Evidence Of Neuronal Loss Research Articles

Biomarkers of Alzheimer's Disease Associated with Programmed Cell Death Reveal Four Repurposed Drugs.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Programmed cell death (PCD) is mainly characterized by unique morphological features and energy-dependent biochemical processes. The predominant pathway leading to cell death in AD has not been thoroughly analyzed, although there is evidence of neuron loss in AD and numerous pathways of PCD have been associated with this process. A better understanding of the systems biology underlying the relationship between AD and PCD could lead to the development of new therapeutic approaches. To this end, publicly available transcriptome data were examined using bioinformatic methods such as differential gene expression and weighted gene coexpression network analysis (WGCNA) to find PCD-related AD biomarkers. The diagnostic significance of these biomarkers was evaluated using a logistic regression-based predictive model. Using these biomarkers, a multifactorial regulatory network was developed. Last, a drug repositioning study was conducted to propose new drugs for the treatment of AD targeting PCD. The development of 3PM (predictive, preventive, and personalized) drugs for the treatment of AD would be enabled by additional research on the effects of these drugs on this disease.

Cell death and survival pathways in Alzheimer's disease: an integrative hypothesis testing approach utilizing -omic data sets

Whether a cell lives or dies is controlled by an array of intercepting and dynamic molecular pathways. Although there is evidence of neuronal loss in Alzheimer's disease (AD) and multiple programmed cell death (PCD) pathways have been implicated in this process, there has been no comprehensive evaluation of the dominant pathway responsible for cell death in AD. Likewise, the relative dominance of survival and PCD pathways in AD remains unclear. Here, we present the results of hypothesis-driven bioinformatic analysis of PCD and survival pathway activation in paired methylation and expression data from the middle temporal gyrus (MTG) as well as expression from laser-captured cells from the MTG and hippocampus. The results not only indicate activation of cell death pathways in AD—of which apoptosis is responsible for the largest fraction of upregulated genes—but also of cell survival pathways. These results are indicative of a complex balance between survival and death pathways in AD that future studies should work to delineate at a single cell level.

Neuropathological Correlates of Cumulative Benzodiazepine and Anticholinergic Drug Use.

Benzodiazepines and anticholinergic drugs have been implicated in causing cognitive decline and potentially increasing dementia risk. However, evidence for an association with neuropathology is limited. To estimate the correlation between neuropathology at death and prior use of benzodiazepines and anticholinergic drugs. We categorized 298 brain donors from the population-based Medical Research Council Cognitive Function and Ageing Study, according to their history of benzodiazepine (including Z-drugs) or anticholinergic medication (drugs scoring 3 on the Anticholinergic Cognitive Burden scale) use. We used logistic regression to compare dichotomized neuropathological features for those with and without history of benzodiazepine and anticholinergic drug use before dementia, adjusted for confounders. Forty-nine (16%) and 51 (17%) participants reported benzodiazepine and anticholinergic drug use. Alzheimer's disease neuropathologic change was similar whether or not exposed to either drug, for example 46% and 57% had intermediate/high levels among those with and without anticholinergic drug use. Although not significant after multiple testing adjustments, we estimated an odds ratio (OR) of 0.40 (95% confidence interval [95% CI] 0.18-0.87) for anticholinergic use and cortical atrophy. For benzodiazepine use, we estimated ORs of 4.63 (1.11-19.24) and 3.30 (1.02-10.68) for neuronal loss in the nucleus basalis and substantial nigra. There was evidence of neuronal loss in the nucleus basalis with anticholinergic drug use, but the association reduced when adjusted for confounders. We found no evidence that benzodiazepine or anticholinergic drug use is associated with typical pathological features of Alzheimer's disease; however, we cannot rule out effects owing to small numbers.

Levels of glial cell line-derived neurotrophic factor are decreased, but fibroblast growth factor 2 and cerebral dopamine neurotrophic factor are increased in the hippocampus in Parkinson's disease.

