scholarly journals Rewiring of the Serotonin System in Major Depression

2021 ◽  
Vol 12 ◽  
Author(s):  
Faranak Vahid-Ansari ◽  
Paul R. Albert
Keyword(s):  
Mental Illness ◽  
Cognitive Impairment ◽  
Major Depression ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Chronic Treatment ◽  
Brain Regions ◽  
Synaptic Organization ◽  
Serotonin System ◽  
The Brain

Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive impairment. Chronic treatment with antidepressants that amplify 5-HT action, such as selective serotonin reuptake inhibitors (SSRIs), appears to accelerate the rewiring of the 5-HT system by mechanisms that may be critical to the behavioral and cognitive improvements induced in these models. In this review, we survey the possible 5-HT receptor mechanisms that could mediate 5-HT rewiring and assess the evidence that 5-HT-mediated brain rewiring is impacting recovery from mental illness. By amplifying 5-HT-induced rewiring processes using SSRIs and selective 5-HT agonists, more rapid and effective treatments for injury-induced mental illness or cognitive impairment may be achieved.

scholarly journals Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability

2021 ◽  
Vol 7 (13) ◽  
pp. eabf3072
Author(s):  
Y. Nagayoshi ◽  
T. Chujo ◽  
S. Hirata ◽  
H. Nakatsuka ◽  
C.-W. Chen ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
State Level ◽  
Memory Deficits ◽  
Ribosome Profiling ◽  
Translation Efficiency ◽  
Trna Modification ◽  
Synaptic Organization ◽  
Transfer Rnas ◽  
The Brain

FtsJ RNA 2′-O-methyltransferase 1 (FTSJ1) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2′-O-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient–derived cells. Loss of 2′-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.

Abnormalities of the HPA axis in affective disorders: clinical subtypes and potential treatments

2006 ◽  
Vol 18 (5) ◽  
pp. 193-209 ◽  
Author(s):  
Richard J. Porter ◽  
Peter Gallagher
Keyword(s):  
Bipolar Disorder ◽  
Cognitive Impairment ◽  
Hpa Axis ◽  
Affective Disorders ◽  
Psychotic Depression ◽  
Review Of The Literature ◽  
Hpa Axis Dysregulation ◽  
New Evidence ◽  
The Brain

Background:New evidence is emerging regarding abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function in subtypes of affective disorders. Adverse effects of HPA axis dysregulation may include dysfunction of monoaminergic transmitter systems, cognitive impairment and peripheral effects. Newer treatments specifically targeting the HPA axis are being developed.Objective:To review these developments focusing particularly on the glucocorticoid receptor (GR) antagonist mifepristone.Method:A selective review of the literature.Results:The function of GRs is increasingly being defined. The role of corticotrophin-releasing hormone (CRH) and dehydroepiandrosterone (DHEA) in the brain is also increasingly understood. HPA axis function is particularly likely to be abnormal in psychotic depression and bipolar disorder, and it is in these conditions that trials of the GR antagonist mifepristone are being focused. CRH antagonists and DHEA are also being investigated as potential treatments.Conclusion:Initial studies of mifepristone and other HPA-axis-targeting agents in psychotic depression and bipolar disorder are encouraging and confirmatory studies are awaited.

Role of adrenal catecholamines in cerebrovasodilation evoked from brain stem

1987 ◽  
Vol 252 (6) ◽  
pp. H1183-H1191
Author(s):  
C. Iadecola ◽  
P. M. Lacombe ◽  
M. D. Underwood ◽  
T. Ishitsuka ◽  
D. J. Reis
Keyword(s):  
Brain Function ◽  
Blood Gases ◽  
Brain Regions ◽  
Elevated Plasma ◽  
Regional Cerebral Blood ◽  
Medullary Reticular Formation ◽  
Alpha Chloralose ◽  
The Brain ◽  
Stimulation Of

