Impaired Brain Function Research Articles

Organic mental illnesses are outlawed: farewell to Karl Bonhoeffer

The article analyzes the reasons for the deletion of the section “Organic mental disorders” from the psychiatric classifications (ICD-11, DSM-5) and its replacement by the sections “Neurocognitive disorders” and “Secondary mental and behavioral disorders associated with disorders and diseases classified in other chapters”. It is argued that at the present stage of development of psychiatry it has become clear that not only organic mental disorders are associated with impaired brain function, but also all others, e.g. the disorders of the schizophrenic spectrum. This leads to the conclusion that the term “organic” has become an anachronism and no longer reflects the essence of psychogenesis. As a result, changes in terminology in modern psychiatric classifications should be recognized as justified. However, the term “organic disorders” did not have a stigmatizing character, unlike, for example, “psychopathy”, “oligophrenia”, “hysteria” or “manic-depressive psychosis”. It undoubtedly had an indeterminate character, as it interpreted pathological changes in the brain broadly and was opposed to the concept of “functional disorders”. At the current stage of development of psychoneurology, organic causes are often found behind the functional. Exclusion of the term “organic” from the psychiatric lexicon, rejection of the Bonhoeffer approach, the Walter-Buell triad and the psychoorganic syndrome can be considered superfluous, since the introduction of the concept of “secondary mental disorders” in their place does not alter the process of understanding the nature of psychogenesis. It is concluded that the division of mental disorders into so-called primary and secondary disorders is no better than the opposition of functional and organic disorders, and that the “outdated” approach can be used in the training of young psychiatrists, emphasizing that the term “organic” can also be extended to mental disorders that used to be called endogenous.

APPLICATION OF COMPUTERISED TECHNOLOGIES IN THE REHABILITATION OF PATIENTS WITH STROKE CONSEQUENCES

A stroke is a sudden onset of focal or generalized impairment of brain function due to vascular causes only, which is related to cerebral blood flow and lasts for more than 24 hours. Cerebral stroke remains the second leading cause of death and the third most significant cause of disability in the world. Over the past 30 years, the absolute number of cases of this disease has increased by 70%, the prevalence by 85%, with a 43% increase in mortality rates. According to the latest Global Burden of Disease (GBD) analysis, in 2019, there were about 12.2 million stroke cases, 143 million disability-adjusted life years and 6.6 million deaths worldwide, 86% of which occurred in low- and lower-middle-income countries. Purpose to analyse and systematise the use of computerised technologies in the rehabilitation of patients with stroke consequences. Materials and methods. To achieve the objectives of the research, the researchers analysed scientific literature and systematised information using electronic databases such as PubMed, Google Scholar and others. Research results. Traditional methods have proven their effectiveness and are widely used in the practice of rehabilitating patients after stroke. However, with the development of science and technology, there is a need to find new approaches to therapy that can provide a more comprehensive and effective treatment of this pathology. Today, computerized technologies deserve special attention in the rehabilitation of patients after stroke, namely robotic systems, specially designed video games and virtual reality, and TV rehabilitation. Robotic systems are devices that automate various tasks and processes. They can be programmed to perform certain functions with high accuracy and repeatability. In rehabilitation, such systems help to restore motor functions, support physical activity, and facilitate recovery from injuries or illnesses, including stroke. Video games and virtual reality technologies are examples of exciting and fun rehabilitation for stroke patients. Traditional therapies can be complex and tedious to repeat, making it less likely that patients will do them at home. Physical therapists are finding that video games are more engaging and easier to incorporate into home treatment regimens. Tele-rehabilitation after stroke is a form of remote medical care that allows patients to receive rehabilitation services via the Internet or other telecommunication technologies. This provides access to the necessary therapy regardless of the patient's place of residence. Conclusions. Computerized technology significantly improves the rehabilitation of patients with stroke. Robotic systems provide high precision and control during movements, which avoids incorrect exercise and reduces the risk of re-injury, regularity of training, and patient comfort. In addition, many robotic systems have built-in sensors that allow you to track the patient's progress and provide feedback to both the patient and the doctor. This helps to adjust the rehabilitation programme according to the patient's needs. The use of video games and virtual reality in stroke rehabilitation offers numerous benefits, including increased motivation, improved motor and cognitive function, psychological support, and social interaction. Tele-rehabilitation after stroke is an innovative approach to patient recovery, providing access to rehabilitation services regardless of where they live.

