either an intervention group (IG; N = 18) or a control group (CG; N = 10). Fitness assessments, mood questionnaires, and resting state functional magnetic resonance imaging (rsfMRI) were performed four times over the duration of 6 months. Using a detailed parcellation of the OFC, we created subregional FC topography maps at each time point and applied a linear mixed model to assess the effects of regular PA. The posterior-lateral right OFC showed a group and time interaction, revealing decreased FC with the left dorsolateral prefrontal cortex in the IG, while FC in the CG increased. Group and time interaction in the anterior-lateral right OFC with the right middle frontal gyrus was driven by increased FC in the IG. The posterior-lateral left OFC showed a group and time interaction based on differential change in FC to the left postcentral gyrus and the right occipital gyrus. This study emphasized regionally distinctive FC changes induced by PA within the lateral OFC territory, while providing aspects for further research.

Effects of photoperiod and diet on BDNF daily rhythms in diurnal sand rats

Brain-derived neurotrophic factor (BDNF), its receptors and epigenetic modulators, are implicated in the pathophysiology of affective disorders, T2DM and the circadian system function. We used diurnal sand rats, which develop type 2 diabetes (T2DM), anxiety and depressive-like behavior under laboratory conditions. The development of these disorders is accelerated when animals are maintained under short photoperiod (5:19L:D, SP) compared to neutral photoperiod (12:12L:D, NP). We compared rhythms in plasma BDNF as well as BDNF and PER2 expression in the frontal cortex and suprachiasmatic nucleus (SCN) of sand rats acclimated to SP and NP. Acclimation to SP resulted in higher insulin levels, significantly higher glucose levels in the glucose tolerance test, and significantly higher anxiety- and depression-like behaviors compared with animals acclimated to NP. NP Animals exhibited a significant daily rhythm in plasma BDNF levels with higher levels during the night, and in BDNF expression levels in the frontal cortex and SCN. No significant BDNF rhythm was found in the plasma, frontal cortex or SCN of SP acclimated animals. We propose that in sand rats, BDNF may, at least in part, mediate the effects of circadian disruption on the development of anxiety and depressive-like behavior and T2DM.

The Effect of Emotional Intelligence on Facial Expression Recognition: An ERP Study

Brain-derived neurotrophic factor (BDNF), its receptors and epigenetic modulators, are implicated in the pathophysiology of affective disorders, T2DM and the circadian system function. We used diurnal sand rats, which develop type 2 diabetes (T2DM), anxiety and depressive-like behavior under laboratory conditions. The development of these disorders is accelerated when animals are maintained under short photoperiod (5:19L:D, SP) compared to neutral photoperiod (12:12L:D, NP). We compared rhythms in plasma BDNF as well as BDNF and PER2 expression in the frontal cortex and suprachiasmatic nucleus (SCN) of sand rats acclimated to SP and NP. Acclimation to SP resulted in higher insulin levels, significantly higher glucose levels in the glucose tolerance test, and significantly higher anxiety- and depression-like behaviors compared with animals acclimated to NP. NP Animals exhibited a significant daily rhythm in plasma BDNF levels with higher levels during the night, and in BDNF expression levels in the frontal cortex and SCN. No significant BDNF rhythm was found in the plasma, frontal cortex or SCN of SP acclimated animals. We propose that in sand rats, BDNF may, at least in part, mediate the effects of circadian disruption on the development of anxiety and depressive-like behavior and T2DM.

Evaluation of 5-HTTLPR (insertion/deletion) and BDNF (rs6265) genetic variations in the Slovakian individuals suffering from affective disorders.

The pathophysiology of affective disorders (AD), including depressive disorders (DD) and anxiety disorders (ANXD), is still unclear. To understand risk factors of the disorders, we evaluated genetic variations of the serotonin reuptake transporter (5-HTTLPR, ins/del) and the brain-derived neurotrophic factor (BDNF, rs6265) in Slovak patients suffering from AD. After genotyping we observed a significantly increased frequency of LS and LL genotypes (5-HTTLPR) in individuals diagnosed with AD compared to controls (OR = 1.99, 95% CI = 1.21-3.27, p = 0.006). There was also a significant relationship between TT (BDNF) genotype and the risk of AD in males (OR = 5.93, 95% CI = 1.42-27.07, p = 0.011). In gene-gene analysis, the LL or LS (5-HTTLPR) and CT or TT (BDNF) genotype combinations had a risk-enhancing effect on AD susceptibility (mainly ANXD in males), while SS (5-HTTLPR) and TT (BDNF) combination had a protective effect on AD risk (mainly ANXD). However, larger prospective studies are needed to confirm our findings.

