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Objective: Stroke is a highly prevalent and devastating condition affecting millions worldwide. The Devil's Claw (DCW) plant is a native African plant whose anti-inflammatory, antioxidant, and neuroprotective properties have been investigated. We postulated that DCW could protect the brain injury caused by cerebral ischemia. Materials and Methods: The rats were randomly divided into four groups. The sham and control (Ctrl) groups received pretreatment with a distilled water vehicle. Doses of 200 and 400 mg/kg were selected for pretreatment with DCW. The filament or intravascular occlusion method was used for middle cerebral artery occlusion (MCAO). The Triphenyl tetrazolium chloride (TTC) staining method was used to investigate the infarct zone and penumbra volume. The neuroprotective effect of DCW was measured by hematoxylin staining. Movement performance was evaluated from neurological deficit score, rotarod performance, and open field tests. Results: TTC staining showed that the DCW/400 group could maintain the penumbra's structure and reduce the infarct volume compared to the Ctrl group (p<0.001). Histological studies confirmed the neuroprotective properties of DCW at doses of 200 and 400 mg/kg compared to the Ctrl group (p<0.01 and p<0.0001, respectively). The results of behavioral tests showed an improvement in behavioral performance in pretreatment 400 mg/kg doses compare to Ctrl group (p<0.0001). Conclusion: The study showed that pretreatment with DCW with its neuron protection potential reduces the infarct area and restores motor function after MCAO. [ABSTRACT FROM AUTHOR]

Objective: Stroke is a highly prevalent and devastating conditionaffecting millions worldwide. The Devil's Claw (DCW) plant is anative African plant whose anti-inflammatory, antioxidant, andneuroprotective properties have been investigated. We postulatedthat DCW could protect the brain injury caused by cerebralischemia.Materials and Methods: The rats were randomly divided into fourgroups. The sham and control (Ctrl) groups received pretreatmentwith a distilled water vehicle. Doses of 200 and 400 mg/kg wereselected for pretreatment with DCW. The filament or intravascularocclusion method was used for middle cerebral artery occlusion(MCAO). The Triphenyl tetrazolium chloride (TTC) stainingmethod was used to investigate the infarct zone and penumbravolume. The neuroprotective effect of DCW was measured byhematoxylin staining. Movement performance was evaluated fromneurological deficit score, rotarod performance, and open field tests.Results: TTC staining showed that the DCW/400 group couldmaintain the penumbra's structure and reduce the infarct volumecompared to the Ctrl group (p

Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510.Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific R2* maps free of magnetic field inhomogeneity artifacts. Light-sheet microscopy of the brains stained with NeuN and MBP served to visualize neuronal nuclei and myelin content respectively.Significant decrease in NeuN staining between 3mo and 5mo was observed in the hippocampus of Tg4510, validating the mouse AD model.Longitudinal analysis showed clear decreases in R2* metric of qGRE signal in the Tg4510 mice hippocampus undergoing neurodegeneration between 3 and 5 months old. Histogram analysis revealed an upward trend in patterns of low R2* value (Dark Matter, DM), and broadening of R2* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R2* Standard Deviation (SD) in Tg4510 mice (p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between the DMVF and myelin content (p=0.01, r=-0.76), suggesting sensitivity of the technique to the loss of myelinated axons.The presented qGRE technique, validated by histological measurements, can be readily applied as in vivo tool in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment.

Alzheimer's disease is characterized by progressive memory loss caused from alterations in the central cholinergic system. While existing medications often have adverse effects, traditional use of Tiliacora triandra in Thailand shows its potential as a revitalizing neurotonic agent. This study explores the impact of T. triandra leaf extract on cognitive behaviors, neuronal density, and oxidative stress in male rats with scopolamine-induced cognitive impairment. Experimental groups composed of a control, vehicle, positive control meditation, and T. triandra extract-treated groups (100, 200, and 400 mg/kg BW) over 14 days, with scopolamine administration (i.p.) between days 8 and 14. Results showed significant enhancements in the discrimination ratio and spontaneous alteration behavior percentage during novel object recognition (NORT) and Y-maze tests for scopolamine-administered rats treated with T. triandra extract or donepezil. In contrast, open field test (OFT)-assessed spontaneous locomotor activity displayed no significant difference. Notably, acetylcholinesterase (AChE) activity and malondialdehyde (MDA) levels reduced significantly in scopolamine-treated rats with T. triandra extract or the positive control. Moreover, neuronal density in the hippocampal CA3 region, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities increased significantly. However, catalase (CAT) activity exhibited no significant difference. In conclusion, T. triandra leaf extract shows promise in mitigating scopolamine-induced memory deficits, potentially attributed to increased neuronal density, inhibited AChE activity, reduced MDA levels, and enhanced antioxidant activities. This extract has potential as a therapeutic agent for Alzheimer's disease-associated memory impairment.

Parkinson's disease (PD) is a progressive age-related neurodegenerative pathology of the central nervous system, characterized by a selective loss of dopaminergic neurons of the nigrostriatal pathway and the presence of specific inclusions (Lewy bodies) in dopaminergic neurons. To study the mechanisms of this pathology and to search for possible ways for its correction, genetic mouse models of PD have been designed. Transgenic mice of the B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J strain (hereinafter referred to as B6.Cg-Tg), one of such models, carry the A53T mutation in the human alpha-synuclein gene. The aim of this work was to study the locomotor activity and the level of anxiety, as well as the density of neurons in the brain of male B6.Cg-Tg mice aged six months. Sex- and age-matched wild type C57BL/6J mice were used as controls. The obtained results demonstrate that B6.Cg-Tg mice are characterized by a high locomotor activity and low anxiety. In addition, they demonstrate a selective decrease in the density of neurons in the subventricular zone and substantia nigra, as well as in the hippocampal CA1, CA3, CA4 regions and the granular layer of the dentate gyrus. Thus, B6.Cg-Tg mice at the age of six months only partially match the key pathophysiological hallmarks of PD, such as a reduced neuronal density in the substantia nigra and hippocampal CA1 and CA3 regions. Meanwhile, these mice have neither bradykinesia nor high levels of anxiety. [ABSTRACT FROM AUTHOR]