We studied whether adrenal medullary catecholamines (CAs) contribute to the metabolically linked increase in regional cerebral blood flow (rCBF) elicited by electrical stimulation of the dorsal medullary reticular formation (DMRF). Rats were anesthetized (alpha-chloralose, 30 mg/kg), paralyzed, and artificially ventilated. The DMRF was electrically stimulated with intermittent trains of pulses through microelectrodes stereotaxically implanted. Blood gases were controlled and, during stimulation, arterial pressure was maintained within the autoregulated range for rCBF. rCBF and blood-brain barrier (BBB) permeability were determined in homogenates of brain regions by using [14C]iodoantipyrine and alpha-aminoisobutyric acid (AIB), respectively, as tracers. Plasma CAs (epinephrine and norepinephrine) were measured radioenzymatically. DMRF stimulation increased rCBF throughout the brain (n = 5; P less than 0.01, analysis of variance) and elevated plasma CAs substantially (n = 4). Acute bilateral adrenalectomy abolished the increase in plasma epinephrine (n = 4), reduced the increases in flow (n = 6) in cerebral cortex (P less than 0.05), and abolished them elsewhere in brain (P greater than 0.05). Comparable effects on rCBF were obtained by selective adrenal demedullation (n = 7) or pretreatment with propranolol (1.5 mg/kg iv) (n = 5). DMRF stimulation did not increase the permeability of the BBB to AIB (n = 5). We conclude that the increases in rCBF elicited from the DMRF has two components, one dependent on, and the other independent of CAs. Since the BBB is impermeable to CAs and DMRF stimulation fails to open the BBB, the results suggest that DMRF stimulation allows, through a mechanism not yet determined, circulating CAs to act on brain and affect brain function.

scholarly journals The Effects of Doxorubicin-based Chemotherapy and Omega-3 Supplementation on Mouse Brain Lipids

Metabolites ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 208
Author(s):  
Djawed Bennouna ◽  
Melissa Solano ◽  
Tonya S. Orchard ◽  
A. Courtney DeVries ◽  
Maryam Lustberg ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Breast Cancer Survivors ◽  
Omega 3 ◽  
Resolvin D1 ◽  
Brain Lipids ◽  
Fatty Acid Supplementation ◽  
Ovariectomized Mice ◽  
The Brain ◽  
Injection Study

Chemotherapy-induced cognitive impairment affects ~30% of breast cancer survivors, but the effects on how chemotherapy impacts brain lipids, and how omega-3 polyunsaturated fatty acid supplementation may confer protection, is unknown. Ovariectomized mice were randomized to two rounds of injections of doxorubicin + cyclophosphamide or vehicle after consuming a diet supplemented with 2% or 0% EPA+DHA, and sacrificed 4, 7, and 14 days after the last injection (study 1, n = 120) or sacrificed 10 days after the last injection (study 2, n = 40). Study 1 whole brain samples were extracted and analyzed by UHPLC-MS/MS to quantify specialized pro-resolving mediators (SPMs). Lipidomics analyses were performed on hippocampal extracts from study 2 to determine changes in the brain lipidome. Study 1 results: only resolvin D1 was present in all samples, but no differences in concentration were observed (P > 0.05). Study 2 results: chemotherapy was positively correlated with omega-9 fatty acids, and EPA+DHA supplementation helped to maintain levels of plasmalogens. No statistically significant chemotherapy*diet effect was observed. Results demonstrate a limited role of SPMs in the brain post-chemotherapy, but a significant alteration of hippocampal lipids previously associated with other models of cognitive impairment (i.e., Alzheimer’s and Parkinson’s disease).

scholarly journals Neural Substrates of Social Status Inference: Roles of Medial Prefrontal Cortex and Superior Temporal Sulcus

2014 ◽  
Vol 26 (5) ◽  
pp. 1131-1140 ◽  
Author(s):  
Malia Mason ◽  
Joe C. Magee ◽  
Susan T. Fiske
Keyword(s):  
Social Order ◽  
Neural Substrates ◽  
Brain Regions ◽  
Third Party ◽  
Social Interdependence ◽  
Medial Pfc ◽  
State Inference ◽  
The Brain ◽  
Track Status