Growth factors can facilitate hippocampus-based learning and memory and are potential targets for treatment of cognitive dysfunction via their neuroprotective and neurorestorative effects. Dementia is common in Parkinson's disease (PD), but treatment options are limited. We aimed to determine if levels of growth factors are altered in the hippocampus of patients with PD, and if such alterations are associated with PD pathology. Enzyme-linked immunosorbent assays were used to quantify seven growth factors in fresh frozen hippocampus from 10 PD and nine age-matched control brains. Western blotting and immunohistochemistry were used to explore cellular and inflammatory changes that may be associated with growth factor alterations. In the PD hippocampus, protein levels of glial cell line-derived neurotrophic factor were significantly decreased, despite no evidence of neuronal loss. In contrast, protein levels of fibroblast growth factor 2 and cerebral dopamine neurotrophic factor were significantly increased in PD compared to controls. Levels of the growth factors epidermal growth factor, heparin-binding epidermal growth factor, brain-derived neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor did not differ between groups. Our data demonstrate changes in specific growth factors in the hippocampus of the PD brain, which potentially represent targets for modification to help attenuate cognitive decline in PD. These data also suggest that multiple growth factors and direction of change needs to be considered when approaching growth factors as a potential treatment for cognitive decline.

Molecular pathogenesis of polymerase γ-related neurodegeneration.

ObjectivePolymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using postmortem tissue from a large number of patients.MethodsClinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls was studied employing a combination of histopathology, immunohistochemistry, and molecular studies of microdissected neurons.ResultsThe primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I–deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and that showed massive neuronal loss.InterpretationPOLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to 2 distinct but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears to be related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy. ANN NEUROL 2014;76:66–81

Neuronal c-Abl Overexpression Leads to Neuronal Loss and Neuroinflammation in the Mouse Forebrain

Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). Additionally, c-Abl has been shown to phosphorylate tau on tyrosine 394. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis. To examine the consequences of c-Abl activation in the adult brain, we have constructed two lines of transgenic mice expressing either a constitutively active form of c-Abl (AblPP/tTA mice) or its sister protein, Arg (ArgPP/tTA mice), with a neuron-specific promoter (CamKIIα) regulated by doxycycline (Tet-Off). Expression of active c-Abl in adult mouse forebrain neurons results in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocyctosis. Despite careful examination, no c-Abl expression is found in glial cells, indicating that neuronal c-Abl expression is responsible for the gliosis. In contrast, ArgPP/tTA mice have no evidence of neuronal loss or gliosis, even though protein expression and kinase activity levels are similar to those in the AblPP/tTA mice. Given the evidence of c-Abl activation in the human AD brain combined with the pathological phenotype of AblPP/tTA mice, it is likely that aberrant c-Abl activity may play a role in neurodegenerative disease.

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

A dysfunction of the fronto-striatal loop has been associated with obsessive-compulsive disorder (OCD). Functional imaging studies suggest that reversal learning is affected by deficits in fronto-striatal brain areas and thus should be impaired in patients with OCD. The authors compared patients with OCD and healthy comparison subjects on a reversal learning task. Correlation analyses and group comparisons showing prolonged reaction times of different response parameters are associated with increasing severity of compulsions. The reversal learning task has been shown to be associated with ventral fronto-striatal brain activation by functional magnetic resonance imaging (fMRI) in healthy comparison subjects. The purpose of this article is to suggest that the reversal learning task can be used as a neuropsychiatric measurement of the ventral fronto-striatal dysfunction in OCD.