Abstract—This research is aimed at determining the long-term effects of in vitro culture (IVC) and embryo transfer (ET) on neonatal development of offspring, as well as on adult hippocampal neuronal densities and hippocampal neurogenesis in C57BL/6J mice. Offspring of naturally born C57BL/6J mice (C57BL group) were compared with C57BL/6J mice born as a result of the IVC combined with ET to C57BL/6J recipient females (ET-C57BL group). At the age of 3 months, no group differences were observed in the body weight and brain-to-body ratio, although sex differences in these variables were observed. The offspring of both sexes born after IVC–ET exhibited a lower level of neurogenesis in the dentate gyrus (DG) of the hippocampus compared to the control C57BL group. Thus, IVC and ET exerted no major effects on body and brain weight in offspring, but affected hippocampal neurogenesis in the adult offspring of both sexes. As well, the number of pyramidal neurons in the CA3 area of hippocampus was lower in female offspring of the ET-C57BL group. [ABSTRACT FROM AUTHOR]

Autistic spectrum disorders (ASD) represent conditions starting in childhood, which are characterized by difficulties with social interaction and communication, as well as non-typical and stereotyping models of behavior. The mechanisms and the origin of these disorders are not yet understood and thus far there is a lack of prophylactic measures for these disorders. The current study aims to estimate neuronal density in the prefrontal cortex and four hippocampal subfields, i. e. СA1, СA2, СA3, and DG in Clstn2-KO mice as a genetic model of ASD. In addition, the level of neurogenesis was measured in the DG area of the hippocampus. This mouse strain was obtained by a knockout of the calsinthenin-2 gene (Clsnt2) in C57BL/6J mice; the latter (wild type) was used as controls. To estimate neuronal density, serial sections were prepared on a cryotome for the above-mentioned brain structures with the subsequent immunohistochemical labeling and confocal microscopy; the neuronal marker (anti-NeuN) was used as the primary antibody. In addition, neurogenesis was estimated in the DG region of the hippocampus; for this purpose, a primary antibody against doublecortin (anti-DCX) was used. In all cases Goat anti-rabbit IgG was used as the secondary antibody. The density of neurons in the CA1 region of the hippocampus was lower in Clstn2-KO mice of both sexes as compared with controls. Moreover, in males of both strains, neuronal density in this region was lower as compared to females. Besides, the differences between males and females were revealed in two other hippocampal regions. In the CA2 region, a lower density of neurons was observed in males of both strains, and in the CA3 region, a lower density of neurons was also observed in males as compared to females but only in C57BL/6J mice. No difference between the studied groups was revealed in neurogenesis, nor was it in neuronal density in the prefrontal cortex or DG hippocampal region. Our new findings indicate that calsyntenin-2 regulates neuronal hippocampal density in subfield-specific manner, suggesting that the CA1 neuronal subpopulation may represent a cellular target for earlylife preventive therapy of ASD.

Introduction: The Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene encoding the Delta-like ligand 1 for Notch (Dll1lacZ) have a reduced neuronal density in the substantia nigra pars compacta. The aim of the present work was to evaluate whether this alteration extends to other brain structures and the behavioral consequences of affected subjects. Methods: Brains of Dll1+/lacZ embryos and mice at different ages were phenotypically compared against their wild type (WT) counterpart. Afterwards, brain histological analyses were performed followed by determinations of neural cell markers in tissue slices. Neurological deficits were diagnosed by applying different behavioral tests to Dll1+/lacZ and WT mice. Results: Brain weight and size of Dll1+/lacZ mice was significantly decreased compared with WT littermates (i.e., microcephaly), a phenotype detected early after birth. Interestingly, enlarged ventricles (i.e., hydrocephalus) was a common characteristic of brains of Dll1 haploinsufficient mice since early ages. At the cell level, general cell density and number of neurons in several brain regions, including the cortex and hippocampus, of Dll1+/lacZ mice were reduced as compared with those regions of WT mice. Also, fewer neural stem cells were particularly found in the adult dentate gyrus of Dll1+/lacZ mice but not in the subventricular zone. High myelination levels detected at early postnatal ages (P7–P24) were an additional penetrant phenotype in Dll1+/lacZ mice, observation that was consistent with premature oligodendrocyte differentiation. After applying a set of behavioral tests, mild neurological alterations were detected that caused changes in motor behaviors and a deficit in object categorization. Discussion: Our observations suggest that Dll1 haploinsufficiency limits Notch signaling during brain development which, on one hand, leads to reduced brain cell density and causes microcephaly and hydrocephalus phenotypes and, on the other, alters the myelination process after birth. The severity of these defects could reach levels that affect normal brain function. Therefore, Dll1 haploinsufficiency is a risk factor that predisposes the brain to develop abnormalities with functional consequences. [ABSTRACT FROM AUTHOR]

The superior colliculus (SC) is a layered midbrain structure with functions that include polysensory and sensorimotor integration. Here, we describe the distribution of different immunohistochemically identified classes of neurons in the SC of adult marmoset monkeys (Callithrix jacchus). Neuronal nuclei (NeuN) staining was used to determine the overall neuronal density in the different SC layers. In addition, we studied the distribution of neurons expressing different calcium‐binding proteins (calbindin [CB], parvalbumin [PV] and calretinin [CR]). Our results indicate that neuronal density in the SC decreases from superficial to deep layers. Although the neuronal density within the same layer varies little across the mediolateral axis, it tends to be lower at rostral levels, compared to caudal levels. Cells expressing different calcium‐binding proteins display differential gradients of density according to depth. Both CB‐ and CR‐expressing neurons show markedly higher densities in the stratum griseum superficiale (SGS), compared to the stratum opticum and intermediate and deep layers. However, CR‐expressing neurons are twice as common as CB‐expressing neurons outside the SGS. The distribution of PV‐expressing cells follows a shallow density gradient from superficial to deep layers. When normalized relative to total neuronal density, the proportion of CR‐expressing neurons increases between the superficial and intermediate layers, whereas that of CB‐expressing neurons declines toward the deep layers. The proportion of PV‐expressing neurons remains constant across layers. Our data provide layer‐specific and accurate estimates of neuronal density, which may be important for the generation of biophysical models of how the primate SC transforms sensory inputs into motor signals. [ABSTRACT FROM AUTHOR]