Сон и депрессия: что мы знаем и что предстоит узнать?

Presently, a lot of data indicate that the disturbance of mechanisms underlying the regulation of sleep-waking cycle coincides with the mechanisms underlying the development of depression. The disturbance of circadian rhythms is one of the core factors in the genesis of the most affective disorders including depression, which indicates the role of the internal biological clock in the pathophysiology of affective disorders. The episodes of depression, mania or hypomania may result from the disturbances in endogenous biological timing. In this review, we have summarized the literature data obtained in animal models or in the patients with affective pathology, in which the connection between the function of sleep and depression was demonstrated. Specifically, we highlight the mechanisms underlying sleep dysfunction during depression (imbalance of circadian rhythms, melatonin metabolism and mechanisms of neuroinflammatory dysregulation) and provide an evidence for the link between sleep function and depression (sleep disturbances during depressive episodes, the effects of pharmacotherapy, chronotherapy, the effect of sleep deprivation, comorbidity of obstructive sleep apnea and depression).

Salivary Aldosterone, Cortisol, and Their Morning to Evening Slopes in Patients with Depressive Disorder and Healthy Subjects: Acute Episode and Follow-Up 6 Months after Reaching Remission

Background/Objective: Cortisol is thought to be involved in the pathophysiology of affective disorders. Less attention has been given to other neuroendocrine factors. The aim of the present study was to test the hypothesis that adrenocortical steroids aldosterone and cortisol show different dynamic changes in the course of clinical depression with the assumption that aldosterone is a state marker of depression. Methods: A total of 78 adult subjects (39 patients with depressive disorder and 39 healthy controls) participated in a prospective non-interventional clinical study. Patients were investigated at the time of an acute episode and 6 months after reaching remission. The clinical and personal characteristics, and morning and evening salivary concentrations of aldosterone and cortisol were evaluated. Results: Patients with an acute depressive episode exhibited higher evening aldosterone and lower morning cortisol concentrations compared to healthy subjects. In these patients, both hormone concentrations showed flatter morning to evening slopes. Salivary aldosterone, but not cortisol concentrations, were lower in patients 6 months after reaching remission compared to those in the acute state. Similarly, 6 months of remission resulted in a steeper morning to evening slope of salivary aldosterone compared to the acute state. The cortisol rhythm remained dysregulated. A significant negative correlation between trait anxiety scores and morning cortisol concentrations in patients at 6 months of clinical remission was observed. Conclusion: Diurnal changes in salivary aldosterone concentrations appear to be a state marker, whilst those of cortisol a trait marker of depression.

Lmo3 deficiency in the mouse is associated with alterations in mood-related behaviors and a depression-biased amygdala transcriptome

The highly conserved transcription factor LIM-only 3 (Lmo3) is involved in important neurodevelopmental processes in several brain areas including the amygdala, a central hub for the generation and regulation of emotions. Accordingly, a role for Lmo3 in the behavioral responses to ethanol and in the display of anxiety-like behavior in mice has been demonstrated while the potential involvement of Lmo3 in the control of mood-related behavior has not yet been explored.Using a mouse model of Lmo3 depletion (Lmo3z), we here report that genetic Lmo3 deficiency is associated with altered performance in behavioral paradigms assessing anxiety-like and depression-like traits and additionally accompanied by impairments in learned fear. Importantly, long-term potentiation (LTP) in the basolateral amygdala (BLA), a proposed cellular correlate of fear learning, is impaired in Lmo3z mice. RNA-Seq analysis of BLA tissue and gene set enrichment analysis (GSEA) of differentially expressed genes in Lmo3z mice reveals a significant overlap between genes overexpressed in Lmo3z mice and those enriched in the amygdala of a cohort of patients suffering from major depressive disorder. Consequently, we propose that Lmo3 may play a role in the regulation of gene networks that are relevant to the regulation of emotions. Future work may aid to further explore the role of Lmo3 in the pathophysiology of affective disorders and its genetic foundations.