Assessment of brain iron and neuronal integrity in patients with Parkinson's disease using novel MRI contrasts

Postmortem demonstration of increased iron in the substantia nigra (SN) is a well-appreciated finding in Parkinson's disease (PD). Iron facilitates generation of free radicals, which are thought to play a role in dopamine neuronal loss. To date, however, magnetic resonance imaging (MRI) has failed to show significant in vivo differences in SN iron levels in subjects with PD versus control subjects. This finding may be due to the limitations in tissue contrasts achievable with conventional T(1)- and T(2)-weighted MRI sequences that have been used. With the recent development of novel rotating frame transverse (T(2rho)) and longitudinal (T(1rho)) relaxation MRI methods that appear to be sensitive to iron and neuronal loss, respectively, we embarked on a study of 8 individuals with PD (Hoehn & Yahr, Stage II) and 8 age-matched control subjects. Using these techniques with a 4T MRI magnet, we assessed iron deposits and neuronal integrity in the SN. First, T(2rho) MRI, which is reflective of iron-related dynamic dephasing mechanisms (e.g., chemical exchange and diffusion in the locally different magnetic susceptibilities), demonstrated a statistically significant difference between the PD and control group, while routine T(2) MRI did not. Second, T(1rho) measurements, which appear to reflect upon neuronal count, indicated neuronal loss in the SN in PD. We show here that sub-millimeter resolution T(1rho) and T(2rho) MRI relaxation methods can provide a noninvasive measure of iron content as well as evidence of neuronal loss in the midbrain of patients with PD.

Overstimulation of PrPC Signaling Pathways by Prion Peptide 106-126 Causes Oxidative Injury of Bioaminergic Neuronal Cells

Transmissible spongiform encephalopathies, also called prion diseases, are characterized by neuronal loss linked to the accumulation of PrP(Sc), a pathologic variant of the cellular prion protein (PrP(C)). Although the molecular and cellular bases of PrP(Sc)-induced neuropathogenesis are not yet fully understood, increasing evidence supports the view that PrP(Sc) accumulation interferes with PrP(C) normal function(s) in neurons. In the present work, we exploit the properties of PrP-(106-126), a synthetic peptide encompassing residues 106-126 of PrP, to investigate into the mechanisms sustaining prion-associated neuronal damage. This peptide shares many physicochemical properties with PrP(Sc) and is neurotoxic in vitro and in vivo. We examined the impact of PrP-(106-126) exposure on 1C11 neuroepithelial cells, their neuronal progenies, and GT1-7 hypothalamic cells. This peptide triggers reactive oxygen species overflow, mitogen-activated protein kinase (ERK1/2), and SAPK (p38 and JNK1/2) sustained activation, and apoptotic signals in 1C11-derived serotonergic and noradrenergic neuronal cells, while having no effect on 1C11 precursor and GT1-7 cells. The neurotoxic action of PrP-(106-126) relies on cell surface expression of PrP(C), recruitment of a PrP(C)-Caveolin-Fyn signaling platform, and overstimulation of NADPH-oxidase activity. Altogether, these findings provide actual evidence that PrP-(106-126)-induced neuronal injury is caused by an amplification of PrP(C)-associated signaling responses, which notably promotes oxidative stress conditions. Distorsion of PrP(C) signaling in neuronal cells could hence represent a causal event in transmissible spongiform encephalopathy pathogenesis.

Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics

Early onset torsion dystonia is a movement disorder inherited as an autosomal dominant syndrome with reduced penetrance. Symptoms appear to result from altered neuronal circuitry within the brain with no evidence of neuronal loss. Most cases are caused by loss of a glutamic acid residue in the AAA+ chaperone protein, torsinA, encoded in the DYT1 gene. In this study, torsinA was found to move in conjunction with vimentin in three cell culture paradigms-recovery from microtubule depolymerization, expression of a dominant-negative form of kinesin light chain and respreading after trypsinization. Co-immune precipitation studies revealed association between vimentin and torsinA in a complex including other cytoskeletal elements, actin and tubulin, as well as two proteins previously shown to interact with torsinA-the motor protein, kinesin light chain 1, and the nuclear envelope protein, LAP1. Morphologic and functional differences related to vimentin were noted in primary fibroblasts from patients carrying this DYT1 mutation as compared with controls, including an increased perinuclear concentration of vimentin and a delayed rate of adhesion to the substratum. Overexpression of mutant torsinA inhibited neurite extension in human neuroblastoma cells, with torsinA and vimentin immunoreactivity enriched in the perinuclear region and in cytoplasmic inclusions. Collectively, these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain.