Impact of obesity on allergic respiratory diseases and on mental and cognitive performance

Summary Background Obesity and allergies are among the most common diseases of our civilization. Given the simultaneous rise in the prevalence of these diseases in recent years, a potential causal link between the two has been proposed. In particular, obese patients are at an increased risk of developing bronchial asthma, likely due to mechanical restrictions but also to metabolic changes that adversely affect immune function. Neuroscience studies have also shown that obesity can lead to impaired brain function and mental health. In the following review, we will take a closer look at our studies that focus on the influence of obesity on allergic diseases and cognitive performance. Results Both human studies and animal models (mice) have shown that obesity leads to increased allergic responses in the airways. Our studies in a mouse model of obesity confirm that an obese phenotype is associated with increased allergic sensitization and manifestation. These changes are associated with significant shifts in the composition of the gut microbial flora. The microbiome changes are further associated with allergic airway inflammation and an increased incidence of T helper 1 (Th1) type pulmonary macrophages. Interestingly, despite the changes in the microbiome, it is possible to effectively prevent allergy development by inducing oral tolerance. Furthermore, it was observed that obese mice show increased signs of anxiety and depression, as well as reduced cognitive performance. Conclusion Obesity is a complex metabolic disease that significantly impacts our body’s gut microbiome and immune system, resulting in an increased incidence of allergic asthma and neurological/psychological changes. Attention should be given to both the prophylactic and therapeutic measures to mitigate the impact of obesity, including oral tolerance for managing existing allergic diseases.

Remote ischemic preconditioning plays a neuroprotective role in cerebral ischemia-reperfusion mice by inhibiting mitophagy

Remote ischemic preconditioning (RIPC) represents a clinically feasible method for safeguarding vital organs against ischemic injury. However, its specific role in cerebral ischemia-reperfusion (I/R) injury remains to be definitively elucidated. In this study, we investigated the neuroprotective effects of RIPC on mice at 7 days post-cerebral I/R and its involvement in mitophagy and mitochondrial dysfunction. Cerebral I/R led to impaired brain function, as well as structural and functional damage to mitochondria. Notably, RIPC treatment ameliorated the neurological dysfunction induced by cerebral I/R. Compared with the I/R group, the expression levels of NeuN, MBP, PDH, and Tom20 were significantly elevated in the RIPC + I/R group. Furthermore, mitochondria in the RIPC + I/R group exhibited more intact structure compared to those in the I/R group. In mice subjected to I/R injury, RIPC treatment markedly increased ATP content, ADP content, TAN level and glucose uptake while upregulating expression levels of Parkin, Pink1 and P62 proteins; it also reduced both the volume of ischemic foci and the number of mitochondrial autophagosomes along with decreasing LC3B II/I ratio. In conclusion, RIPC may exert a neuroprotective role by inhibiting excessive mitophagy during subacute stages following an ischemic stroke.

