Hippocampal capillaries in different age groups of chronically ethanol-intoxicated rats.

The influence of chronic ethanol intoxication on the terminal vascularization of particular hippocampal fields and layers was investigated in different age groups of rats. Thirty-six male Wistar rats aged 6 weeks were used in the study. For twelve months 24 of them drank only 25% ethanol — 12 starting at 6-week-age and 12 at 3-month-age. The control group of 12 rats drank only water. As an effect of long-term ethanol exposure on hippocampal capillaries we observed the increase in the terminal vessel diameter and the decrease in microvascular length, surface, and volume densities. These changes varied between different age groups and between particular hippocampal regions. The observed age and regional differentiation of ethanol-related microvascular changes did not correlate well with the damaging effects of alcohol on corresponding neuronal elements, which emphasizes the very complicated pathogenesis of ethanol-induced injuries

Neuropathology of aging in cats and its similarities to human Alzheimer’s disease

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling

Assessment of β-amyloid deposits in human brain: a study of the BrainNet Europe Consortium

β-Amyloid (Aβ) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as ι and α synuclein related lesions, also Aβ related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of Aβ, i.e. phase 1 = deposition of Aβ exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of Aβ phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of Aβ-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer’s disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the Aβ phase in AD is feasible even in large scale retrospective studies

Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [11C]PBR28 PET study

Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [11C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45±13; M:F 14:6) and nine ADP (45±6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331±15 MBq [11C]PBR28. Regional volumes of distribution (VT) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an ~20% lower [11C]PBR28 VT, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in VT in other ROIs. Hippocampal [11C]PBR28 VT was positively correlated with verbal memory performance in a combined group of HC and ADP (r=0.720, P<0.001), an effect seen in HC alone (r=0.738; P=0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [11C]PBR28 VT, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bia

Variations in Effects of Elevated Corticosterone Related to Drug Delivery Method: Plasma Concentration, Dentate Gyrus Neurogenesis, and Development of Trace Eyeblink Conditioning

Exogenous glucocorticoids are commonly used in modern medications even though adverse effects on hippocampal-dependent learning and memory have been reported. Studies examining the effects of glucocorticoids on the developing brain and behavior report inconsistent results. Such studies require a reliable, long-term method of drug administration, and recent reports have questioned the reliability of available drug delivery methods in mice. In our laboratory, variable behavioral results using trace eyeblink conditioning (EBC) suggest that we may be having similar problems in developing rat pups.To better understand this issue, we conducted a detailed time-course assessment of blood plasma concentrations of corticosterone (CORT) to compare 3 common methods of administration starting on postnatal day 15 in Long-Evans rat pups: s.c. pellet (35 mg, 21-day slow-release), s.c.injection (twice daily, 3 days, 20 mg/kg), and s.c. osmotic mini-pump (release rate 1μL/hr), with appropriate vehicle controls for each. For CORT plasma assays, blood samples were taken over the course of 7 days for pellets and over 3 days for injections and minipumps. Additionally, some of the animals in each group received three daily intraperitoneal injections of BrdU (50 mg/kg) on postnatal days 16-18, in order to study possible CORT effects on neurogenesis. Ten days after the last BrdU injection, brains were harvested. Coronal sections containing dorsal hippocampus were collected, immunostained and scanned with a confocal microscope. Stereological analysis focused on quantifying newly generated neurons using the Rare Events Protocol.Trace EBC was impaired by pellets and minipumps but facilitated by injections. Pellets produced peak plasma CORT elevations up to 3800 ng/ml at 4 hours post-surgery and returned to baseline within 5 days. Injection produced a peak plasma elevation of CORT of up to 2000 ng/ml at 1 hour after each injection, which returned to baseline within 4 hours, producing a fluctuating pattern of elevations. Minipumps produced peak CORT elevation of 527 ng/ml 1 hour after surgery, which corresponded with surgical stress-related elevation in control animals. CORT elevation then dropped to a relatively steady level for the next 3 days at 200-300 ng/ml. These findings suggest that the different peak levels and elevation patterns of these three CORT delivery methods are likely to yield differences in behavioral outcomes. However, the total number of newly generated neurons in the days immediately following CORT administration, and their density in dorsal dentate gyrus, were not significantly influenced by the elevated CORT, regardless of delivery method