Differential responses in three thalamic nuclei in moderately disabled, severely disabled and vegetative patients after blunt head injury.

In vivo imaging techniques have indicated for many years that there is loss of white matter after human traumatic brain injury (TBI) and that the loss is inversely related to cognitive outcome. However, correlated, quantitative evidence for loss of neurons from either the cerebral cortex or the diencephalon is largely lacking. There is some evidence in models of TBI that neuronal loss occurs within the thalamus, but no systematic studies of such loss have been undertaken in the thalamus of humans after blunt head injury. We have undertaken a stereological analysis of changes in numbers of neurons within the dorsomedial, ventral posterior and lateral posterior thalamic nuclei in patients assessed by the Glasgow Outcome Scale as moderately disabled (n = 9), severely disabled (n = 12) and vegetative (n = 10) head-injured patients who survived between 6 h and 3 years, and controls (n = 9). In histological sections at the level of the lateral geniculate body, the cross-sectional area of each nucleus and the number and the mean size of neurons within each nucleus was quantified. A statistically significant loss of cross-sectional area and number of neurons occurred in the dorsomedial nucleus in moderately disabled, and both the dorsomedial and ventral posterior thalamic nuclei in severely disabled and vegetative head-injured patients. However, there was no change in neuronal cell size. In the lateral posterior nucleus, despite a reduction in mean cell size, there was not a significant change in either nuclear area or number of neurons in cases of moderately disabled, severely disabled or vegetative patients. We posit, although detailed neuropsychological outcome for the patients included within this study was not available, that neuronal loss in the dorsomedial thalamus in moderately and severely disabled and vegetative patients may be the structural basis for the clinical assessment in the Glasgow Outcome Scale. In severely disabled and vegetative patients, loss of neurons from the ventral posterior thalamic nucleus may also reflect loss of response to afferent stimuli.

Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: a cautionary note

NeuN immunoreactivity is used as a specific marker for neurons. The number of NeuN-positive cells decreases under pathological conditions. This finding is usually considered as an evidence of neuronal loss. However, decrease in NeuN labeling may also be caused by depletion of the protein or loss of its antigenicity. Hence, we have investigated the morphological features of neurons that lost NeuN immunoreactivity and the NeuN protein levels in mouse brain after cerebral ischemia. The number of NeuN-labeled cells was decreased 6 h after a mild ischemic insult (30 min middle cerebral artery occlusion) in penumbral and core regions. Hematoxylin and eosin (H&E) staining of adjacent sections showed that neurons in the penumbra were not disintegrated but displayed early ischemic changes. The nuclear NeuN staining was dramatically reduced or lost in some neurons. However, Hoechst 33258 staining of the same sections revealed that these nuclei were preserved with an intact membrane. Labeling of neurons that had lost NeuN-positivity with antibodies against caspase-3-p20, which is constitutively not present but emerges in neurons after ischemia, disclosed that these neurons still preserved their integrity. Moreover, Western blots showed that NeuN protein levels were not decreased, suggesting that reduced NeuN antigenicity accounted for loss of immunoreactivity in this mild brain injury model. Supporting this idea, NeuN labeling was partially restored after antigenic retrieval. In conclusion, since NeuN immunoreactivity readily decreases after metabolic perturbations, reduced NeuN labeling should not be taken as an indicator of neuronal loss and, quantitative analysis based on NeuN-positivity should be used cautiously after central nervous system (CNS) injury.