The allometric scaling of the brain size and neuron number across species has been extensively studied in recent years. With the exception of primates, parrots, and songbirds, larger brains have more neurons but relatively lower neuronal densities than smaller brains. Conversely, when considering withinpopulation variability, it has been shown that mice with larger brains do not necessarily have more neurons but rather more neurons in the brain reflect higher neuronal density. To what extent this intraspecific allometric scaling pattern of the brain applies to individuals from other species remains to be explored. Here, we investigate the allometric relationships among the sizes of the body, brain, telencephalon, cerebellum, and optic tectum, and the numbers of neurons and non-neuronal cells of the telencephalon, cerebellum, and optic tectum across 66 individuals originated from an intercross between wild and domestic chickens. Our intercross of chickens generates a population with high variation in brain size, making it an excellent model to determine the allometric scaling of the brain within population. Our results show that larger chickens have larger brains with moderately more neurons and non-neuronal cells. Yet, absolute number of neurons and nonneuronal cells correlated strongly and positively with the density of neurons and non-neuronal cells, respectively. As previously shown in mice, this scaling pattern is in stark contrast with what has been found across different species. Our findings suggest that neuronal scaling rules across species are not a simple extension of the neuronal scaling rules that apply within a species, with important implications for the evolutionary developmental origins of brain diversity. [ABSTRACT FROM AUTHOR]

• There is an unmet need for a non-invasive neurodegeneration measurement method in preclinical AD models. • Novel MRI approach allows capturing of neuronal loss in hippocampus of Tg4510 mice. • Presence of regions of low R2* relaxation rate is correlated with demyelination. • This method can be readily applied in AD drug discovery for efficacy quantification. Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510. Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific R 2 * maps free of magnetic field inhomogeneity artifacts. Light-sheet microscopy of the brains stained with NeuN and MBP served to visualize neuronal nuclei and myelin content respectively. Significant decrease in NeuN staining between 3mo and 5mo was observed in the hippocampus of Tg4510, validating the mouse AD model. Longitudinal analysis showed clear decreases in R 2 * metric of qGRE signal in the Tg4510 mice hippocampus undergoing neurodegeneration between 3 and 5 months old. Histogram analysis revealed an upward trend in patterns of low R 2 * value (Dark Matter, DM), and broadening of R 2 * distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R 2 * Standard Deviation (SD) in Tg4510 mice (p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between the DMVF and myelin content (p=0.01, r=-0.76), suggesting sensitivity of the technique to the loss of myelinated axons. The presented qGRE technique, validated by histological measurements, can be readily applied as in vivo tool in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment. [ABSTRACT FROM AUTHOR]

IntroductionThe Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene encoding the Delta-like ligand 1 for Notch (Dll1lacZ) have a reduced neuronal density in the substantia nigra pars compacta. The aim of the present work was to evaluate whether this alteration extends to other brain structures and the behavioral consequences of affected subjects.MethodsBrains of Dll1+/lacZ embryos and mice at different ages were phenotypically compared against their wild type (WT) counterpart. Afterwards, brain histological analyses were performed followed by determinations of neural cell markers in tissue slices. Neurological deficits were diagnosed by applying different behavioral tests to Dll1+/lacZ and WT mice.ResultsBrain weight and size of Dll1+/lacZ mice was significantly decreased compared with WT littermates (i.e., microcephaly), a phenotype detected early after birth. Interestingly, enlarged ventricles (i.e., hydrocephalus) was a common characteristic of brains of Dll1 haploinsufficient mice since early ages. At the cell level, general cell density and number of neurons in several brain regions, including the cortex and hippocampus, of Dll1+/lacZ mice were reduced as compared with those regions of WT mice. Also, fewer neural stem cells were particularly found in the adult dentate gyrus of Dll1+/lacZ mice but not in the subventricular zone. High myelination levels detected at early postnatal ages (P7–P24) were an additional penetrant phenotype in Dll1+/lacZ mice, observation that was consistent with premature oligodendrocyte differentiation. After applying a set of behavioral tests, mild neurological alterations were detected that caused changes in motor behaviors and a deficit in object categorization.DiscussionOur observations suggest that Dll1 haploinsufficiency limits Notch signaling during brain development which, on one hand, leads to reduced brain cell density and causes microcephaly and hydrocephalus phenotypes and, on the other, alters the myelination process after birth. The severity of these defects could reach levels that affect normal brain function. Therefore, Dll1 haploinsufficiency is a risk factor that predisposes the brain to develop abnormalities with functional consequences.

The allometric scaling of the brain size and neuron number across species has been extensively studied in recent years. With the exception of primates, parrots, and songbirds, larger brains have more neurons but relatively lower neuronal densities than smaller brains. Conversely, when considering within-population variability, it has been shown that mice with larger brains do not necessarily have more neurons but rather more neurons in the brain reflect higher neuronal density. To what extent this intraspecific allometric scaling pattern of the brain applies to individuals from other species remains to be explored. Here, we investigate the allometric relationships among the sizes of the body, brain, telencephalon, cerebellum, and optic tectum, and the numbers of neurons and non-neuronal cells of the telencephalon, cerebellum, and optic tectum across 66 individuals originated from an intercross between wild and domestic chickens. Our intercross of chickens generates a population with high variation in brain size, making it an excellent model to determine the allometric scaling of the brain within population. Our results show that larger chickens have larger brains with moderately more neurons and non-neuronal cells. Yet, absolute number of neurons and non-neuronal cells correlated strongly and positively with the density of neurons and non-neuronal cells, respectively. As previously shown in mice, this scaling pattern is in stark contrast with what has been found across different species. Our findings suggest that neuronal scaling rules across species are not a simple extension of the neuronal scaling rules that apply within a species, with important implications for the evolutionary developmental origins of brain diversity.

