Search Results (44)

West Nile virus (WNV) is an arthropod-borne flavivirus first identified in 1937. Over time, WNV has spread globally and is now endemic in Italy. Although most human WNV infections are asymptomatic (80%), less than 1% progress to a neuroinvasive disease with high mortality rates. This case involves a 45-year-old woman with post-surgical hypoparathyroidism and Sjögren’s syndrome who developed severe encephalomyelitis linked to WNV, leading to ventilator-associated pneumonia and death. Neuropathological findings revealed a bilaterally cribriform thalamus and reddish punctate lesions near the dentate nucleus of the cerebellum. The trachea and bronchial hilum branches contained whitish foamy liquid. The left lung showed multiple brownish-violet areas, with whitish regions at dissection. The heart appeared unremarkable. A detailed neuropathological examination focused on areas involved in motor control pathways. Tissue samples were stained with hematoxylin and eosin and trichrome techniques, and immunohistochemistry was performed using CD68, CD3, and CD20. A significant damage was observed in the lenticular nucleus and motor thalamus, with prominent concentric vascular calcifications. The cerebellar cortex showed near-total depletion of Purkinje cells. In the spinal cord, CD68 and CD3 positivity was noted in the lateral funiculi, anterior horns, and Clarke’s column. Lung findings showed pulmonary edema, chronic emphysema, and bronchopneumonia. The observed CD3 and CD68 positivity confirms that WNV spreads trans-synaptically along motor control pathways. We speculate on the potential molecular mechanisms by which hypoparathyroidism and Sjögren’s syndrome may have played a role in the neuroinvasive progression of the disease. Full article

Background and Clinical Significance: Adults suffering from cerebellar metastases are often at high risk for rapid deterioration of their neurological status because the posterior fossa has limited compliance and the location of these metastases are close to the brain stem and important cerebrospinal fluid (CSF) pathways. In this paper, we present a longitudinal, patient-centered report on the history of an elderly individual who suffered from cognitive comorbidities and experienced a sudden loss of function in her cerebellum. Our goal in reporting this case is to provide a comparison between the patient’s pre-operative and post-operative neurological examinations; the imaging studies she had before and after surgery; the surgical techniques utilized during her operation; and the outcome of her post-operative course in a way that will be helpful to other patients who have experienced a similar situation. Case Presentation: We report the case of an 80-year-old woman who initially presented with progressive ipsilateral limb-trunk ataxia, impaired smooth pursuit eye movement, and rebound nystagmus, but preserved pyramidal and sensory functions. Her quantitative bedside assessments included some of the components of the Scale for the Assessment and Rating of Ataxia (SARA), and a National Institute of Health Stroke Scale (NIHSS) score of 3. These findings indicated dysfunction of the left neocerebellar hemisphere and possible dentate nucleus involvement. The patient’s magnetic resonance imaging (MRI) results demonstrated an expansive mass with surrounding vasogenic edema and marked compression and narrowing of the exits of the fourth ventricle which placed the patient’s CSF pathways at significant risk of occlusion, while the aqueduct and inlets were patent. She then underwent a left lateral suboccipital craniectomy with controlled arachnoidal CSF release, preservation of venous drainage routes, subpial corticotomy oriented along the lines of the folia, stepwise internal debulking, and careful protection of the cerebellar peduncles and dentate nucleus. Dural reconstruction utilized a watertight pericranial graft to restore the cisternal compartments. Her post-operative intensive care unit (ICU) management emphasized optimal venous outflow, normoventilation, and early mobilization. Histopathology confirmed the presence of metastatic carcinoma, and staging suggested that the most likely source of the primary tumor was the lungs. Immediately post-operation, computed tomography (CT) imaging revealed a smooth resection cavity with open foramina of Magendie and Luschka, intact contours of the brain stem, and no evidence of bleeding or hydrocephalus. The patient’s neurological deficits, including dysmetria, scanning dysarthria, and ataxic gait, improved gradually during the first 48 h post-operatively. Upon discharge, the patient demonstrated an improvement in her limb-kinetic subscore on the International Cooperative Ataxia Rating Scale (ICARS) and demonstrated independent ambulation. At two weeks post-operation, CT imaging revealed decreasing edema and stable cavity size, and the patient’s modified Rankin scale had improved from 3 upon admission to 1. There were no episodes of CSF leakage, wound complications, or new cranial nerve deficits. A transient post-operative psychotic episode that was likely secondary to her underlying Alzheimer’s disease was managed successfully with short-course pharmacotherapy. Conclusions: The current case study demonstrates the value of anatomy-based microsurgical planning, preservation of venous and CSF pathways, and targeted peri-operative management to facilitate rapid recovery of function in older adults who suffer from cerebellar metastasis and cognitive comorbidities. The case also demonstrates the importance of early multidisciplinary collaboration to allow for timely initiation of both adjuvant stereotactic radiosurgery and molecularly informed systemic therapy. Full article