Building a More Perfect Beast: APP Transgenic Mice with Neuronal Loss

While there have been a number of successful attempts to develop transgenic mice that express mutant amyloid precursor protein (APP) and develop amyloid deposits that have features similar to those in aging and Alzheimer’s disease (AD),1 until now there has been either no neuronal loss or less than convincing evidence in favor of neuronal loss. In this issue of The American Journal of Pathology, Schmitz and colleagues2 provide compelling evidence for age-dependent neuronal loss in the hippocampus of bigenic transgenic mice expressing a double mutation in APP (Swedish APP mutation APPK670N, M671L (APPsw) and APPV717I, under the mouse Thy1 promoter) and mutant presenilin-1 (PS-1 M146L under the pHMG promoter). The neuronal loss was ascertained by unbiased stereologic methods on Nissl-stained sections. The animals showed significant (30 to 35%) neuronal loss in the hippocampal pyramidal layer compared to controls, which was disproportionate to the degree of amyloid deposition. No neuronal loss was detected in the dentate fascia of the hippocampus, the only other region assessed for neuronal loss. While the regions analyzed are of interest, if the model is to have relevance to AD, it will be important in future studies to extend neuronal counts to limbic and association cortical regions, which are especially vulnerable to amyloid deposition in humans. The behavioral consequences, if any, of neuronal loss in this model are not described in this report or other descriptions of this model3 and are left to future work.

Neurons, glia, and plasticity in normal brain aging

Early manifestations of brain aging have received much less attention than the drastic degeneration of AD and MID. During nonpathological changes of normal aging, brain systems differ in the involvement of neuron loss. Spatial learning can become impaired without evidence for neuron loss, whereas eye-blink conditioning deficits are well correlated with Purkinje neuron loss. Glial activation, in particular the increased expression of glial fibrillary acidic protein (GFAP), may be a factor in impaired synaptic plasticity. Lastly, it is discussed how developmental variations in the numbers of Purkinje cells and ovarian oocytes can be factors in outcomes of aging that are not under strict genetic control.

Expression of the p75 neurotrophin receptor by striatal cholinergic neurons following global ischemia in rats is associated with neuronal degeneration

The induction of the p75 neurotrophin receptor (p75NTR) on striatal cholinergic neurons by global hypoxic-ischemia has been reported to promote neuron survival. We have found, however, while the p75NTR-expressing neurons survive the insult for the first 5 days, subsequently they undergo shrinkage, loss of choline acetyl transferase (ChAT) expression, and more than 96% are eventually lost by 8 days. In contrast ChAT-expressing cells in the surrounding region of the infarction, do not express p75NTR and there is no evidence of neuronal loss. These results suggest the expression of p75NTR on cholinergic interneurons of the rat striatum is associated with delayed neuronal degeneration.

Differential neuronal responses between brain nuclei after blunt head‐injury

Introduction: Stereological evidence for loss of neurons after human blunt head‐injury is lacking. A quantitative analysis of total numbers of neurons in two different brain regions in nonhead‐injured control (n = 10) and severely head‐injured patients (n = 24) (age range 18–64) was undertaken.Material and methods: 8 µm paraffin sections of the left and right thalami and of the left hippocampus from all patients were cut and cresyl violet stained. The neuronal size in subfields of the hippocampus, and dorsomedial, lateral and ventral thalamic nuclei was measured to determine the size of the counting box and, within this, the total number of neurons was counted. Statistical analysis used the Student's t‐test.Results: At 1 week, pyramidal neurons were lost from hippocampal subfields CA1 (P = 0.012), CA3 (P = 0.003) and CA4 (P = 0.002), but not from CA2. Further loss occurred at 6 months but only in CA1 (P = 0.033) and CA4 (P = 0.013). No evidence for loss of neurons from any thalamic nucleus was obtained.Conclusions: Loss of neurons from different nuclei of the brain after blunt head‐injury occurs both with a different timescale and to a different extent. Anecdotal evidence of damage to thalamic nuclei after head‐injury has not been supported using stereology.

Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I.