Neuronal densities vary enormously across sites within a brain. Does the density of the capillary bed vary accompanying the presumably larger energy requirement of sites with more neurons, or with larger neurons, or is energy supply constrained by a mostly homogeneous capillary bed? Here we find evidence for the latter, with a capillary bed that represents typically between 0.7 and 1.5% of the volume of the parenchyma across various sites in the mouse brain, whereas neuronal densities vary by at least 100-fold. As a result, the ratio of capillary cells per neuron decreases uniformly with increasing neuronal density and therefore with smaller average neuronal size across sites. Thus, given the relatively constant capillary density compared to neuronal density in the brain, blood and energy availability per neuron is presumably dependent on how many neurons compete for the limited supply provided by a mostly homogeneous capillary bed. Additionally, we find that local capillary density is not correlated with local synapse densities, although there is a small but significant correlation between lower neuronal density (and therefore larger neuronal size) and more synapses per neuron within the restricted range of 6,500-9,500 across cortical sites. Further, local variations in the glial/neuron ratio are not correlated with local variations in the number of synapses per neuron or local synaptic densities. These findings suggest that it is not that larger neurons, neurons with more synapses, or even sites with more synapses demand more energy, but simply that larger neurons (in low density sites) have more energy available per cell and for the totality of its synapses than smaller neurons (in high density sites) due to competition for limited resources supplied by a capillary bed of fairly homogeneous density throughout the brain. [ABSTRACT FROM AUTHOR]

Neuronal densities vary enormously across sites within a brain. Does the density of the capillary bed vary accompanying the presumably larger energy requirement of sites with more neurons, or with larger neurons, or is energy supply constrained by a mostly homogeneous capillary bed? Here we find evidence for the latter, with a capillary bed that represents typically between 0.7 and 1.5% of the volume of the parenchyma across various sites in the mouse brain, whereas neuronal densities vary by at least 100-fold. As a result, the ratio of capillary cells per neuron decreases uniformly with increasing neuronal density and therefore with smaller average neuronal size across sites. Thus, given the relatively constant capillary density compared to neuronal density in the brain, blood and energy availability per neuron is presumably dependent on how many neurons compete for the limited supply provided by a mostly homogeneous capillary bed. Additionally, we find that local capillary density is not correlated with local synapse densities, although there is a small but significant correlation between lower neuronal density (and therefore larger neuronal size) and more synapses per neuron within the restricted range of 6,500–9,500 across cortical sites. Further, local variations in the glial/neuron ratio are not correlated with local variations in the number of synapses per neuron or local synaptic densities. These findings suggest that it is not that larger neurons, neurons with more synapses, or even sites with more synapses demand more energy, but simply that larger neurons (in low density sites) have more energy available per cell and for the totality of its synapses than smaller neurons (in high density sites) due to competition for limited resources supplied by a capillary bed of fairly homogeneous density throughout the brain.

We report in a companion paper that in the mouse brain, in contrast to the 1,000-fold variation in local neuronal densities across sites, capillary density (measured both as capillary volume fraction and as density of endothelial cells) show very little variation, of the order of only fourfold. Here we confirm that finding in the rat brain and, using published rates of local blood flow and glucose use at rest, proceed to show that what small variation exists in capillary density across sites in the rat brain is strongly and linearly correlated to variations in local rates of brain metabolism at rest. Crucially, we show that such variations in local capillary density and brain metabolism are not correlated with local variations in neuronal density, which contradicts expectations that use-dependent self-organization would cause brain sites with more neurons to have higher capillary densities due to higher energetic demands. In fact, we show that the ratio of endothelial cells per neuron serves as a linear indicator of average blood flow and glucose use per neuron at rest, and both increase as neuronal density decreases across sites. In other words, because of the relatively tiny variation in capillary densities compared to the large variation in neuronal densities, the anatomical infrastructure of the brain is such that those sites with fewer neurons have more energy supplied per neuron, which matches a higher average rate of energy use per neuron, compared to sites with more neurons. Taken together, our data support the interpretation that resting brain metabolism is not demand-based, but rather limited by its capillary supply, and raise multiple implications for the differential vulnerability of diverse brain areas to disease and aging. [ABSTRACT FROM AUTHOR]

Background and Aims: When a neuronal axon is damaged, it returns to the neuron cell body and destroys it. Tanacetum bodjnordens as antioxidant and anti-apoptotic effects. This study aimed to determine the neuroprotective effects of ethyl acetate and n-butanol and hydroalcoholic extracts of Tanacetum bodjnordens on sciatic nerve compression in male rats. Materials and Methods: In this experimental study, 36 male Wistar rats weighing 200-250 g were randomly divided into 6 groups )n=6). In the control group, the right thigh muscle of the rats was split after the anesthetization of the rats, while in the compression and treatment groups, the sciatic nerve was compressed for 60 seconds. The plant extract was injected intraperitoneally on the day of compression and seven days later. After 28 days, samples were taken from the lumbar spinal cord subsequent to performing the perfusion method. Afterward, 7-μm serial sections were prepared and stained using toluidine blue stain after tissue passage. Eventually, the neuronal density of rats in the six groups was compared. Results: Based on the results, the neuronal density in the compression group decreased significantly compared to controls and showed a significant increase in the hydroalcoholic, n-butanol, and aqueous phase treatment groups compared to that in the compression group (P

We report in a companion paper that in the mouse brain, in contrast to the 1,000-fold variation in local neuronal densities across sites, capillary density (measured both as capillary volume fraction and as density of endothelial cells) show very little variation, of the order of only fourfold. Here we confirm that finding in the rat brain and, using published rates of local blood flow and glucose use at rest, proceed to show that what small variation exists in capillary density across sites in the rat brain is strongly and linearly correlated to variations in local rates of brain metabolism at rest. Crucially, we show that such variations in local capillary density and brain metabolism are not correlated with local variations in neuronal density, which contradicts expectations that use-dependent self-organization would cause brain sites with more neurons to have higher capillary densities due to higher energetic demands. In fact, we show that the ratio of endothelial cells per neuron serves as a linear indicator of average blood flow and glucose use per neuron at rest, and both increase as neuronal density decreases across sites. In other words, because of the relatively tiny variation in capillary densities compared to the large variation in neuronal densities, the anatomical infrastructure of the brain is such that those sites with fewer neurons have more energy supplied per neuron, which matches a higher average rate of energy use per neuron, compared to sites with more neurons. Taken together, our data support the interpretation that resting brain metabolism is not demand-based, but rather limited by its capillary supply, and raise multiple implications for the differential vulnerability of diverse brain areas to disease and aging.

