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Rationale During pregnancy and postpartum period, 20 % of women are affected by depression, which is a growing health concern. Selective serotonin reuptake inhibitor (SSRI) medications are popular treatments for maternal depression; however, the effect of maternal depression and perinatal SSRI exposure on offspring’s neural development needs further investigation. Objectives This study aims to determine the role of developmental fluoxetine exposure on hippocampal plasticity in the adult offspring. Methods Sprague-Dawley rat offspring were exposed to fluoxetine beginning on postnatal day 1. Offspring were also exposed to prenatal maternal stress. Four groups of male and female offspring were used: (1) prenatal stress + fluoxetine, (2) prenatal stress + vehicle, (3) fluoxetine alone, and (4) vehicle alone. Hippocampi were analyzed for levels of cell proliferation, immature neurons, and new cell survival (3 weeks after 5-bromo-2-deoxyuridine injection) in the granule cell layer, as well as synaptophysin density in the CA3 region and granule cell layer. TPH staining was assessed in the dorsal raphe nucleus. Results Developmental fluoxetine exposure to prenatally stressed offspring reversed the effect of prenatal stress or fluoxetine exposure alone on the number of immature neurons. Prenatal stress alone, regardless of developmental exposure to fluoxetine, markedly decreased hippocampal cell proliferation and tended to decrease new cell survival. Furthermore, in adult female offspring, developmental fluoxetine exposure greatly increased new cell survival and significantly decreased synaptophysin density in the granule cell layer. Conclusions There are long-term effects of developmental SSRI exposure on hippocampal plasticity that is differentially affected by expose to maternal adversity and offspring sex.

Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB.

Acquiring the recommended daily allowance of vitamins is crucial for maintaining homeostatic balance in humans and other animals. A deficiency in or dysregulation of vitamins adversely affects the neuronal metabolism, which may lead to neurodegenerative diseases. In this article, we discuss how novel vitamin-based approaches aid in attenuating abnormal neuronal functioning in neurodegeneration-based brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, and Prion disease. Vitamins show their therapeutic activity in Parkinson’s disease by antioxidative and anti-inflammatory activity. In addition, different water- and lipid-soluble vitamins have also prevented amyloid beta and tau pathology. On the other hand, some results also show no correlation between vitamin action and the prevention of neurodegenerative diseases. Some vitamins also exhibit toxic activity too. This review discusses both the beneficial and null effects of vitamin supplementation for neurological disorders. The detailed mechanism of action of both water- and lipid-soluble vitamins is addressed in the manuscript. Hormesis is also an essential factor that is very helpful to determine the effective dose of vitamins. PubMed, Google Scholar, Web of Science, and Scopus were employed to conduct the literature search of original articles, review articles, and meta-analyses.

Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer’s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. Objective The aim of this review was to provide an overview of the effects of phosphodiesterase inhibitors (PDE-Is) on cognition, the possible underlying mechanisms, and the relationship to current theories about memory formation. Materials and methods Studies of the effects of inhibitors of different PDE families (2, 4, 5, 9, and 10) on cognition were reviewed. In addition, studies related to PDE-Is and blood flow, emotional arousal, and long-term potentiation (LTP) were described. Results PDE-Is have a positive effect on several aspects of cognition, including information processing, attention, memory, and executive functioning. At present, these data are likely to be explained in terms of an LTP-related mechanism of action. Conclusion PDE-Is are a promising target for cognition enhancement; the most suitable candidates appear to be PDE2-Is or PDE9-Is. The future for PDE-Is as cognition enhancers lies in the development of isoform-specific PDE-Is that have limited aversive side effects.

Depression is a major health problem with a high prevalence and a heavy socioeconomic burden in western societies. It is associated with atrophy and impaired functioning of cortico-limbic regions involved in mood and emotion regulation. It has been suggested that alterations in neurotrophins underlie impaired neuroplasticity, which may be causally related to the development and course of depression. Accordingly, mounting evidence suggests that antidepressant treatment may exert its beneficial effects by enhancing trophic signaling on neuronal and synaptic plasticity. However, current antidepressants still show a delayed onset of action, as well as lack of efficacy. Hence, a deeper understanding of the molecular and cellular mechanisms involved in the pathophysiology of depression, as well as in the action of antidepressants, might provide further insight to drive the development of novel fast-acting and more effective therapies. Here, we summarize the current literature on the involvement of neurotrophic factors in the pathophysiology and treatment of depression. Further, we advocate that future development of antidepressants should be based on the neurotrophin theory.