Neurosteroids and Affective Disorders in Women

Background: Neurosteroids (NS) are steroid derived molecules synthesized in the central nervous system (CNS) involved in modulating brain transmission by its activity on gamma-aminobutyric acid (GABA) receptors; this interaction has been identified as an important factor in the pathophysiology of affective disorders. Objective: The aim of the present paper is to describe the relation of neurosteroids with affective disorders in women and novel treatments in this regard in an understandable and synthesized review of the subject. Methods: A thoroughly made research has been performed in order to find the latest information in this regard using scientific databases such as PubMed and Google Scholar using the keywords Neurosteroids, affective disorders, depression, postpartum depression and dysphoric premenstrual disorder. Results: It has been seen that NS levels during physiological fluctuation such as during menstrual cycle or postpartum may modify the response to GABA by GABA-A receptors in susceptible women. Recent pharmacological assays have been developed in order to treat affective disorders in women focusing on NS fluctuations. Conclusion: Within this paper, we review recent findings in NS modulating mechanisms, its pathophysiological implications in affective disorders and recent clinical assays in this regard.

Targeted Manipulation of Brain Serotonin: RNAi-Mediated Knockdown of Tryptophan Hydroxylase 2 in Rats.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT). Two existing TPH isoforms are responsible for the generation of two distinct serotonergic systems in vertebrates. TPH1, predominantly expressed in the gastrointestinal tract and pineal gland, mediates 5-HT biosynthesis in non-neuronal tissues, while TPH2, mainly found in the raphe nuclei of the brain stem, is accountable for the production of 5-HT in the brain. Neuronal 5-HT is a key regulator of mood and behavior and its deficiency has been implicated in a variety of neuropsychiatric disorders, e.g., depression and anxiety. To gain further insights into the complexity of central 5-HT modulations of physiological and pathophysiological processes, a new transgenic rat model, allowing an inducible gene knockdown of Tph2, was established based on doxycycline-inducible shRNA-expression. Biochemical phenotyping revealed a functional knockdown of Tph2 mRNA expression following oral doxycycline administration, with subsequent reductions in the corresponding levels of TPH2 enzyme expression and activity. Transgenic rats showed also significantly decreased tissue levels of 5-HT and its degradation product 5-Hydroxyindoleacetic acid (5-HIAA) in the raphe nuclei, hippocampus, hypothalamus, and cortex, while peripheral 5-HT concentrations in the blood remained unchanged. In summary, this novel transgenic rat model allows inducible manipulation of 5-HT biosynthesis specifically in the brain and may help to elucidate the role of 5-HT in the pathophysiology of affective disorders.

Modulation of Anxiolytic-Like and Antidepressant-Like Effects of Melatonin by Imipramine in Wistar Rats: Possible Interaction with Central Monoaminergic Systems

Our current study aims to explore the interaction of melatonin (MEL) with the monoaminergic system on the pathophysiology of affective disorders in Wistar rats. We mention here that, the role of monoaminergic transmission in the pathophysiology of affective disorders in humans is demonstrated in most recent reports. In this sense, our current work aims to explore the effect of melatonin (MEL) with or without imipramine (IMP) on levels of depression and anxiety in Wistar rats and would determine the role of MEL in modulating serotonin, noradrenaline and dopamine neurotransmission. From this point, twenty-four female Wister rats were divided into 4 groups of 6 animals and received subcutaneously during 4 weeks different doses of MEL (4 mg/kg), IMP (2 mg/kg) or MEL (4 mg/kg) + IMP (2 mg/kg). Behavioral performance especially anxiety and depression is measured in the open field (OFT), elevated plus maze (EPM) and forced swim test (FST). The anxiety-like and antidepressant-like effects were observed with MEL at 4 mg/Kg and IMP at 2 mg/Kg but the potentiating effect was more observed with the two combined molecules (MEL and IMP), since locomotors activity assessed by the OFT and EPM was not affected. These effects suggest that psychopharmacological actions of MEL are due, at least in part, to its ability to potentiate the central monoaminergic transmitter effects.