The present study aimed to evaluate the effects of Apelin–13 on scopolamine–induced memory impairment in rats. Forty male rats were divided into five groups of eight. The control group received no intervention; the scopolamine group underwent stereotaxic surgery and received 3 mg/kg intraperitoneal scopolamine. The treatment groups additionally received 1.25, 2.5 and 5 µg apelin–13 in right lateral ventricles for 7 days. All rats (except the control group) were tested for the passive avoidance reaction, 24 h after the last drug injection. For histological analysis, hippocampal sections were stained with cresyl violet; synaptogenesis biochemical markers were determined by immunoblotting. Apelin–13 alleviated scopolamine–induced passive avoidance memory impairment and neuronal loss in the rats' hippocampus (P<0.001). The reduction observed in mean concentrations of hippocampal synaptic proteins (including neurexin1, neuroligin, and postsynaptic density protein 95) in scopolamine–treated animals was attenuated by apelin–13 treatment. The results demonstrated that apelin–13 can protect against passive avoidance memory deficiency, and neuronal loss, induced by scopolamine in male rats. Further experimental and clinical studies are required to confirm its therapeutic potential in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract Anabolic substances have been increasingly used by bodybuilders and athletes with the goal of improving performance and aesthetics. However, this practice has caused some concern to physicians and researchers because of unknowledge of consequences that the indiscriminate and illicit use of these substances can cause. Thus, this study analyzed the effects of two commercially available anabolic steroids (AS), Winstrol Depot® (Stanozolol) and Deposteron® (Testosterone Cypionate), in the neuronal density of limbic, motor and sensory regions on the cerebral cortex and in CA1, CA2, CA3 regions of the hippocampus. A total of 60 Swiss mice were used (30 males and 30 females), separated into three groups: control and two experimental groups, which received the AAS. From each brain, homotypic and semi-serial samples were taken in frontal sections from areas established for the study. The results showed that females treated with testosterone cypionate presented a reduction in all regions tested and the ones treated with Stanozolol showed a decrease in some hippocampal areas. Regarding male animals, stanozolol led to a decrease in neuron number in one hippocampal region. These data allow us to conclude that supra-physiological doses of steroids used in this study, can cause considerable damage to nervous tissue with ultrastructural and consequently behavioral impairment. These changes could interfere with the loss of physical yield and performance of athletes and non-athletes and may cause irreparable damage to individuals making irresponsible use of anabolic steroids.

Lesions in the primary visual cortex (V1) cause extensive retrograde degeneration in the lateral geniculate nucleus, but it remains unclear whether they also trigger any neuronal loss in other subcortical visual centers. The inferior (IPul) and lateral (LPul) pulvinar nuclei have been regarded as part of the pathways that convey visual information to both V1 and extrastriate cortex. Here, we apply stereological analysis techniques to NeuN-stained sections of marmoset brain, in order to investigate whether the volume of these nuclei, and the number of neurons they comprise, change following unilateral long-term V1 lesions. For comparison, the medial pulvinar nucleus (MPul), which has no connections with V1, was also studied. Compared to control animals, animals with lesions incurred either 6 weeks after birth or in adulthood showed significant LPul volume loss following long (> 11 months) survival times. However, no obvious areas of neuronal degeneration were observed. In addition, estimates of neuronal density in lesioned hemispheres were similar to those in the non-lesioned hemispheres of same animals. Our results support the view that, in marked contrast with the geniculocortical projection, the pulvinar pathway is largely spared from the most severe long-term effects of V1 lesions, whether incurred in early postnatal or adult life. This difference can be linked to the more divergent pattern of pulvinar connectivity to the visual cortex, including strong reciprocal connections with extrastriate areas. The results also caution against interpretation of volume loss in brain structures as a marker for neuronal degeneration. [ABSTRACT FROM AUTHOR]

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Background and Aims: When a neuronal axon is damaged, it returns to the neuron cell body and destroys it. Tanacetum bodjnordens as antioxidant and anti-apoptotic effects. This study aimed to determine the neuroprotective effects of ethyl acetate and n-butanol and hydroalcoholic extracts of Tanacetum bodjnordens on sciatic nerve compression in male rats. Materials and Methods: In this experimental study, 36 male Wistar rats weighing 200-250 g were randomly divided into 6 groups) n=6). In the control group, the right thigh muscle of the rats was split after the anesthetization of the rats, while in the compression and treatment groups, the sciatic nerve was compressed for 60 seconds. The plant extract was injected intraperitoneally on the day of compression and seven days later. After 28 days, samples were taken from the lumbar spinal cord subsequent to performing the perfusion method. Afterward, 7-μm serial sections were prepared and stained using toluidine blue stain after tissue passage. Eventually, the neuronal density of rats in the six groups was compared. Results: Based on the results, the neuronal density in the compression group decreased significantly compared to controls and showed a significant increase in the hydroalcoholic, n-butanol, and aqueous phase treatment groups compared to that in the compression group (P<0.001). Conclusion: According to the results, it seems that Tanacetum bodjnordens leaf extract has neuroprotective effects that promote the regeneration process in damaged neurons and these effects are higher in the aqueous phase fraction. [ABSTRACT FROM AUTHOR]

