The monoamine hypothesis of depression posits that an imbalance in monoaminergic neurotransmission is causally related to the clinical features of depression. Antidepressants influencing serotonin ...mainly aim at raising serotonin concentrations, thereby increasing serotonergic transmission at the level of the synapse, for example by inhibiting the serotonin transporter. However, the serotonin system is multifaceted. Different serotonin receptor subtypes turn the serotonergic system into a complex neurochemical arrangement that influences diverse neurotransmitters in various brain regions. Classical antidepressants as well as other psychopharmacological agents have various crucial effects on serotonin receptors. We aim at providing a clinically useful characterization of serotonin receptor subtypes in the treatment of depression. Clarifying the mode of action and the interplay of serotonin receptors with pharmacological agents should help antidepressant mechanisms and typical side effects to be better understood. Against this background, we feature the novel antidepressants vortioxetine, vilazodone and milnacipran/levomilnacipran with regard to their serotonin receptor targets such as the 5-HT1A, 5-HT3 and 5-HT7 which may account for their specific effects on certain symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile.
Post‐traumatic stress disorder (PTSD) is a psychiatric disorder of high prevalence and major socioeconomic impact. Patients suffering from PTSD typically present intrusion and avoidance symptoms and ...alterations in arousal, mood and cognition that last for more than 1 month. Animal models are an indispensable tool to investigate underlying pathophysiological pathways and, in particular, the complex interplay of neuroendocrine, genetic and environmental factors that may be responsible for PTSD induction. Since the 1960s, numerous stress paradigms in rodents have been developed, based largely on Seligman's seminal formulation of ‘learned helplessness’ in canines. Rodent stress models make use of physiological or psychological stressors such as foot shock, underwater trauma, social defeat, early life stress or predator‐based stress. Apart from the brief exposure to an acute stressor, chronic stress models combining a succession of different stressors for a period of several weeks have also been developed. Chronic stress models in rats and mice may elicit characteristic PTSD‐like symptoms alongside, more broadly, depressive‐like behaviours. In this review, the major existing rodent models of PTSD are reviewed in terms of validity, advantages and limitations; moreover, significant results and implications for future research—such as the role of FKBP5, a mediator of the glucocorticoid stress response and promising target for therapeutic interventions—are discussed.
The piriform cortex receives input from the olfactory bulb and (via the entorhinal cortex) sends efferents to the hippocampus, thereby connecting the two canonical neurogenic regions of the adult ...rodent brain. Doublecortin (DCX) is a cytoskeleton-associated protein that is expressed transiently in the course of adult neurogenesis. Interestingly, the adult piriform cortex, which is usually considered non-neurogenic (even though some reports exist that state otherwise), also contains an abundant population of DCX-positive cells. We asked how similar these cells would be to DCX-positive cells in the course of adult hippocampal neurogenesis. Using BAC-generated transgenic mice that express GFP under the DCX promoter, we studied DCX-expression and electrophysiological properties of DCX-positive cells in the mouse piriform cortex in comparison with the dentate gyrus. While one class of cells in the piriform cortex indeed showed features similar to newly generated immature granule neurons, the majority of DCX cells in the piriform cortex was mature and revealed large Na+ currents and multiple action potentials. Furthermore, when proliferative activity was assessed, we found that all DCX-expressing cells in the piriform cortex were strictly postmitotic, suggesting that no DCX-positive "neuroblasts" exist here as they do in the dentate gyrus. We conclude that DCX in the piriform cortex marks a unique population of postmitotic neurons with a subpopulation that retains immature characteristics associated with synaptic plasticity. DCX is thus, per se, no marker of neurogenesis but might be associated more broadly with plasticity.
After stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we ...here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30 min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia. The differentially regulated genes were further collated with oligodendrocyte, astrocyte, and neuron transcriptomes, resulting in a dataset of microglia- and monocyte-specific genes in the ischemic brain. Functional categories significantly enriched in monocytes included migration, proliferation, and calcium signaling, indicative of strong activation. Whole-cell patch-clamp analysis further confirmed this highly activated state by demonstrating delayed outward K
+
currents selectively in invading cells. Although both cell types displayed a mixture of known phenotypes pointing to the significance of ‘intermediate states’ in vivo, blood-derived macrophages were generally more skewed toward an M2 neuroprotective phenotype. Finally, we found that decreased engraftment of blood-borne cells in the ischemic brain of chimeras reconstituted with BM from Selplg
−/−
mice resulted in increased lesions at 7 days and worse post-stroke sensorimotor performance. In aggregate, our study establishes crucial differences in activation state between resident microglia and invading macrophages after stroke and identifies unique genomic signatures for either cell type.
Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen–glucose deprivation (OGD) mimics key aspects of ischemic ...injury in vitro. Here, we studied the effects of 24-h pretreatment with serotonin (5-HT), citalopram (CIT), fluoxetine (FLU), and tianeptine (TIA) on primary mouse cortical neurons subjected to transient OGD. 5-HT (50 μM) significantly enhanced neuron viability as measured by MTT assay and reduced cell death and LDH release. CIT (10 μM) and FLU (1 μM) did not increase the effects of 5-HT and neither antidepressant conferred neuroprotection in the absence of supplemental 5-HT in serum-free cell culture medium. By contrast, pre-treatment with TIA (10 μM) resulted in robust neuroprotection, even in the absence of 5-HT. Furthermore, TIA inhibited mRNA transcription of candidate genes related to cell death and hypoxia and attenuated lipid peroxidation, a hallmark of neuronal injury. Finally, deep RNA sequencing of primary neurons subjected to OGD demonstrated that OGD induces many pathways relating to cell survival, the inflammation-immune response, synaptic dysregulation and apoptosis, and that TIA pretreatment counteracted these effects of OGD. In conclusion, this study highlights the comparative strength of the 5-HT independent neuroprotective effects of TIA and identifies the molecular pathways involved.
The interaction between depression and stroke is highly complex. Post‐stroke depression (PSD) is among the most frequent neuropsychiatric consequences of stroke. Depression also negatively impacts ...stroke outcome with increased morbidity, mortality and poorer functional recovery. Antidepressants such as the commonly prescribed selective serotonin reuptake inhibitors improve stroke outcome, an effect that may extend far beyond depression, e.g., to motor recovery. The main biological theory of PSD is the amine hypothesis. Conceivably, ischaemic lesions interrupt the projections ascending from midbrain and brainstem, leading to a decreased bioavailability of the biogenic amines – serotonin (5HT), dopamine (DA) and norepinephrine (NE). Acetylcholine would also be involved. So far, preclinical and translational research on PSD is largely lacking. The implementation and characterization of suitable animal models is clearly a major prerequisite for deeper insights into the biological basis of post‐stroke mood disturbances. Equally importantly, experimental models may also pave the way for the discovery of novel therapeutic targets. If we cannot prevent stroke, we shall try to limit its long‐term consequences. This review therefore presents animal models of PSD and summarizes potential underlying mechanisms including genomic signatures, neurotransmitter and neurotrophin signalling, hippocampal neurogenesis, cellular plasticity in the ischaemic lesion, secondary degenerative changes, activation of the hypothalamo‐pituitary‐adrenal (HPA) axis and neuroinflammation. As stroke is a disease of the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD in aged animals.
Physical activity induces adult hippocampal neurogenesis. We here show that the acute up-regulating effect of voluntary wheel running on precursor cell proliferation decreases with continued ...exercise, but that continued exercise reduces the age-dependent decline in adult neurogenesis. Cell proliferation peaked at 3 days of running. After 32 days of exercise this response returned to baseline. Running-induced proliferation of transiently amplifying progenitor cells led to a consecutive increase in the number of more mature cells. Increasing age reduced adult neurogenesis at 9 months to 50% of the value at 6 weeks and to 17% at the age of 2 years. At both 1 and 2 years, precursor cell divisions remained inducible by physical activity. Exercise from 3 to 9 months of age significantly reduced the age-dependent decline in cell proliferation but (presumably in the absence of additional stimuli) did not maintain net neurogenesis at levels corresponding to a younger age. We propose that physical activity might contribute to successful aging by increasing the potential for neurogenesis represented by the pool of proliferating precursor cells.
Plaque neovascularization accompanies local inflammation and critically contributes to plaque instability. Correct identification of intraplaque neovascularization by contrast-enhanced ultrasound ...(CEUS) may provide an additional risk marker in carotid stenosis. This pilot study investigates the correlation between histological evaluation of carotid plaque specimens and pre-surgery CEUS to identify neovascularization.
17 patients with high-grade internal carotid artery (ICA) stenosis were studied. CEUS was performed in all patients shortly before carotid endarterectomy. Neovascularization, infiltration of T cells and macrophages along with intraplaque hemorrhage were studied in excised plaques by immunohistochemistry. Ultrasound-based four-level and two-level classification systems for neovascularization were used. CEUS findings were compared with histological findings.
Scores on the CEUS-based four-level and two-level classifications were robustly correlated with the density of intraplaque vessels (r = 0.635, p = 0.006 and r = 0.578, p = 0.015, respectively). Histological evaluation of regions with strong and prolonged intraplaque enhancement typically showed strong intraplaque neovascularization in conjunction with acute intraplaque hemorrhage. Moreover, higher grades of intraplaque neovascularization as determined by ultrasound were associated with a higher percentage of macrophage-rich areas.
CEUS is a technique well suited to gauge the degree of neovascularization of carotid plaques. Future research will have to define the reliability and validity of CEUS in everyday clinical practice. Further, our study suggests that CEUS may also be useful to pick up features of vulnerable plaques such as acute intraplaque hemorrhages.
The serendipitous discovery of ketamine's antidepressant effects represents one of the major landmarks in neuropsychopharmacological research of the last 50 years. Ketamine provides an exciting ...challenge to traditional concepts of antidepressant drug therapy, producing rapid antidepressant effects seemingly without targeting monoaminergic pathways in the conventional way. In consequence, the advent of ketamine has spawned a plethora of neurobiological research into its putative mechanisms. Here, we provide a brief overview of current theories of antidepressant drug action including monoaminergic signaling, disinhibition of glutamatergic neurotransmission, neurotrophic and neuroplastic effects, and how these might relate to ketamine. Given that research into ketamine has not yet yielded new therapies beyond ketamine itself, current knowledge gaps and limitations of available studies are also discussed.
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