Clemastine enhances exercise-induced motor improvement in hypoxic ischemic rats

Neonatal hypoxic ischemia (HI) occurs owing to reduced cerebral oxygen levels and perfusion during the perinatal period. Brain injury after HI triggers neurological manifestations such as motor impairment, and the improvement of impaired brain function remains challenging. Recent studies suggest that cortical myelination plays a role in motor learning, but its involvement in motor improvement after HI injury is not well understood. This study aimed to investigate the impact of myelination on motor improvement following neonatal HI injury. We employed a modified Rice-Vannucci model; the right common carotid artery of postnatal day 7 (P7) Wistar rats was isolated and divided, and the rats were then exposed to hypoxic condition (90 min, 8 % O2). A total of 101 rats (66 males) were divided into four groups: trained-HI (n = 38), trained-Sham (n = 16), untrained-HI (n = 31), and untrained-Sham (n = 16). The trained groups underwent rotarod-based exercise training from P22 to P41 (3 days per week). Structural analysis using magnetic resonance imaging and immunohistochemistry (n = 6 per group) revealed increased fractional anisotropy and myelin density in the primary somatosensory cortex of the trained-HI group. We further evaluated the effect of myelination promotion on rotarod performance by administering clemastine, a myelination-promoting drug, via daily intraperitoneal injections. Clemastine did not enhance motor improvement in untrained-HI rats. However, clemastine-administered trained-HI rats (n = 7) exhibited significantly improved motor performance compared to both saline-administered trained-HI rats (n = 11) and clemastine-administered untrained-HI rats (n = 7). These findings suggest that myelination may be a key mechanism in motor improvement after HI injury and that combining exercise training with clemastine administration could be an effective therapeutic strategy for motor improvement following HI injury.

Iron Deposition and Functional Connectivity Differences in Females With Migraine Without Aura: A Comparative Study of Headache Sides.

The pathophysiological mechanisms underlying migraine without aura (MwoA) in females remain incompletely elucidated. Currently, the association between headache laterality and iron deposition (ID), and functional connectivity (FC) in female MwoA patients has not been fully studied. We prospectively recruited 63 female patients with MwoA and 31 matched healthy controls (HC) from the hospital. ID and FC among the four groups were analyzed using two-sample t-tests (with cluster-wise family-wise error [FWE] correction). Pearson correlation analysis was used to evaluate the relationships between clinical variables and both ID and FC values. Significance level: p<0.05. Compared to HC, left-sided MwoA exhibited differences in ID in various brain regions, including the cerebellum, left orbital inferior frontal gyrus, left calcarine gyrus, right putamen, and left caudate nucleus, as well as exhibited enhanced FC between the left lobule III of the cerebellum and the right superior temporal gyrus. Compared to bilateral MwoA, left-sided MwoA showed significantly enhanced in FC values in the left calcarine gyrus, the right precentral gyrus, the right postcentral gyrus, and the right lingual gyrus. Additionally, significant differences were observed in the Pearson correlations between clinical variables and both ID and FC in the female MwoA subgroups. Our study provided preliminary evidence indicating significant differences in ID, FC, and correlations among subgroups of female MwoA. This provides neuroimaging references for further subclassifying MwoA patients. This offers valuable insights into potential pathophysiological mechanisms linked to the brain functional impairment in female MwoA.

Inhibition of the NLRP3/caspase-1 cascade related pyroptosis relieved propofol-induced neuroinflammation and cognitive impairment in developing rats

BackgroundNumerous preclinical studies have demonstrated that prolonged exposure to propofol (A general anaesthetics) can lead to hippocampus injury in immature brains and impact long-term learning and memory functions. Neuroinflammation plays a pivotal role in the impairment of brain function associated with early exposure to anesthetic drugs. Nevertheless, the involvement of hippocampal pyroptosis and neuroinflammation mediated by the NLRP3/caspase-1 signaling cascade in propofol-induced developmental neurotoxicity remains unclear. MethodsPostnatal day (PND) 7 SD rats, PC12 cells, and HAPI cells were used to establish propofol neurotoxicity models in vivo and in vitro, respectively. We examined the potential hippocampal injury and cognitive dysfunction caused by propofol in neonatal rats through the NLRP3/caspase-1 signaling pathway using MCC950 and VX765 to inhibit the pathway. This investigation involved assessing histological changes in the hippocampus, behavioral performance in adulthood, NLRP3-related pyroptosis indicators, and neuroinflammatory cytokines. ResultsBoth in vivo and in vitro studies have demonstrated that exposure to propofol activates the NLRP3/caspase-1 signaling cascade in the hippocampus of PND7 rats, leading to pyroptosis, neuroinflammation, and subsequent hippocampal injury and behavioral changes in adulthood. However, MCC950 and VX765 inhibit the NLRP3/caspase-1 signaling cascade, reversing the developmental neurotoxicity of propofol. ConclusionOur study findings suggest that negative regulation of NLRP3/caspase-1 activation may serve as a potential therapeutic strategy for developmental neuroinflammation induced by propofol.