• The human amygdaloid complex contains less parvalbumin interneurons than calretinin. • Parvalbumin neurons are abundant in the human basolateral group and its lateral nucleus. • Calretinin neurons are abundant and broadly distributed in the human amygdala. • Calretinin neurons abound in the corticomedial group of the human amygdaloid complex. • The amount of parvalbumin and calretinin neurons varies through the phylogenetic scale. The primate amygdaloid complex (AC) contains projection neurons as well as subsets of interneurons (IN), many of which express calcium-binding proteins, that through their local circuits control the activity of the projection neurons. The inhibitory parvalbumin (PV) and calretinin (CR)-positive (+) AC IN have a crucial role in the appearance of synchronized oscillations in local ensembles of projection neurons that mediate the consolidation and recall of fear memories. The GABAergic transmission of these subsets of IN is modulated by dopamine. To expand the knowledge regarding the cellular composition and distribution of IN in the human AC, we focused on two non-overlapping populations: the PV+ and CR+. We have analyzed the distribution of these IN throughout the AC from subjects without any neurological or psychiatric disorders and estimated their absolute number and density using stereological methods. We have also provided percentages of the IN with respect to the total AC neurons. The CR + IN were distributed throughout the AC, whereas the PV+ were only present in the basolateral nuclear group. The quantity of CR + IN was four times higher than that of PV+ and the percentages varied from less than 1% for PV + IN to 6–20% for CR+. The differences in quantity and distribution of CR+ and PV + IN could be related to their differential inhibitory properties and to the intrinsic and extrinsic connections of every amygdaloid region. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral small vessel disease. Previous neuroimaging studies have suggested loss of hippocampal volume is a pathway for cognitive impairment in CADASIL. We used unbiased stereological methods to estimate SMI32-positive and total numbers and volumes of neurons in the hippocampal formation of 12 patients with CADASIL and similar age controls (young controls) and older controls. We found densities of SMI32-positive neurons in the entorhinal cortex, layer V, and cornu ammonis CA2 regions were reduced by 26%–50% in patients with CADASIL compared with young controls (p < 0.01), with a decreasing trend observed in older controls in the order of young controls> older controls ≥ CADASIL. These changes were not explained by any hippocampal infarct or vascular pathology or glial changes. Our results suggest notable loss of subsets of projection neurons within the hippocampal formation that may contribute to certain memory deficits in CADASIL, which is purely a vascular disease. It is likely that the severe arteriopathy leads to white matter damage which disconnects cortico-cortical and subcortical-cortical networks including the hippocampal formation. • Hippocampal volume loss was associated with cognitive dysfunction in CADASIL. • SMI32+ neurons in entorhinal cortex (V) and CA2 regions were reduced in CADASIL. • Hippocampal cellular changes were not explained by any infarct pathology. • Neuronal volumes or glial cell numbers per neuron were not changed. • Selective loss of projection neurons within the hippocampal formation in CADASIL. [ABSTRACT FROM AUTHOR]

A variety of anatomical alterations have been reported in the hippocampal formation of patients with Alzheimer’s Disease (AD) and these alterations have been correlated with cognitive symptoms in the early stages of the disease. Major hallmarks in AD are the presence of paired helical filaments of tau protein (PHFTau) within neurons, also known as neurofibrillary tangles (NFTs), and aggregates of amyloid-β protein (Aβ) which form plaques in the extracellular space. Nevertheless, how the density of plaques and NFTs relate to the severity of cell loss and cognitive decline is not yet clear. The aim of the present study was to further examine the possible relationship of both Aβ plaques and NFTs with neuronal loss in several hippocampal fields (DG, CA3, CA1, and subiculum) of 11 demented AD patients. For this purpose, using stereological techniques, we compared neuronal densities (Nissl-stained, and immunoreactive neurons for NeuN) with: (i) numbers of neurons immunostained for two isoforms of PHFTau (PHFTau-AT8 and PHFTau-pS396); and (ii) number of Aβ plaques. We found that CA1 showed the highest number of NFTs and Aβ plaques, whereas DG and CA3 displayed the lowest number of these markers. Furthermore, AD patients showed a variable neuronal loss in CA1 due to tangle-related cell death, which seems to correlate with the presence of extracellular tangles.

Background and Objective: Brain is not able to produce new neurons by neurogenesis after maturity. Neurogenesis after the maturity was reported in Hippocampus and subventricular areas in the brain. Rosa canina L has various vitamins and other valuable compounds such as polyphenols, carotenoid, carbohydrates and fatty acids. This study was conducted to evaluate the effect of the alcoholic extract of the fruit of Rosa canina L plant on neuronal density of the hippocampus in animal model. Methods: In this experimental study 24 adult male mice were randomly allocated into 4 groups including: control and three treatent groups. Animals in treatment groups 1, 2 and 3 were received the alcoholic extract with extract with a dose of 25, 50, 75 mg/kg/bw intraperitoneally (IP), for 21 day continuously with an invertal of 24 hours, respectively. Animals in control group were received normal saline injection. One month after the first injection, the animals were anesthetized and brain gently was out of the skull. After processing, seven-micron serial sections were stained with blue toluidine and erythrosine. Different regions of the hippocampus were photographed and neuronal density was evaluated by stereological methods and was compared with control group. Results: The mean neuronal density of CA1 area of hippocampus in control and the treated group with a dose of 25, 50, 75 mg/kg/bw was 55±2, 70±3, 65±3 and 61±2, respectively. Neuronal density significantly increased in treatment group with dosage of 25 mg/kg/bw in compared to control group (P

The Kv3.1b potassium channel subunit, which facilitates the fast-spiking phenotype characteristic of parvalbumin (PV)-expressing inhibitory interneurons, is also expressed by subpopulations of excitatory neurons in macaque cortex. We have previously shown that V1 neurons expressing Kv3.1b but not PV or GABA were largely concentrated within layers 4Cα and 4B of V1, suggesting laminar or pathway specificity. In the current study, the distribution and pattern of co-immunoreactivity of GABA, PV, and Kv3.1b across layers in extrastriate cortical areas V2 and MT of the macaque monkey were measured using the same triple immunofluorescence labeling, confocal microscopy, and partially automated cell-counting strategies used in V1. For comparison, densities of the overall cell and neuronal populations were also measured for each layer of V2 and MT using tissue sections immunofluorescence labeled for the pan-neuronal marker NeuN. GABAergic neurons accounted for 14% of the total neuronal population in V2 and 25% in MT. Neurons expressing Kv3.1b but neither GABA nor PV were present in both areas. This subpopulation was most prevalent in the lowest subcompartment of layer 3, comprising 5% of the total neuronal population in layer 3C of both areas, and 41% and 36% of all Kv3.1b+ neurons in this layer in V2 and MT, respectively. The prevalence and laminar distribution of this subpopulation were remarkably consistent between V2 and MT and showed a striking similarity to the patterns observed previously in V1, suggesting a common contribution to the cortical circuit across areas. [ABSTRACT FROM AUTHOR]