Background: Hippocampal neurogenesis in the dentate gyrus persists into adulthood and plays a crucial role in learning and memory. Early-life exposure to low-dose propofol has been reported to enhance neural development in rodent models, but detailed mechanisms remain unclear. To address this gap, we aimed to investigate how low-dose propofol alters neurogenic lineage differentiation, transcriptional programs, and underlying molecular mechanisms within the early postnatal hippocampal neurogenic niche. Results: We conducted an in-depth re-analysis of a published single-nucleus RNA-sequencing (snRNA-seq) dataset from hippocampal tissue of postnatal day 10 (PND10) mice, collected 3 days after low-dose propofol treatment. Uniform Manifold Approximation and Projection (UMAP)-based clustering revealed twelve major cell types, including a population of Ntng1⁺Fxyd7⁺Pcp1⁺ immature pyramidal neurons (imPYR), lacking the mature markers Meis2 and Spock1. Trajectory analysis revealed two neurogenic lineages (granule and pyramidal) and indicated that propofol biases progenitor fate commitment towards the granule lineage. CellChat analysis demonstrated that propofol enhances Neurexin (Nrxn) signaling to neural progenitor cells, suggesting increased synaptic adhesion and maturation. Differential expression analysis (|log₂FC| ≥ 0.26, adjusted p < 0.01) followed by pathway enrichment revealed that propofol upregulates neurogenic maturation pathways—including synaptogenesis, synaptic transmission, dendritic morphogenesis, and memory-related processes—specifically within neural intermediate progenitor cells (nIPC). Conclusions: Together, these findings delineate a coordinated transcriptional and intercellular mechanism by which low-dose propofol reprograms hippocampal neurogenesis during early postnatal development, highlighting progenitor-specific and synapse-oriented processes that may underlie its cognitive-enhancing effects. Full article

Adult neurogenesis is well established in canonical niches—the dentate gyrus and the subventricular zone, where aerobic exercise reliably enhances progenitor proliferation, survival, and synaptic integration via increased cerebral blood flow, neurotrophins (e.g., BDNF, IGF-1), neurotransmitter regulation, and reduced neuroinflammation. Nutraceuticals (e.g., polyphenols, omega-3, creatine, vitamins) further support neuroplasticity and neuronal survival through convergent trophic, anti-inflammatory, and metabolic pathways. By contrast, the hypothalamus, a metabolically pivotal, non-canonical niche, remains comparatively understudied. Here, we synthesize anatomical and functional features of hypothalamic neural stem cells, primarily tanycytes (α1, α2, β1, β2), which line the third ventricle and differentially contribute to neuronal activity regulation, metabolic signaling, and cerebrospinal fluid–portal vasculature coupling, thereby linking neurogenesis to endocrine control. Notably, tanycytes can form neurospheres in vitro, enabling mechanistic interrogation. Although evidence for adult hypothalamic neurogenesis in humans is debated due to methodological constraints, animal data suggest potential relevance to disorders characterized by neuronal loss, metabolic dysregulation, and impaired neuroendocrine function. We propose that an integrative framework is timely: exercise and diet likely interact in the hypothalamic niche through shared mediators (BDNF, IGF-1, CNTF, GPR40) and exercise-derived signals (e.g., lactate, IL-6) that may be complemented by defined nutraceuticals. Yet critical uncertainties persist, including the extent of bona fide hypothalamic neurogenesis, nucleus-specific responses (arcuate nucleus, paraventricular nucleus, ventromedial hypothalamic nucleus), and the mechanistic integration of lifestyle signals in this region. To address these gaps, we outline actionable priorities: (i) single-cell and lineage-tracing studies of tanycyte subtypes under distinct training modalities (aerobic, high-intensity interval training, resistance); (ii) combinatorial interventions pairing structured exercise with nutraceuticals to test synergy on progenitor dynamics and inflammation; and (iii) multi-omics and translational studies to identify biomarkers and establish clinical relevance. Clarifying these interactions will determine whether lifestyle and supplementation strategies can synergistically modulate hypothalamic neurogenesis and inform therapies for neurological, neuropsychiatric, and metabolic disorders. Full article