MiR-124 mediates the effects of gut microbial dysbiosis on brain function in chronic stressed mice

The gut microbiota plays a key role in the brain function impairment caused by chronic stress, yet its exact mechanism remains unclear. Many studies have revealed the important role of miR-124 in the central nervous system. Meanwhile, previous studies have indicated that miR-124 may be regulated by chronic stress and gut microbiota. Here, we aimed to explore whether miR-124 serves as a mediator for the impacts of gut microbial dysbiosis on brain function in mice subjected to chronic stress. Repeated daily restraint stress for 4 weeks was used to induce chronic stress in mice. Chronic stress resulted in gut microbial dysbiosis, abnormal behaviors, and a decrease in hippocampal miR-124 levels. Treatment with different probiotic mixtures significantly alleviated the effects of chronic stress on hippocampal miR-124 levels and mouse behaviors. Suppression of hippocampal miR-124 expression reversed the beneficial effects of probiotics on cognitive function, neurogenesis, and related molecular markers in chronically stressed mice. Bioinformatics analysis and qPCR suggested that Ptpn11 might be a target gene for miR-124 in mediating the effects of gut microbial dysbiosis on brain function in these mice. These findings suggest that miR-124 is a pivotal regulator that mediates the detrimental effects of gut microbial dysbiosis on brain function and the subsequent cognitive impairment during chronic stress.

BCL2 interacting protein 3 as a potential biomarker for Alzheimer’s disease: an observational study

As important organelles for energy production, mitochondria exhibit dysfunction as an early hallmark of Alzheimer’s disease, potentially leading to cell death and impaired brain function. The mitophagy receptors BCL2 interacting protein 3 and BCL2 interacting protein 3 like (NIX), which are regulated by protein phosphatase targeting COQ7 (PPTC7), play crucial roles in controlling the quantity of mitochondria within cells. In this study, we found that the expression level of BCL2 interacting protein 3 was positively correlated with Mini-Mental State Examination scores, indicating that a lower BCL2 interacting protein 3 expression was associated with a higher degree of dementia. Under pathological conditions of Alzheimer’s disease, the expression levels of protein phosphatase targeting COQ7, BCL2 interacting protein 3, and BCL2 interacting protein 3 like were decreased. Overall, BCL2 interacting protein 3 may serve as a potential biomarker of Alzheimer’s disease.

Impairment of brain function in a mouse model of Alzheimer's disease during the pre-depositing phase: The role of α7 nicotinic acetylcholine receptors

Alzheimer’s disease (AD) is an age-dependent incurable neurodegenerative disorder accompanied by neuroinflammation, amyloid accumulation, and memory impairment. It begins decades before the first clinical symptoms appear, and identifying early biomarkers is key for developing disease-modifying therapies. We show now in a mouse model of AD that before any amyloid deposition the brains of 1.5-month-old mice contain increased levels of pro-inflammatory cytokines IL-1β and IL-6, decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain and brain mitochondria and increased amounts of α7 nAChR-bound Aβ1–42, along with impaired episodic memory and increased risk of apoptosis. Both acute (1-week-long) and chronic (4-month-long) treatments with α7-selective agonist PNU282987, starting at 1.5 months of age, were well tolerated. The acute treatment did not affect the levels of soluble Aβ1–42 but consistently upregulated the α7 nAChR expression, decreased the level of α7-Aβ1–42 complexes, and improved episodic memory of 1.5-month-old mice. The chronic treatment, covering the disease development phase, strongly upregulated the expression of all abundant brain nAChRs, reduced both free and α7-coupled Aβ1–42 within the brain, had anti-inflammatory and antiapoptotic effects, and potently upregulated cognition, thus identifying α7 nAChRs as both early biomarker and potent therapeutic target for fighting this devastating disease.