Glutaric acidemia type I (GA-I) is an autosomal recessive disorder of amino acid metabolism resulting from a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients accumulate glutaric acid (GA) and 3-OH glutaric acid (3-OHGA) in their blood, urine and CSF. Clinically, GA-I is characterized by macrocephaly, progressive dystonia and dyskinesia. Degeneration of the caudate and putamen of the basal ganglia, widening of the Sylvian fissures, fronto-temporal atrophy and severe spongiform change in the white matter are also commonly observed. In this report we describe the phenotype of a mouse model of GA-I generated via targeted deletion of the Gcdh gene in embryonic stem cells. The Gcdh-/- mice have a biochemical phenotype very similar to human GA-I patients, including elevations of GA and 3-OHGA at levels similar to those seen in GA-I patients. The affected mice have a mild motor deficit but do not develop the progressive dystonia seen in human patients. Pathologically, the Gcdh-/- mice have a diffuse spongiform myelinopathy similar to that seen in GA-I patients. However, unlike in human patients, there is no evidence of neuron loss or astrogliosis in the striatum. Subjecting the Gcdh-/- mice to a metabolic stress, which often precipitates an encephalopathic crisis and the development of dystonia in GA-I patients, failed to have any neurologic effect on the mice. We hypothesize that the lack of similarity in regards to the neurologic phenotype and striatal pathology of GA-I patients, as compared with the Gcdh-/- mice, is due to intrinsic differences between the striata of mice and men.

Congenital Spongiform Change in the Brain Stem Nuclei of a Domestic Kitten

This report describes a novel spongiform change in the brain stem nuclei of a 9-month-old mixed breed kitten with neurological signs. Histologically, vacuoles were found in perineuronal spaces and neuropil, with mild to moderate astrocytosis in the brain stem nuclei. Vacuoles were not observed in the cytoplasm of neurons and no evidence of neuronal loss was found. Ultrastructurally, there were intramyelinic vacuoles with separation of lamellae at intraperiod lines and larger spaces formed by coalescence of ruptured vacuoles. Immunohistochemically, abnormal accumulation of prion protein (PrP) was not detected in the brain stem lesions. This is, to our knowledge, the first report of a feline spongiform change localized in the brain stem nuclei.

Depletion of brain histamine produces regionally selective protection against thiamine deficiency-induced lesions in the rat.

Breakdown of the blood brain barrier and the subsequent accumulation of free radicals, lactate, and glutamate appear to be the immediate causes of thiamine deficiency (TD)-induced damage to thalamus. The mechanisms triggering these events are unknown but recent evidence suggests an important role of histamine. We therefore studied the effects of histamine depletion on thalamic lesions in the pyrithiamine-induced thiamine deficient (PTD) rat. Chronic intracerebroventricular (i.c.v., 7 days) infusion of alpha-fluoromethylhistidine (FMH), combined with bilateral ibotenate destruction of the histamine-containing neurons in the tuberomammillary (TM) nucleus and bolus i.c.v. infusion of 48/80, a potent mast cell degranulating agent, was used to deplete brain histamine levels. PTD rats receiving combined FMH + 48/80 + TM lesions developed acute neurological symptoms, including spontaneous seizures, approximately 1 day earlier than PTD rats treated with i.c.v. infusion of vehicle and sham lesions of the TM. When examined 1 week after restoration of thiamine, the PTD vehicle + sham lesion animals contained severe neuronal loss and gliosis in midline, intralaminar, ventral, lateral, and posterior nuclei. PTD animals treated with FMH + 48/80 + TM lesions had little evidence of neuronal loss or microglial proliferation in thalamus except in the gelatinosus and anteroventral nuclei, in which there was complete neuronal loss. These data demonstrate a significant and regionally selective role of histamine in the development of thalamic lesions in a rat model of Wernicke's encephalopathy. Furthermore, these data suggest either a dissociation between seizures and thalamic lesions or a significant role of histamine in seizure-related damage to the thalamus.