Traumatic brain injury (TBI) is a major source of disability worldwide, with cognitive and memory deficits being pervasive after injury. The hippocampus, a major structure involved in learning and memory, is particularly vulnerable to TBI, and cellular dysfunction within the hippocampal dentate gyrus is believed to be a major contributor to cognitive deficits after TBI. However, there is little known about the transcriptomic changes occurring directly within the dentate gyrus at subacute-to-chronic timepoints after TBI. To address this, we performed bulk RNA sequencing and single-nucleus RNA sequencing of the isolated dentate gyrus three weeks after lateral fluid percussion injury in male rats. We report here that there is evidence of an ongoing neuroinflammatory response marked by increased neuroinflammatory genes that implicate various neuroinflammatory pathways that are associated with a subset of microglia and astrocyte populations. Full article

Brain pathophysiology in Down syndrome (DS), the most common genetic cause of intellectual disability, has traditionally been considered a consequence of neuronal dysfunction. However, although it is well documented that astrocytes play a critical role in brain homeostasis, synaptic regulation, and neuronal support, and their malfunction has been associated with the onset and progression of different neurological disorders, only a few studies have addressed whether astrocyte dysfunction can contribute to the DS pathophysiology. Astrocytes are increased in number and size, and show increased levels of expression of astroglial markers like S100β and GFAP. In this study, we detected a region-specific increase in astrocyte population in CA1 and, to a lesser extent, in the dentate gyrus. Single-nucleus transcriptomic profiling identified markers associated with reactive astroglia, synaptic transmission, and neuroinflammation in trisomic astrocytes. Functional analysis revealed abnormal Ca²⁺ oscillations in trisomic astrocytes and impaired astrocyte-to-neuron communication in CA1, the most affected subregion, leading to astrocyte-mediated excitatory synaptic depression. Our findings demonstrate that astrocytes play an active and critical role in the pathophysiology of DS, not only as reactive responders to neuronal injury but as key contributors to the disease process itself. This astrocytic dysfunction presents a region-specific distribution within the hippocampus, suggesting localized vulnerability and complex glial involvement in DS-related neuropathology. Full article

Background: Parkinsonism, characterized by motor symptoms, is typically attributed to basal ganglia dysfunction. Recent evidence suggests that the cerebellum may also influence these symptoms. This study investigated Crus II, the dentate nucleus (DN), and the inferior olive (IO) in a rat model of parkinsonism induced by a bilateral ventrolateral striatal (VLS) lesion. Materials and Methods: Twenty-four male Wistar rats were divided into control (n = 12) and experimental (n = 12) groups. Monopolar electrodes were implanted in target structures. The experimental group received a bilateral VLS lesion. Animals underwent four weekly sessions of electrophysiological recordings and blind behavioral assessments (resting, grooming, locomotion, rearing, sniffing) via video tracking. Power spectral density (PSD) in the 300–500 Hz band was computed. Statistical analyses included Mann–Whitney U, Friedman with Wilcoxon post hoc, and Spearman correlation tests. Results: During weeks one and two, there were significant PSD increases in the experimental group compared to the control, particularly in Crus II—grooming (p = 0.005), locomotion (p = 0.007), and rearing (p = 0.026); in IO—sniffing (p = 0.0167); and in DN—grooming (p < 0.001) and locomotion (p = 0.0008). Additionally, intragroup analysis revealed significant PSD elevations relative to baseline in these structures. Significant correlations were observed only for grooming (negative correlations) and sniffing (positive correlations) across all cerebellar regions. Conclusions: These findings suggest compensatory cerebellar hyperactivity induced by VLS lesion, potentially modulating hypokinetic symptoms and highlighting dynamic network interactions. Interpretation warrants caution due to limitations inherent to the acute lesion model and experimental duration. Full article