RAGE mediates hippocampal pericyte responses and neurovascular unit lesions after TBI

Traumatic brain injury impairs brain function through various mechanisms. Recent studies have shown that alterations in pericytes in various diseases affect neurovascular function, but the effects of TBI on hippocampal pericytes remain unclear. Here, we investigated the effects of RAGE activation on pericytes after TBI using male C57BL/6 J mice. Hippocampal samples were collected at different time points within 7 days after TBI, the expression of PDGFR-β, NG2 and the HMGB1-S100B/RAGE signaling pathway was assessed by Western blotting, and the integrity of the hippocampal BBB at different time points was measured by immunofluorescence. RAGE-associated BBB damage in hippocampal pericytes occurred early after cortical impact. By culturing primary mouse brain microvascular pericytes, we determined the different effects of HMGB1-S100B on pericyte RAGE. To investigate whether RAGE blockade could protect neurological function after TBI, we reproduced the process of CCI by administering FPS-ZM1 to RAGE−/− mice. TEM images and BBB damage-related assays showed that inhibition of RAGE resulted in a significant improvement in the number of hippocampal vascular basement membranes and tight junctions and a reduction in perivascular oedema compared with those in the untreated group. In contrast, mouse behavioural testing and doublecortin staining indicated that targeting the HMGB1-S100B/RAGE axis after CCI could protect neurological function by reducing pericyte-associated BBB damage. In conclusion, the present study provides experimental evidence for the strong correlation between the pericyte HMGB1-S100B/RAGE axis and NVU damage in the hippocampus at the early stage of TBI and further demonstrates that pericyte RAGE serves as an important target for the protection of neurological function after TBI.

Near-death experience: memory recovery during hypnosis

Increasing numbers of research studies have offered evidence regarding awareness of verified events during near-death experiences (NDEs) occurring during cardiac arrest and severely impaired brain function. The prevalence of patients reporting core NDEs under these conditions is reported as 10–12 %. One question that is often asked is why this percentage is low. Though it may be hypothesized that NDEs are limited to this low percentage of patients, it is also possible that more patients experience an NDE, but that memory is impaired sufficiently such that the NDE is not recalled. In this article I present a detailed and extensively verified case study of a woman, Stephanie Arnold, who experienced an NDE during the birth of her second child when she was 41 years old. The data provide evidence that supports the hypotheses 1) that during cardiac arrest an NDE may occur, but not be remembered until hypnotic regression therapy reveals extensive details of the events that could not have been perceived with the five senses, both in the operating room and elsewhere during resuscitation. 2) that there may also be pre-cognition of the events leading to the cardiac arrest, reported in clear detail, and 3) that NDEs lead to a fundamental transformation in an individual's understanding of the nature of consciousness, their quest for meaning and purpose, their concern for others, and their appreciation of life.

Genetic components of microdeletion syndromes and their role in determining schizophrenia traits.

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms such as hallucinations, delusions, and disordered thinking. The etiology of this disease is unknown; however, it has been linked to many microdeletion syndromes that are likely to contribute to the pathology of schizophrenia. In this review we have comprehensively analyzed the role of various microdeletion syndromes, like 3q29, 15q13.3, and 22q11.2, which are known to be involved with schizophrenia. A variety of factors lead to schizophrenia phenotypes, but copy number variants that disrupt gene regulation and impair brain function and cognition are one of the causes that have been identified. Multiple case studies have shown that loss of one or more genes in the microdeletion regions lead to brain activity defects. In this article, we present a coherent paradigm that connects copy number variations (CNVs) to numerous neurological and behavioral abnormalities associated with schizophrenia. It would be helpful in understanding the different aspects of the microdeletions and how they contribute in the pathophysiology of schizophrenia.

Cholesterol Metabolism in Neurodegenerative Diseases.