Differences in a Cage Escape Behaviour between Two Migrating Warblers of Different Stop-Over Strategy

Cognitive abilities play an important role for migratory birds that are briefly visiting a variety of unfamiliar stop-over habitats. Here, we compared cognitive abilities-linked behaviour (escape from an experimental cage) between two long-distant migrants differing in stop-over ecology, Sedge Warbler (Acrocephalus schoenobaenus; not territorial, searching for locally superabundant food) and Reed Warbler (A. scirpaceus; territorial, foraging on a common prey) during the autumn migration. After two minutes of acclimatization in the cage, we remotely opened the cage door and recorded the bird’s reaction. We measured latency that individuals needed to escape from a cage. Sedge warblers were 1.61 times more likely to escape from the cage than Reed Warblers. Sedge warblers generally escaped earlier after the door was opened and were 1.79 times more likely to escape at any given time than Reed Warblers. We interpret the prevalence of non-escaped individuals as a general feature of migratory birds. In contrast to resident species, they are more likely to enter an unfamiliar environment, but they are less explorative. We attributed inter-species differences in escape latency to species-specific autumn stop-over refuelling strategies in the context of specialist-generalist foraging. Our study provides ecological insight into the cognitive abilities-linked behaviour of wild animals

Variations in Effects of Elevated Corticosterone Related to Drug Delivery Method: Plasma Concentration, Dentate Gyrus Neurogenesis, and Development of Trace Eyeblink Conditioning

Exogenous glucocorticoids are commonly used in modern medications even though adverse effects on hippocampal-dependent learning and memory have been reported. Studies examining the effects of glucocorticoids on the developing brain and behavior report inconsistent results. Such studies require a reliable, long-term method of drug administration, and recent reports have questioned the reliability of available drug delivery methods in mice. In our laboratory, variable behavioral results using trace eyeblink conditioning (EBC) suggest that we may be having similar problems in developing rat pups.To better understand this issue, we conducted a detailed time-course assessment of blood plasma concentrations of corticosterone (CORT) to compare 3 common methods of administration starting on postnatal day 15 in Long-Evans rat pups: s.c. pellet (35 mg, 21-day slow-release), s.c.injection (twice daily, 3 days, 20 mg/kg), and s.c. osmotic mini-pump (release rate 1μL/hr), with appropriate vehicle controls for each. For CORT plasma assays, blood samples were taken over the course of 7 days for pellets and over 3 days for injections and minipumps. Additionally, some of the animals in each group received three daily intraperitoneal injections of BrdU (50 mg/kg) on postnatal days 16-18, in order to study possible CORT effects on neurogenesis. Ten days after the last BrdU injection, brains were harvested. Coronal sections containing dorsal hippocampus were collected, immunostained and scanned with a confocal microscope. Stereological analysis focused on quantifying newly generated neurons using the Rare Events Protocol.Trace EBC was impaired by pellets and minipumps but facilitated by injections. Pellets produced peak plasma CORT elevations up to 3800 ng/ml at 4 hours post-surgery and returned to baseline within 5 days. Injection produced a peak plasma elevation of CORT of up to 2000 ng/ml at 1 hour after each injection, which returned to baseline within 4 hours, producing a fluctuating pattern of elevations. Minipumps produced peak CORT elevation of 527 ng/ml 1 hour after surgery, which corresponded with surgical stress-related elevation in control animals. CORT elevation then dropped to a relatively steady level for the next 3 days at 200-300 ng/ml. These findings suggest that the different peak levels and elevation patterns of these three CORT delivery methods are likely to yield differences in behavioral outcomes. However, the total number of newly generated neurons in the days immediately following CORT administration, and their density in dorsal dentate gyrus, were not significantly influenced by the elevated CORT, regardless of delivery method