Chronic cocaine use triggers inflammatory and oxidative processes in the central nervous system, resulting in impaired microglia. Mesenchymal stem cells, known for their immunomodulatory properties, have shown promise in reducing inflammation and enhancing neuronal survival. The study employed the cocaine self-administration model, focusing on ionized calcium-binding adaptor protein 1 (Iba-1) and cell morphology as markers for microglial impairment and PLX-PAD cells as a treatment for attenuating cocaine craving. The results revealed an addiction-stage and region-specific impairment in microglia following chronic cocaine exposure, with deficits observed in the Nucleus Accumbens (NAc) during the maintenance stage and in both the NAc and Dentate Gyrus (DG) during the extinction and reinstatement stages. Furthermore, PLX-PAD cell therapy demonstrated a significant reduction in cocaine craving and seeking behavior, interestingly accompanied by the prevention of Iba-1 level decrease and restoration of microglial activity in the NAc and DG. These findings highlight the unique role of microglia in modulating cocaine addiction behaviors through their influence on synaptic plasticity and neuronal remodeling associated with memory formation. They also suggest that PLX-PAD therapy may mitigate the detrimental effects of chronic cocaine exposure on microglia, underscoring the importance of incorporating microglia in comprehensive addiction rehabilitation strategies. Full article

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments. Full article

Background: Folate, an essential vitamin B9, is crucial for diverse biological processes, including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Objectives/Methods: Here, we employed a mouse model and spatial transcriptomic and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Results: Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Conclusions: Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation. Full article

Background: Febrile seizures are a common form of convulsions in childhood, with poorly known cellular mechanisms. The objective of this pioneering study was to provide qualitative and quantitative ultrastructural research on the large neuronal perikarya in the cerebellar dentate nucleus (DN), using an experimental model of hyperthermia-induced seizures (HSs), comparable to febrile seizures in children. Methods: The study used young male Wistar rats, divided into experimental and control groups. The HSs were evoked by a hyperthermic water bath at 45 °C for 4 min for four consecutive days. Specimens (1 mm³) collected from the DN were routinely processed for transmission electron microscopy studies. Results: The ultrastructure of the large neurons in the DN affected by hyperthermic stress showed variously pronounced lesions in the perikarya, including total cell disintegration. The most pronounced neuronal lesions exhibited specific morphological signs of aponecrosis, i.e., dark cell degeneration (‘dark neurons’). In close vicinity to the ‘dark neurons’, the aponecrotic bodies were found. The findings of this qualitative ultrastructural study correspond with the results of the morphometric analysis of the neuronal perikarya. Conclusions: Our results may constitute interesting comparative material for similar submicroscopic observations on large DN neurons in HS morphogenesis and, in the future, may help to find potential treatment targets to prevent febrile seizures or reduce recurrent seizures in children. Full article

Background: Multiple sclerosis (MS) is a clinically heterogeneous disease underpinned by inflammatory, demyelinating and neurodegenerative processes, the extent of which varies between individuals and over the course of the disease. Recognising the clinicopathological features that most strongly associate with disease outcomes will inform future efforts at patient phenotyping. Aims: We used a digital pathology workflow, involving high-resolution image acquisition of immunostained slides and opensource software for quantification, to investigate the relationship between clinical and neuropathological features in an autopsy cohort of progressive MS. Methods: Sequential sections of frontal, cingulate and occipital cortex, thalamus, brain stem (pons) and cerebellum including dentate nucleus (n = 35 progressive MS, females = 28, males = 7; age died = 53.5 years; range 38–98 years) were immunostained for myelin (anti-MOG), neurons (anti-HuC/D) and microglia/macrophages (anti-HLA). The extent of demyelination, neurodegeneration, the presence of active and/or chronic active lesions and quantification of brain and leptomeningeal inflammation was captured by digital pathology. Results: Digital analysis of tissue sections revealed the variable extent of pathology that characterises progressive MS. Microglia/macrophage activation, if found at a higher level in a single block, was typically elevated across all sampled blocks. Compartmentalised (perivascular/leptomeningeal) inflammation was associated with age-related measures of disease severity and an earlier death. Conclusion: Digital pathology identified prognostically important clinicopathological correlations in MS. This methodology can be used to prioritise the principal pathological processes that need to be captured by future MS biomarkers. Full article