Significance: Cholesterol plays a crucial role in the brain, where it is highly concentrated and tightly regulated to support normal brain functions. It serves as a vital component of cell membranes, ensuring their integrity, and acts as a key regulator of various brain processes. Dysregulation of cholesterol metabolism in the brain has been linked to impaired brain function and the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. Recent Advances: A significant advancement has been the identification of astrocyte-derived apoliprotein E as a key regulator of de novo cholesterol biosynthesis in neurons, providing insights into how extracellular signals influence neuronal cholesterol levels. In addition, the development of antibody-based therapies, particularly for AD, presents promising opportunities for therapeutic interventions. Critical Issues: Despite significant research, the association between cholesterol and neurodegenerative diseases remains inconclusive. It is crucial to distinguish between plasma cholesterol and brain cholesterol, as these pools are relatively independent. This differentiation should be considered when evaluating statin-based treatment approaches. Furthermore, assessing not only the total cholesterol content in the brain but also its distribution among different types of brain cells is essential. Future Direction: Establishing a causal link between changes in brain/plasma cholesterol levels and the onset of brain dysfunction/neurodegenerative diseases remains a key objective. In addition, conducting cell-specific analyses of cholesterol homeostasis in various types of brain cells under pathological conditions will enhance our understanding of cholesterol metabolism in neurodegenerative diseases. Manipulating cholesterol levels to restore homeostasis may represent a novel approach for alleviating neurological symptoms.

Synaptic reorganization of synchronized neuronal networks with synaptic weight and structural plasticity.

Abnormally strong neural synchronization may impair brain function, as observed in several brain disorders. We computationally study how neuronal dynamics, synaptic weights, and network structure co-emerge, in particular, during (de)synchronization processes and how they are affected by external perturbation. To investigate the impact of different types of plasticity mechanisms, we combine a network of excitatory integrate-and-fire neurons with different synaptic weight and/or structural plasticity mechanisms: (i) only spike-timing-dependent plasticity (STDP), (ii) only homeostatic structural plasticity (hSP), i.e., without weight-dependent pruning and without STDP, (iii) a combination of STDP and hSP, i.e., without weight-dependent pruning, and (iv) a combination of STDP and structural plasticity (SP) that includes hSP and weight-dependent pruning. To accommodate the diverse time scales of neuronal firing, STDP, and SP, we introduce a simple stochastic SP model, enabling detailed numerical analyses. With tools from network theory, we reveal that structural reorganization may remarkably enhance the network's level of synchrony. When weaker contacts are preferentially eliminated by weight-dependent pruning, synchrony is achieved with significantly sparser connections than in randomly structured networks in the STDP-only model. In particular, the strengthening of contacts from neurons with higher natural firing rates to those with lower rates and the weakening of contacts in the opposite direction, followed by selective removal of weak contacts, allows for strong synchrony with fewer connections. This activity-led network reorganization results in the emergence of degree-frequency, degree-degree correlations, and a mixture of degree assortativity. We compare the stimulation-induced desynchronization of synchronized states in the STDP-only model (i) with the desynchronization of models (iii) and (iv). The latter require stimuli of significantly higher intensity to achieve long-term desynchronization. These findings may inform future pre-clinical and clinical studies with invasive or non-invasive stimulus modalities aiming at inducing long-lasting relief of symptoms, e.g., in Parkinson's disease.

A Comprehensive Review on Hepatic Encephalopathy: Pathophysiology, Symptoms, Epidemiology, Classification, Diagnosis and Treatment