Retrospective studies in human populations indicate that protein deprivation during pregnancy and early life (early protein malnutrition, EPM) is associated with cognitive impairments, learning disabilities and may represent a risk factor for the late onset of some psychiatric disorders, fundamentally schizophrenia, a condition where the prefrontal cortex plays an important role. The purpose of this study was to analyze whether EPM affects structural aspects of the rat medial prefrontal cortex (mPFC), such as cortical volume, neuronal density and neuronal soma size, which seem altered in patients with schizophrenia. For this, a rat model of EPM (5% casein from conception to postnatal day 60) was adopted and the rat mPFC volume, total number of neurons and average neuronal volume were evaluated on postnatal day 60 (post-pubertal animals) by histo- and immunohistochemical techniques using unbiased stereological analysis. EPM did not alter the number of NeuN+ neurons in the rat mPFC. However, a very significant decrease in mPFC volume and average neuronal size was observed in malnourished rats. Although the present study does not establish causal relationships between malnutrition and schizophrenia, our results may indicate a similar structural phenomenon in these two situations.

A variety of anatomical alterations have been reported in the hippocampal formation of patients with Alzheimer's Disease (AD) and these alterations have been correlated with cognitive symptoms in the early stages of the disease. Major hallmarks in AD are the presence of paired helical filaments of tau protein (PHFTau) within neurons, also known as neurofibrillary tangles (NFTs), and aggregates of amyloid-β protein (Aβ) which form plaques in the extracellular space. Nevertheless, how the density of plaques and NFTs relate to the severity of cell loss and cognitive decline is not yet clear. The aim of the present study was to further examine the possible relationship of both Aβ plaques and NFTs with neuronal loss in several hippocampal fields (DG, CA3, CA1, and subiculum) of 11 demented AD patients. For this purpose, using stereological techniques, we compared neuronal densities (Nissl-stained, and immunoreactive neurons for NeuN) with: (i) numbers of neurons immunostained for two isoforms of PHFTau (PHFTau-AT8 and PHFTau-pS396); and (ii) number of Aβ plaques. We found that CA1 showed the highest number of NFTs and Aβ plaques, whereas DG and CA3 displayed the lowest number of these markers. Furthermore, AD patients showed a variable neuronal loss in CA1 due to tangle-related cell death, which seems to correlate with the presence of extracellular tangles. [ABSTRACT FROM AUTHOR]

Background: Hippocampus organization is a part of temporal lobe, which consists of several sections including hippocampal body, dentate gyrus and subiculum. Panicum miliaceum L. contains proteins, vitamins and antioxidants for human health. This study was conducted to examine the effect of the alcoholic extract of the seed of Panicum miliaceum L. plant on hippocampus neuronal density. Materials and Methods: In this experimental study, 24 male mice were divided into 4 groups (n=6, each group). The alcoholic extract of the seed of the Panicum miliaceum L. plant was prepared by soxhlet extraction. Three doses of the extract 25, 50, 75 mg/kg were intraperitoneally injected to 3 treatment groups for 21 days and the control group received normal saline injection. At the end of the experiment, the animals were anesthetized and after perfusion, their brains were removed from the skull. After tissue processing, slices of the brain were prepared and stained. Then, different regions of the hippocampus were photographed and neuronal densities were evaluated. Results: Results showed that the neuronal density in the CA1, CA3 regions of the group treated with 50 mg/kg of the alcoholic extract and in all regions of hippocampus (CA1,CA2,CA3) in groups treated with dose of 75 mg/kg of the alcoholic extract had a significant increase compared to the control group (P

Alzheimer's disease is characterized by progressive memory loss caused from alterations in the central cholinergic system. While existing medications often have adverse effects, traditional use of Tiliacora triandra in Thailand shows its potential as a revitalizing neurotonic agent. This study explores the impact of T. triandra leaf extract on cognitive behaviors, neuronal density, and oxidative stress in male rats with scopolamine-induced cognitive impairment. Experimental groups composed of a control, vehicle, positive control meditation, and T. triandra extract-treated groups (100, 200, and 400 mg/kg BW) over 14 days, with scopolamine administration (i.p.) between days 8 and 14. Results showed significant enhancements in the discrimination ratio and spontaneous alteration behavior percentage during novel object recognition (NORT) and Y-maze tests for scopolamine-administered rats treated with T. triandra extract or donepezil. In contrast, open field test (OFT)-assessed spontaneous locomotor activity displayed no significant difference. Notably, acetylcholinesterase (AChE) activity and malondialdehyde (MDA) levels reduced significantly in scopolamine-treated rats with T. triandra extract or the positive control. Moreover, neuronal density in the hippocampal CA3 region, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities increased significantly. However, catalase (CAT) activity exhibited no significant difference. In conclusion, T. triandra leaf extract shows promise in mitigating scopolamine-induced memory deficits, potentially attributed to increased neuronal density, inhibited AChE activity, reduced MDA levels, and enhanced antioxidant activities. This extract has potential as a therapeutic agent for Alzheimer's disease-associated memory impairment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