The negotiation of social order is intimately connected to the capacity to infer and track status relationships. Despite the foundational role of status in social cognition, we know little about how the brain constructs status from social interactions that display it. Although emerging cognitive neuroscience reveals that status judgments depend on the intraparietal sulcus, a brain region that supports the comparison of targets along a quantitative continuum, we present evidence that status judgments do not necessarily reduce to ranking targets along a quantitative continuum. The process of judging status also fits a social interdependence analysis. Consistent with third-party perceivers judging status by inferring whose goals are dictating the terms of the interaction and who is subordinating their desires to whom, status judgments were associated with increased recruitment of medial pFC and STS, brain regions implicated in mental state inference.

scholarly journals The NCX3 Isoform of the Na+/Ca2+ Exchanger Contributes to Neuroprotection Elicited by Ischemic Postconditioning

2010 ◽  
Vol 31 (1) ◽  
pp. 362-370 ◽  
Author(s):  
Giuseppe Pignataro ◽  
Elga Esposito ◽  
Ornella Cuomo ◽  
Rossana Sirabella ◽  
Francesca Boscia ◽  
...  
Keyword(s):  
Brain Regions ◽  
Ischemic Postconditioning ◽  
Intracerebroventricular Infusion ◽  
Ionic Transporters ◽  
Relevant Role ◽  
Ischemic Episode ◽  
Study Support ◽  
Interfering Rna ◽  
The Brain

It has been recently shown that a short sublethal brain ischemia subsequent to a prolonged harmful ischemic episode may confer ischemic neuroprotection, a phenomenon termed ischemic postconditioning. Na+/Ca2+ exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are plasma membrane ionic transporters widely distributed in the brain and involved in the control of Na+ and Ca2+ homeostasis and in the progression of stroke damage. The objective of this study was to evaluate the role of these three proteins in the postconditioning-induced neuroprotection. The NCX protein and mRNA expression was evaluated at different time points in the ischemic temporoparietal cortex of rats subjected to tMCAO alone or to tMCAO plus ischemic postconditioning. The results of this study showed that NCX3 protein and ncx3 mRNA were upregulated in those brain regions protected by postconditioning treatment. These changes in NCX3 expression were mediated by the phosphorylated form of the ubiquitously expressed serine/threonine protein kinase p-AKT, as the p-AKT inhibition prevented NCX3 upregulation. The relevant role of NCX3 during postconditioning was further confirmed by results showing that NCX3 silencing, induced by intracerebroventricular infusion of small interfering RNA (siRNA), partially reverted the postconditioning-induced neuroprotection. The results of this study support the idea that the enhancement of NCX3 expression and activity might represent a reasonable strategy to reduce the infarct extension after stroke.

scholarly journals Role of the glymphatic system in ageing and diabetes mellitus impaired cognitive function

2019 ◽  
Vol 4 (2) ◽  
pp. 90-92 ◽  
Author(s):  
Li Zhang ◽  
Michael Chopp ◽  
Quan Jiang ◽  
Zhenggang Zhang
Keyword(s):  
Diabetes Mellitus ◽  
Cognitive Impairment ◽  
Interstitial Fluid ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Glymphatic System ◽  
Impaired Cognitive Function ◽  
Increased Risk ◽  
The Brain

Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment.

scholarly journals Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1018
Author(s):  
Caitlyn A. Mullins ◽  
Ritchel B. Gannaban ◽  
Md Shahjalal Khan ◽  
Harsh Shah ◽  
Md Abu B. Siddik ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Energy Homeostasis ◽  
Dorsal Striatum ◽  
Brain Regions ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Obesity Prevalence ◽  
Beneficial Effects ◽  
The Brain