The condition known as hepatic encephalopathy (HE) is a state of impaired brain function that can be reversed and is experienced by patients who are suffering from severe liver diseases. Neurotoxins, decreased neurotransmission as a result of metabolic anomalies in liver failure, changes in brain energy metabolism, systemic inflammatory response, and alterations of the blood brain barrier are the primary hypotheses that are still being explored in relation to the precise pathophysiology of hepatic encephalopathy (HE). There is a wide spectrum of severity regarding the neurological and mental symptoms that can be brought on by HE. For the purpose of diagnosing limited HE, abnormal psychometric tests are utilised. Alterations in personality, altered states of consciousness, gradual spatial and temporal disorientation, lethargy, stupor, and coma are some of the characteristics of HE that are clinically noticeable. For the purpose of diagnosis, specific testing is not required outside of clinical studies. HE is classified according to the underlying disease, the severity of symptoms, the length of time it has been present, and whether or not there are triggers that cause it to occur. Hepatic encephalopathy refers to a collection of neuropsychiatric illnesses that can be treated and are characterised by the presence of symptoms in individuals who have liver disease or who have undergone portosystemic shunting. Entephalopathy, a disabling result of cirrhosis, affects thirty-five percent to forty-five percent of cirrhotic patients. Before recently, the treatment choices for HE that were available in hospitals were depending on anecdotal evidence, the availability of medication, and the norms of the relevant institutions. An increasing number of randomised controlled trials (RCTs) are providing further confirmation of the central significance of the basic HE therapy techniques (lactulose, branched-chain amino acids, and rifaximin), as well as the rising body of evidence showing the large beneficial advantages associated with these strategies. The liver transplantation and embolisation of large PSSs are two treatments that have proven to be effective for a select group of patients who have been carefully selected. Not only does it have a significant influence on the day-to-day lives of patients and carers, but it is also associated with increased rates of sickness and death and consumes a significant amount of resources in the healthcare system. In this article, we examine the history of hepatic encephalopathy, as well as the current understanding of the condition and the potential treatments for it.

Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations.

Cognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity (∼40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders.

Vortioxetine improved schizophrenia-like behavioral deficits in a Poly I:C-induced maternal immune activation model of schizophrenia in rats.

Several studies provide clear evidence that exposure to various infections during pregnancy are linked with an increased risk for schizophrenia. In preclinical studies, administration of polyinosinic-polycytidylic acid (Poly I:C) in pregnant rodents can induce maternal immune activation leading to impairments in brain function in the offspring. The aim of this study was to investigate the effect of vortioxetine, a multimodal selective serotonin reuptake inhibitor (SSRI), in the pathophysiology of Poly I:C-induced schizophrenia-like model in rats. For this purpose, Poly I:C (8 mg/kg, ip) was injected into pregnant animals 14 days after mating, and tail blood was taken for determination of IL-6 levels after 2 h. At postnatal days 83-86, behavioral tests were performed. Our results revealed that Poly I:C caused impairments in prepulse inhibition, novel object recognition, social interaction, and open-field tests. Chronic administration of vortioxetine (2.5, 5, and 10 mg/kg, ip, postnatal days 69-83) caused significant improvements in these deficits. Overall, our findings indicate that vortioxetine may provide new therapeutic approaches for the treatment of schizophrenia. We think that increased serotonergic activity in frontal brain regions may provide the ameliorative effect of vortioxetine, especially on negative and cognitive symptoms. Therefore, it will be useful to determine the efficacy of vortioxetine with combined drugs with further studies.

Safety Implications of Modulating Nuclear Receptors: A Comprehensive Analysis from Non-Clinical and Clinical Perspectives.

The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.

TRMT10A dysfunction perturbs codon translation of initiator methionine and glutamine and impairs brain functions in mice.

In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1-methylguanosine modification at position nine of various cytoplasmic tRNAs. Pathogenic mutations in TRMT10A cause intellectual disability, microcephaly, diabetes, and short stature in humans, and generate cytotoxic tRNA fragments in cultured cells; however, it is not clear how TRMT10A supports codon translation or brain functions. Here, we generated Trmt10a null mice and showed that tRNAGln(CUG) and initiator methionine tRNA levels were universally decreased in various tissues; the same was true in a human cell line lacking TRMT10A. Ribosome profiling of mouse brain revealed that dysfunction of TRMT10A causes ribosome slowdown at the Gln(CAG) codon and increases translation of Atf4 due to higher frequency of leaky scanning of its upstream open reading frames. Broadly speaking, translation of a subset of mRNAs, especially those for neuronal structures, is perturbed in the mutant brain. Despite not showing discernable defects in the pancreas, liver, or kidney, Trmt10a null mice showed lower body weight and smaller hippocampal postsynaptic densities, which is associated with defective synaptic plasticity and memory. Taken together, our study provides mechanistic insight into the roles of TRMT10A in the brain, and exemplifies the importance of universal tRNA modification during translation of specific codons.