In patients with temporal lobe epilepsy (TLE), presurgical magnetic resonance imaging (MRI) often reveals hippocampal atrophy, while neuropathological assessment indicates the different types of hippocampal sclerosis (HS). Different HS types are not discriminated in MRI so far. We aimed to define the volume of each hippocampal subfield on MRI manually and to compare automatic and manual segmentations for the discrimination of HS types. The T2-weighted images from 14 formalin-fixed age-matched control hippocampi were obtained with 4.7T MRI to evaluate the volume of each subfield at the anatomical level of the hippocampal head, body, and tail. Formalin-fixed coronal sections at the level of the body of 14 control cases, as well as tissue samples from 24 TLE patients, were imaged with a similar high-resolution sequence at 3T. Presurgical three-dimensional (3D) T1-weighted images from TLE went through a FreeSurfer 6.0 hippocampal subfield automatic assessment. The manual delineation with the 4.7T MRI was identified using Luxol Fast Blue stained 10-μm-thin microscopy slides, collected at every millimeter. An additional section at the level of the body from controls and TLE cases was submitted to NeuN immunohistochemistry for neuronal density estimation. All TLE cases were classified according to the International League Against Epilepsy's (ILAE's) HS classification. Manual volumetry in controls revealed that the dentate gyrus (DG)+CA4 region, CA1, and subiculum accounted for almost 90% of the hippocampal volume. The manual 3T volumetry showed that all TLE patients with type 1 HS (TLE-HS1) had lower volumes for DG+CA4, CA2, and CA1, whereas those TLE patients with HS type 2 (TLE-HS2) had lower volumes only in CA1 (p ≤ 0.038). Neuronal cell densities always decreased in CA4, CA3, CA2, and CA1 of TLE-HS1 but only in CA1 of TLE-HS2 (p ≤ 0.003). In addition, TLE-HS2 had a higher volume (p = 0.016) and higher neuronal density (p < 0.001) than the TLE-HS1 in DG + CA4. Automatic segmentation failed to match the manual or histological findings and was unable to differentiate TLE-HS1 from TLE-HS2. Total hippocampal volume correlated with DG+CA4 and CA1 volumes and neuronal density. For the first time, we also identified subfield-specific pathology patterns in the manual evaluation of volumetric MRI scans, showing the importance of manual segmentation to assess subfield-specific pathology patterns.

One of the hallmarks of Alzheimer's disease (AD) is extracellular deposition of amyloid-β peptides, particularly in the hippocampus. Despite the antioxidant properties of taurine, its neuroprotective potential against amyloid-β accumulation in scopolamine-induced AD model remain unclear. In such a model, we aimed to assess the effects of taurine on passive avoidance memory impairment, accumulation of congophilic amyloid-β plaques, and neuronal density in the rat hippocampus. Rats, except the control group, were i.p. injected with 3 mg/kg scopolamine. The pretreated and treated groups were also injected with taurine (25, 50, or 100 mg/kg/day, i.p.) for 14 days before or after scopolamine introduction. All rats (except the control group) were tested for the passive avoidance reaction 24 h after the last drug injection. For histological analysis, hippocampal sections were stained with Congo red and cresyl violet. Administration of taurine for 14 days, both before and after scopolamine injection, significantly alleviated passive avoidance memory impairment. Pretreatment with taurine in any of the mentioned dosages significantly decreased the number of congophilic amyloid-β plaques in the rat hippocampus, including the CA3 area. Taurine also reduced scopolamine-induced neuronal loss in the hippocampus. [ABSTRACT FROM AUTHOR]

Although traffic noise exposure is a well-known environmental pollutant whose negative health effect has been discussed in different aspects of the human life, only a few animal studies have tackled this issue as a cohort study, which is not feasible to be addressed in human studies. In addition to the deleterious impact of the daytime noise on well-being, chronic nocturnal noise can also disturb sleep and affects physical and mental health, but to date, little research has examined the neurobiological effects of light/dark cycles of traffic noise exposure. We investigated the effects of light/dark cycles and sex on the impact of chronic traffic noise exposure on mouse brain structure-function. The mice were randomly assigned to either one of two stress conditions or a control condition. Animals were exposed to traffic noise on either the light-cycle (LC) or dark-cycle (DC) for 30 days. Traffic noise exposure caused the hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, anxiety-like behavior, impairments in learning and memory, dysfunction in balance and motor coordination, and a reduction in variety of brain measures including a brain volume, medial prefrontal cortex (mPFC) area, cortical thickness, hippocampal volume, amygdala area, and the neural density in mPFC and dentate gyrus. All behavioral and brain measures revealed adverse effects of the chronic noise stress irrespective of the LC/DC exposure or sex. Our findings were a re-emphasis on the significance of noise prevention and mitigation strategies for public health. [ABSTRACT FROM AUTHOR]

Ischemic postconditioning renders brain tissue tolerant to brain ischemia, thereby alleviating ischemic brain injury. However, the exact mechanism of action is still unclear. In this study, a rat model of global brain ischemia was subjected to ischemic postconditioning treatment using the vessel occlusion method. After 2 hours of ischemia, the bilateral common carotid arteries were blocked immediately for 10 seconds and then perfused for 10 seconds. This procedure was repeated six times. Ischemic postconditioning was found to mitigate hippocampal CA1 neuronal damage in rats with brain ischemia, and up-regulate acid-sensing ion channel 2a expression at the mRNA and protein level. These findings suggest that ischemic postconditioning up-regulates acid-sensing ion channel 2a expression in the rat hippocampus after global brain ischemia, which promotes neuronal tolerance to ischemic brain injury.

Study of the developmental characteristics and mechanisms of senescence is an important field in brain aging research. The OXYS strain was selected from Wistar rats in Novosibirsk, and it serves as a rat model of accelerated aging. Previously, neurodegenerative processes and aberrant behavior were reported in experiments with adult OXYS rats. In our study, neurodevelopmental reflexes, neuronal density in the prefrontal cortex and hippocampus, and global DNA methylation in the hippocampus are compared between OXYS and WAG (Wistar Albino Glaxo) neonatal pups. The development of the righting, forelimb grasp, and cliff avoidance reflexes is delayed, and body weight gain was deferred in neonatal OXYS pups. Neuronal density in the hippocampus does not differ between one-day-old OXYS and WAG pups. On the sixth day, the neuronal density in OXYS pups is reduced in the CA2 hippocampal zone, augmented in CA3 and DG, and unchanged in CA1. Six-day-old OXYS pups have fewer and smaller pyramidal neurons in the prefrontal cortex as compared to WAG controls. Global DNA methylation levels in the hippocampus of OXYS newborns are significantly lower than in the WAG newborn pups. At the age of six days, the global DNA methylation level decreases in WAG pups, but does not change in OXYS pups. Thus, neonatal OXYS rats show delayed neurodevelopment accompanied by changes in the global DNA methylation pattern in the hippocampus and in neuronal density in the hippocampus and the prefrontal cortex. These changes may be related to accelerated senescence in adult OXYS rats. [ABSTRACT FROM AUTHOR]