GNB1 encephalopathy is a rare genetic disease caused by pathogenic variants in the G Protein Subunit Beta 1 (GNB1) gene, with only around 68 cases documented worldwide. Although most cases had been caused by de novo germline mutations, in this case, the pathogenic variant was inherited from patient’s mother, indicating an autosomal dominant inheritance pattern. The patient presented at 25 years of age with mild developmental delay and cognitive impairment, prominent generalized dystonia, and horizontal nystagmus which are all characterizing symptoms of GNB1 encephalopathy. Electroencephalography (EEG) showed no epileptiform patterns, and magnetic resonance imaging (MRI) revealed hypointensities in globus pallidus and dentate nucleus areas. The main theory for GNB1 encephalopathy pathogenesis is neuronal hyperexcitability caused by impaired ion channel regulation. Due to low specificity of symptoms, diagnosis relies on genetic testing. As there are no standardized GNB1 encephalopathy treatment guidelines, evaluation of different treatment options is based on anecdotal cases. Reviewing different treatment options, deep brain stimulation and intrathecal baclofen pump, as well as some other medications still in preclinical trials, seem to be the most promising. Full article

Inducing carotid body anoxia through the administration of cyanide can result in oxygen deprivation. The lack of oxygen activates cellular responses in specific regions of the central nervous system, including the Nucleus Tractus Solitarius, hypothalamus, hippocampus, and amygdala, which are regulated by afferent pathways from chemosensitive receptors. These receptors are modulated by the brain-derived neurotrophic factor receptor TrkB. Oxygen deprivation can cause neuroinflammation in the brain regions that are activated by the afferent pathways from the chemosensitive carotid body. To investigate how microglia, a type of immune cell in the brain, respond to an anoxic environment resulting from the administration of NaCN, we studied the effects of blocking the TrkB receptor on this cell-type response. Male Wistar rats were anesthetized, and a dose of NaCN was injected into their carotid sinus to induce anoxia. Prior to the anoxic stimulus, the rats were given an intracerebroventricular (icv) infusion of either K252a, a TrkB receptor inhibitor, BDNF, or an artificial cerebrospinal fluid (aCSF). After the anoxic stimulus, the rats were perfused with paraformaldehyde, and their brains were processed for microglia immunohistochemistry. The results indicated that the anoxic stimulation caused an increase in the number of reactive microglial cells in the hypothalamic arcuate, basolateral amygdala, and dentate gyrus of the hippocampus. However, the infusion of the K252a TrkB receptor inhibitor prevented microglial activation in these regions. Full article

Brain aging has been correlated with high metallothionein I-II (MT-I/II) expression, iron and zinc dyshomeostasis, and Aβ deposition in humans and experimental animals. In the present study, iron and zinc accumulation, the expression of MT-I/II and Aβ42, and their potential association with aging in the feline brain were assessed. Tissue sections from the temporal and frontal grey (GM) and white (WM) matter, hippocampus, thalamus, striatum, cerebellum, and dentate nucleus were examined histochemically for the presence of age-related histopathological lesions and iron deposits and distribution. We found, using a modified Perl’s/DAB method, two types of iron plaques that showed age-dependent accumulation in the temporal GM and WM and the thalamus, along with the age-dependent increment in cerebellar-myelin-associated iron. We also demonstrated an age-dependent increase in MT-I/II immunoreactivity in the feline brain. In cats over 7 years old, Aβ immunoreactivity was detected in vessel walls and neuronal somata; extracellular Aβ deposits were also evident. Interestingly, Aβ-positive astrocytes were also observed in certain cases. ICP-MS analysis of brain content regarding iron and zinc concentrations showed no statistically significant association with age, but a mild increase in iron with age was noticed, while zinc levels were found to be higher in the Mature and Senior groups. Our findings reinforce the suggestion that cats could serve as a dependable natural animal model for brain aging and neurodegeneration; thus, they should be further investigated on the basis of metal ion concentration changes and their effects on aging. Full article