Obesity prevalence is increasing at an unprecedented rate throughout the world, and is a strong risk factor for metabolic, cardiovascular, and neurological/neurodegenerative disorders. While low-grade systemic inflammation triggered primarily by adipose tissue dysfunction is closely linked to obesity, inflammation is also observed in the brain or the central nervous system (CNS). Considering that the hypothalamus, a classical homeostatic center, and other higher cortical areas (e.g. prefrontal cortex, dorsal striatum, hippocampus, etc.) also actively participate in regulating energy homeostasis by engaging in inhibitory control, reward calculation, and memory retrieval, understanding the role of CNS oxidative stress and inflammation in obesity and their underlying mechanisms would greatly help develop novel therapeutic interventions to correct obesity and related comorbidities. Here we review accumulating evidence for the association between ER stress and mitochondrial dysfunction, the main culprits responsible for oxidative stress and inflammation in various brain regions, and energy imbalance that leads to the development of obesity. Potential beneficial effects of natural antioxidant and anti-inflammatory compounds on CNS health and obesity are also discussed.

Serotonin and panic

1998 ◽  
Vol 172 (6) ◽  
pp. 465-471 ◽  
Author(s):  
C. J. Bell ◽  
D. J. Nutt
Keyword(s):  
Panic Disorder ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Monoamine Oxidase Inhibitor ◽  
Brain Regions ◽  
Oxidase Inhibitor ◽  
Tryptophan Depletion ◽  
Laboratory Studies ◽  
The Uk ◽  
The Relationship

BackgroundTricyclic (TCA) and monoamine oxidase inhibitor (MAOI) antidepressants are effective in the treatment of panic disorder. Two selective serotonin reuptake inhibitors (SSRIs) have also been licensed in the UK for this indication and studies with three other SSRIs have recently been completed. These provide further evidence for the role of serotonin in panic.MethodReview of clinical, animal and laboratory studies.ResultsSSRIs have been shown to be effective in the treatment of panic disorder. The reported rates of improvement of 60–70% of patients taking SSRIs are similar to those seen withTCAs and greater than placebo. Other serotonergic agents do not appear to be effective. Animal work and human studies including measures of 5-HT in plasma, cerebrospinal fluid and platelets, challenge paradigms and tryptophan depletion show that the relationship between 5-HT and anxiety is complex.ConclusionClinical trials have shown that of all the serotonergic agents only the SSRIs are effective in panic disorder. They are as beneficial as the TCAs and seem to be better tolerated which may be particularly significant in view of the chronic nature of the condition. Serotonin plays a role in panic disorder and serotonergic dysfunction, however the results and evidence do not fit one theory alone. It is also likely that different brain regions and 5-HTreceptors are involved in specific ways.

scholarly journals Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications

2017 ◽  
Vol 51 (06) ◽  
pp. 229-242 ◽  
Author(s):  
Přemysl Vlček ◽  
Jakub Polák ◽  
Martin Brunovský ◽  
Jiří Horáček
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Brain Regions ◽  
Glutamatergic System ◽  
Obsessive Compulsive ◽  
Therapeutic Implications ◽  
Temporal Lobes ◽  
Compulsive Disorder ◽  
Neuropsychological Evidence

AbstractObsessive-compulsive disorder (OCD) is a chronic psychiatric illness and 1 of the most common anxiety disorders with the prevalence of 3%. Although its pathogenesis remains unclear, the traditional model focused on alternations in the serotonin system. Selective serotonin reuptake inhibitors provide the most effective treatment; however, as much as 40–60% of patients do not respond to antidepressants therapy. Thus, attention has shifted towards other neurotransmitter systems and related neuroanatomical structures. Recently, there is extensive evidence showing a key role of glutamate pathways abnormalities within the cortico-striatal-thalamo-cortical circuitry and temporal lobes in OCD pathogenesis. In this review, we link together the existent neuroanatomical, neurophysiological, and neuropsychological evidence to argue for potential benefits of adjuvant treatment with glutamatergic agents, especially memantine. By a targeted de-excitation effect on the glutamatergic system in the temporal lobes and connected brain regions, memantine might further alleviate OCD symptoms. This effect should be even more pronounced in certain subtypes of patients with specific cognitive deficits and maladaptive compensatory memory processes (e.g., checkers).

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