Testosterone is related to GABA+ levels in the posterior-cingulate in unmedicated depressed women during reproductive life

BackgroundThe role of testosterone (T) in the pathophysiology of affective disorders and anxiety is broadly supported. Evidence suggests that T has anxiolytic and antidepressant properties. One proposed route for the central effects of T is its interaction with the gamma-aminobutyric acid (GABA) system. We explored the relationship between T levels and GABA+ levels in anterior-cingulate (ACC) and the posterior-cingulate (PCC) regions in depressed women, using magnetic resonance spectroscopy (1H-MRS). MethodsTwenty-one depressed patients with regularly cycling who were not taking hormonal or psychotropic drugs were recruited. We assessed severity of depression using the Hamilton Depression Rating Scale (HDRS). Blood samples were taken for quantification of free (FT) and total testosterone (TT) on the day of the magnetic resonance (MR) scan. We evaluated GABA+ levels in the PCC and ACC, using the Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) sequence. Pearson correlations were used to evaluate the association between FT, TT, GABA+ concentrations, and HDRS scores. ResultsTT and FT levels were positively correlated with GABA+ levels in the PCC. No correlation was observed between T levels and GABA+ levels in the ACC. The HDRS total scores correlated negatively with FT levels. LimitationsLimitations include the cross-sectional evaluation and the lack of a comparative healthy group. ConclusionsOur findings suggest that the potential anxiolytic and antidepressant properties of T are related to increased GABA+ levels in the PCC. This observation may contribute to increased understanding of the role of T in depressive and anxiety symptoms in women.

P 156 Correlation of regional brain volume and affective disorders 7T MRI based structural analysis of human hypothalami with anxiety symptoms

Objectives Essential features of the hypothalamus play a constitutive role in the depressive symptomatology and the anxiety generating stress response system. The involvement of the structure in the pathophysiology of affective disorders is undisputed. Only a few studies dealt with the association of anxiety symptoms in psychiatric disorders and the hypothalamus volume, tested via a lower resolution MRI ( Goldstein et al., 2007 , Terlevic et al., 2013 , Cheng et al., 2015 ). Yet their results remained contradictory. This substantiated our interest to verify the correlation of the hypothalamus volume and the anxiety score of affective disorder patients, hypothesizing a negative correlation. Method 61 patients, aged 20–62 years and suffering from major depressive or bipolar disorders participated in the study. The method of Schindler et al. (2013) was used to perform the hypothalamus volumetry. The anxiety score was calculated with items from the Inventory of Depressive Symptomatology (IDS) according to the factor analysis of Rush et al. (1996) . Results Kendall’s correlation shows a significant moderate correlation between the left hypothalamus volume and the anxiety score of patients with a medicated major unipolar depression ( τ b = 0.391 , p = 0,019). For patients with unmedicated major depressive or bipolar disorder the effect was not significant. Conclusions To our knowledge, this is the first study exploring a positive correlation of an anxiety score and the hypothalamus-volume, investigated with high-resolution 7T images, in affective disorders. The formerly presumed negative correlation between hypothalamus and anxiety score was refuted. However due to the contradictory state of research we could only put forward a weak hypothesis. In light of these results, future studies would have to review the correlation with an extended sample, an own factor analysis and a more precise anxiety scale.

P 40 Correlation between hypothalamus and third ventricle of patients with affective disorders

Objectives Former studies proved the key role of the hypothalamus in the pathophysiology of affective disorders. Because of limited imaging methods and difficult delineation, attested volumetric changes has only been verified post-mortem, so in vivo studies made use of the adjacent third ventricle as an indirect marker of hypothalamic changes. Considering that these former ventricle studies leave sufficient scope for methodical improvements, it was our aim to replicate and complement these findings by using a high-resolution 7T-MRI for the first time. Method 84 subjects, aged 20–62 years, with major depressive or bipolar disorder or no history of psychiatric disorders, participated in the study. The hypothalamus volumetry was performed by using the method of Schindler et al. For ascertaining the volume of the ventricle, the software SPM segmented the entire cerebrospinal fluid fully automatically. Afterwards a rater applied a new developed algorithm for the segmentation of the hypothalamic part of the third ventricle. Results The two-factorial ANOVA showed, that patients with bipolar disorder have significant larger ventricles than healthy controls (p = 0.013). For patients with major depressive disorder the effect was not significant. The correlation analysis revealed no relation between hypothalamus and third ventricle after correcting for confounding variables as age, intracranial volume and outliers. Conclusions To our knowledge, this is the first study which investigated the volume of the third ventricle in high-resolution 7T images. Our result, that patients with bipolar disorder have enlarged ventricles, is in line with previous results. The formerly presumed correlation between hypothalamus and ventricle has not been verified, which could be due to the fact that our sample is not large enough to reach the necessary statistical power. A potential influence of psychotropic medication is currently the subject of analysis.