Cerebral small vessels feed and protect the brain parenchyma thanks to the unique features of the blood-brain barrier. Cerebrovascular dysfunction is therefore seen as a detrimental factor for the initiation of several central nervous system (CNS) disorders, such as stroke, cerebral small vessel disease (cSVD), and Alzheimer's disease. The main working hypothesis linking cerebrovascular dysfunction to brain disorders includes the contribution of neuroinflammation. While our knowledge on microglia cells - the brain-resident immune cells - has been increasing in the last decades, the specific populations of microglia and macrophages surrounding brain vessels, vessel-associated microglia (VAM), and perivascular macrophages (PVMs), respectively, have been overlooked. This review aims to summarize the knowledge gathered on VAM and PVMs, to discuss existing knowledge gaps of importance for later studies and to summarize evidences for their contribution to cerebrovascular dysfunction.

Chronic stress or long-term administration of glucocorticoids disrupts the hypothalamus-pituitary-adrenal system leading to continuous high levels of glucocorticoids and insulin resistance (IR). This pre-diabetic state can eventually develop into type 2 diabetes mellitus and has been associated with a higher risk to develop depressive disorders. The mechanisms underlying the link between chronic stress, IR and depression remains unclear. The present study aimed to establish a stress-depression model in mice to further study the effects of stress-induced changes upon insulin sensitivity and behavioural consequences. A pilot study was conducted to establish the optimal administration route and a pragmatic measurement of IR. Subsequently, 6-month-old C57BL/6NCrl mice were exposed to long-term oral corticosterone treatment via the drinking water. To evaluate insulin sensitivity changes, blood glucose and plasma insulin levels were measured at different time-points throughout treatment and mice were behaviourally assessed in the elevated zero maze (EZM), forced swimming test (FST) and open field test to reveal behavioural changes. Long-term corticosterone treatment increased body weight and decreased insulin sensitivity. The latter was revealed by a higher IR index and increased insulin in the plasma, whereas blood glucose levels remained unchanged. Corticosterone treatment induced longer immobility times in the FST, reflecting depressive-like behaviour. No effects were observed upon anxiety as measured in the EZM. The effect of the higher body weight of the CORT treated animals at time of testing did not influence behaviour in the EZM or FST, as no differences were found in general locomotor activity. Long-term corticosterone treatment via the drinking water reduces insulin sensitivity and induces depressive-like behaviour in the C57BL/6 mouse. This mouse model could thus be used to further explore the underlying mechanisms of chronic stress-induced T2DM and its association with increased prevalence of major depressive disorder on the short-term and other behavioural adaptations on the longer term.

Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.

Rationale A growing number of infants are being exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. SSRIs target the serotoninergic system and are a popular treatment for maternal mood disorders. Serotonin itself plays a key role in the sexual differentiation through its role in the development of the hypothalamic–pituitary–gonadal axis, and previous research has shown that developmental SSRI exposure has an effect on sexual behavior in male offspring. Objectives Our aim was to determine the role of developmental exposure to a popular SSRI medication, fluoxetine, on sexual differentiation of the brain and behavior in female offspring using a rodent model of maternal adversity. Methods Stressed and non-stressed Sprague–Dawley rat dams were chronically treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1. Four groups of female offspring were used: (1) control + vehicle, (2) control + fluoxetine, (3) prenatal stress + vehicle, and (4) prenatal stress + fluoxetine. Results Primary results show that in adult female offspring, developmental fluoxetine exposure facilitates proceptive and receptive behaviors with a significant increase in the number of proceptive behaviors, a significant increase in the lordosis quotient, and a significant decrease in the rejection quotient. Conclusions This research contributes in the understanding of the long-term impact developmental fluoxetine exposure on the hypothalamus–pituitary–gonadal (HPG) system in adult female offspring.

Bilateral, high-frequency stimulation (HFS) of the subthalamic nucleus (STN) is the surgical therapy of choice for movement disability in advanced Parkinson's disease (PD), but this procedure evokes debilitating psychiatric effects, including depressed mood, of unknown neural origin. Here, we report the unexpected finding that HFS of the STN inhibits midbrain 5-hydroxytryptamine (5-HT) neurons to evoke depression-related behavioral changes. We found that bilateral HFS of the STN consistently inhibited (40-50%) the firing rate of 5-HT neurons in the dorsal raphe nucleus of the rat, but not neighboring non-5-HT neurons. This effect was apparent at clinically relevant stimulation parameters (>=100 Hz, >=30 μA), was not elicited by HFS of either neighboring or remote structures to the STN, and was still present in rat models of PD. We also found that bilateral HFS of the STN evoked clear-cut, depressive-like behavior in a widely used experimental paradigm of depression (forced swim test), and this effect was also observed in a PD model. Importantly, the depressive-like behavior elicited by HFS of the STN was reversed by a selective 5-HT-enhancing antidepressant, thereby linking the behavioral change to decreased 5-HT neuronal activity. Overall, these findings link reduced 5-HT function to the psychiatric effects of HFS of the STN observed in PD patients and provide a rational basis for their clinical management. More generally, the powerful interaction between the STN and 5-HT system uncovered here offers insights into the high level of comorbidity of basal ganglia disease and mood disorder.