L’influence de la puberté sur les circuits neuronaux sous-tendant la régulation des émotions : implications pour la compréhension des risques de troubles affectifs

Adolescence, with the onset of puberty, represents a developmental period that, in the context of adverse events, renders youth vulnerable to the onset of psychopathology such as affective disorders. It is also a time when fronto-striatal-limbic systems supporting the processing and regulation of emotion and reward undergo important neuromaturational changes. Despite evidence from epidemiological research suggesting that, particularly in girls, the increase in the rate of depression is more strongly associated with pubertal development than maturational age, researchers are just beginning to scratch the surface regarding the specific influence of puberty on the development of fronto-striatal-limbic systems implicated in the pathophysiology of affective disorders. The goal of this review is to a) summarize findings from human neuroimaging studies focusing on the specific influence of puberty or sex hormones on the neurodevelopment of emotional processes, b) highlight the need for a better understanding of neurodevelopmental changes during puberty and how such changes could contribute to developmental trajectories toward the onset of an affective disorder and, c) discuss the potential value of investigating how these changes may contribute to unique opportunities for developing intervention strategies for affective disorders in adolescence.

Pathophysiology of affective disorders: functional interaction of stress hormones and hippocampal excitation.

An important new study by Kvarta, Bradbrook, Dantrassy, Bailey, and Thompson (J Neurophysiol 114: 1713-1724, 2015) examined the effects of persistent stress and excessive glucocorticoid levels on hippocampal function and emotional behavior in rodents. The authors specifically implicate the temporoammonic pathway as being susceptible to reductions in excitatory function in the context of chronic stress. We discuss the importance of this new finding in the broader context of medication development for major depressive disorder.

Effects of Mood Stabilizers on Brain Energy Metabolism in Mice Submitted to an Animal Model of Mania Induced by Paradoxical Sleep Deprivation.

There is a body of evidence suggesting that mitochondrial dysfunction is involved in bipolar disorder (BD) pathogenesis. Studies suggest that abnormalities in circadian cycles are involved in the pathophysiology of affective disorders; paradoxical sleep deprivation (PSD) induces hyperlocomotion in mice. Thus, the present study aims to investigate the effects of lithium (Li) and valproate (VPA) in an animal model of mania induced by PSD for 96 h. PSD increased exploratory activity, and mood stabilizers prevented PSD-induced behavioral effects. PSD also induced a significant decrease in the activity of complex II-III in hippocampus and striatum; complex IV activity was decreased in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex. Additionally, VPA administration was able to prevent PSD-induced inhibition of complex II-III and IV activities in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex, whereas Li administration prevented PSD-induced inhibition only in prefrontal cortex and hippocampus. Regarding the enzymes of Krebs cycle, only citrate synthase activity was increased by PSD in prefrontal cortex. We also found a similar effect in creatine kinase, an important enzyme that acts in the buffering of ATP levels in brain; its activity was increased in prefrontal cortex, hippocampus and cerebral cortex. These results are consistent with the connection of mitochondrial dysfunction and hyperactivity in BD and suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

Possible involvement of 5-HT₇ receptor in pathophysiology of affective disorders and action of antidepressant drugs

The 5-HT7 receptor has recently received considerable attention since its involvement has been implicated in cognitive disturbances, sleep and circadian rhythmicity disorders, anxiety and depression. At the cellular level, 5-HT7 receptors increase the excitability of excitatory cells and appear to modulate both glutamatergic and GABAergic transmission in the hippocampus. It has been proposed that 5-HT7 receptors also modulate glutamatergic and GABAergic transmission in the raphe nuclei and these effects may play a role in the regulation of circadian rhythms. Repeated administration of the selective 5-HT7 receptor antagonist induced functional desensitization of the 5-HT7 receptor system at the level of its reactivity and effector proteins. These effects resemble the outcome of treatment of rats with antidepressant drugs. Chronic stress and elevated level of corticosterone increase the reactivity of 5-HT7 receptors in the hippocampus. Treatment of rats with a selective 5-HT7 receptor antagonist also results in attenuation of glutamatergic transmission in the frontal cortex and it prevents the occurrence of stress-induced modifications of glutamatergic transmission and long-term synaptic plasticity. These results are consistent with the hypothesis that 5-HT7 receptor antagonism might, potentially, be used for the treatment of cognitive deficits and mood disorders.

Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function.

Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2-P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2-P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors.