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Gulf War illness (GWI) is a chronic, multi-symptom disorder that has impacted approximately one third of Gulf War veterans. GWI and its symptoms have been linked to the exposure to neurological chemicals, including the anti-nerve gas drug pyridostigmine bromide (PB) and the insecticide permethrin (PER), among others. Mouse models utilizing these chemicals have reported symptomology analogous to human GWI. These changes include behavioral and cognitive impairment, neuroinflammation and hippocampal pathogenesis. Disease modifying interventions that target these pathological components are desperately needed. Vagus nerve stimulation (VNS) is FDA approved for drug-resistant epilepsy and depression. VNS has also been used off-label to target a myriad of symptoms, some of which are encompassed within the Kansas and CDC definitions of clinical GWI symptomology. A GWI animal model in which mice are exposed to a daily injection of PB and PER for 10 consecutive days has been shown to exhibit cognitive impairment and hippocampal pathology. The purpose of this study was to determine if 2-4 weeks of continuous vagus nerve stimulation initiated at 32 weeks after exposure to PB and PER would improve cognitive performance and hippocampal pathology. The results of the study revealed that exposure to PB and PER produces long-term cognitive deficits and reduced hippocampal neurogenesis. The results also showed that the VNS treatment was anxiolytic, improved some aspects of pattern separation deficits, and mitigated the reduced hippocampal neurogenesis. Thus, VNS improves outcomes in a mouse model of GWI and should be examined as a potential therapeutic strategy for mitigating some symptomology associated with GWI.

The journal "Aging and Disease" has released a special issue focused on novel concepts in understanding the pathophysiology and treatment of neurological and neurodegenerative disorders. The special issue comprises review and original research articles discussing the various disease mechanisms and/or treatment updates on aging, mild cognitive impairment, dementia, acute stroke, pediatric stroke, super-refractory status epilepticus, reflex epilepsy, drug-resistant epilepsy, Parkinson's disease, and traumatic brain injury. This editorial discusses the highlights from these articles.

Following spinal cord injury, 18-26% of patients are diagnosed with depressive disorders, compared to 8-12% in the general population. As increased inflammation strongly correlates with depression in both animal and human studies, we hypothesized that the immune activation inherent to SCI could increase depression-like behavior. Thus, we proposed that reducing immune activation with minocycline, a microglial inhibitor, would decrease depression-like behavior following injury. Male Sprague-Dawley rats were given minocycline in their drinking water for 14 days following a moderate, mid-thoracic (T12) spinal contusion. An array of depression-like behaviors (social activity, sucrose preference, forced swim, open field activity) were examined prior to injury as well as on days 9-10, 19-20, and 29-30 post-injury. Peripheral cytokine levels were analyzed in serum collected prior to injury and 10 days post-injury. Hierarchical cluster analysis divided subjects into two groups based on behavior: depressed and not-depressed. Depressed subjects displayed lower levels of open field activity and social interaction relative to their not-depressed counterparts. Depressed subjects also showed significantly greater expression of pro-inflammatory cytokines both before and after injury and displayed lower levels of hippocampal neurogenesis than not-depressed subjects. Intriguingly, subjects who later showed depressive behaviors had higher baseline levels of the pro-inflammatory cytokine IL-6, which persisted throughout the duration of the experiment. Minocycline, however, did not affect serum cytokine levels and did not block the development of depression; equal numbers of minocycline versus vehicle-treated subjects appeared in both phenotypic groups. Despite this, these data overall suggest that molecular correlates of inflammation prior to injury could predict the development of depression after a physical stressor.

Background Traumatic brain injury (TBI) occurs in as many as 64–74 million people worldwide each year and often results in one or more post-traumatic syndromes, including depression, cognitive, emotional, and behavioral deficits. TBI can also increase seizure susceptibility, as well as increase the incidence of epilepsy, a phenomenon known as post-traumatic epilepsy (PTE). Injury type and severity appear to partially predict PTE susceptibility. However, a complete mechanistic understanding of risk factors for PTE is incomplete. Main body From the earliest days of modern neuroscience, to the present day, accumulating evidence supports a significant role for neuroinflammation in the post-traumatic epileptogenic progression. Notably, substantial evidence indicates a role for astrocytes, microglia, chemokines, and cytokines in PTE progression. Although each of these mechanistic components is discussed in separate sections, it is highly likely that it is the totality of cellular and neuroinflammatory interactions that ultimately contribute to the epileptogenic progression following TBI. Conclusion This comprehensive review focuses on the neuroinflammatory milieu and explores putative mechanisms involved in the epileptogenic progression from TBI to increased seizure-susceptibility and the development of PTE.

Acute toxicity of sodium nitrite (NaNO2) was assessed in chickens (Gallus gallus domesticus) and domestic mallard ducks (Anas platyrhynchos domestica) by oral gavage and in free-feeding trials with chickens, domestic mallard ducks, pigeons (Columba livia f. domestica), budgerigars (Melopsittacus undulates) and wētā (Family: Rhaphidophoridae). Free-feeding trials involved the presentation of toxic paste and pellet baits containing encapsulated NaNO2 developed for the control of common brushtail possums (Trichosurus vulpecula) and feral pigs (Sus scrofa). The oral gavage LD50 value for NaNO2 in solution was approximately 68.50 mg/kg (95% CI 55.00–80.00 mg/kg) for both chickens and ducks. In feeding trials, six out of 12 chickens consumed toxic paste bait and four of these birds consumed a lethal dose. When chickens consumed toxic paste bait, the LD50 value was approximately 254.6 mg/kg (95% CI 249.1–260.2 mg/kg). Of the other three species of birds presented with toxic baits only one duck consumed a...

Key teaching points •Malignant atrophic papulosis is a rare vasculopathy that may cause isolated cutaneous disease or severe, widespread disease involving the skin, gastrointestinal tract, central nervous system, and cardiovascular system. •Early skin lesions of malignant atrophic papulosis appear as multiple rose-colored papules that evolve over several weeks to form a scar with an atrophic, porcelain-white center surrounded by an inflamed, telangiectatic border. •Traditional therapeutic approaches appear to be ineffective, but new drugs, including eculizumab and treprostinil, have shown benefit in a small number of patients.

Gulf war illness (GWI), is a chronic multi-symptom illness that has impacted approximately one-third of the veterans who served in the 1990 to 1991 Gulf War. GWI symptoms include cognitive impairments (eg, memory and concentration problems), headaches, migraines, fatigue, gastrointestinal and respiratory issues, as well as emotional deficits. The exposure to neurological chemicals such as the anti-nerve gas drug, pyridostigmine bromide (PB), and the insecticide permethrin (PER), may contribute to the etiologically related factors of GWI. Various studies utilizing mouse models of GWI have reported the interplay of these chemical agents in increasing neuroinflammation and cognitive dysfunction. Astrocytes are involved in the secretion of neuroinflammatory cytokines and chemokines in pathological conditions and have been implicated in GWI symptomology. We hypothesized that exposure to PB and PER causes lasting changes to hippocampal astrocytes, concurrent with chronic cognitive deficits that can be reversed by cervical vagus nerve stimulation (VNS). GWI was induced in CD1 mice by injecting the mixture of PER (200 mg/kg) and PB (2 mg/kg), i.p. for 10 consecutive days. VNS stimulators were implanted at 33 weeks after GWI induction. The results show age-related cognitive alterations at approximately 9 months after exposure to PB and PER. The results also showed an increased number of GFAP-labeled astrocytes in the hippocampus and dentate gyrus that was ameliorated by VNS.

Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABAA) receptors. The inhibitory activity of GABAA receptor activation depends on low intracellular Cl−, which is achieved by the opposing regulation of Na+–K+–Cl− cotransporter 1 (NKCC1) and K+–Cl−–cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl− concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFβ expression was also increased after TBI and competitive antagonism of TGFβ reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFβ might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFβ, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway. Electronic supplementary material The online version of this article (doi:10.1007/s00429-016-1292-z) contains supplementary material, which is available to authorized users.

Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1 ), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents/mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sub-lethal uptake/accompanying bait shyness. It is recognized that the pharmacological profile of NRB is highly sensitive to its stereoisomeric composition, yet no comprehensive endeavor has been made to impart any stereochemical control in its manufacture. The effect of temperature/concentration/reaction solvent/Lewis acid on the Diels–Alder synthesis of NRB is investigated. An attempted stereoselective synthesis of key NRB precursor 2-fulvenylmethanol 4 is also described. Palatability/efficacy data in rats is reported for novel NRB batches 1a – 1e . Disappointingly, given the level of stereocontrol now available in the synthesis of NRB as a result of this research, no clear relationship between stereoisomeric composition and palatability was observed.

Traumatic brain injury (TBI) is a widespread epidemic with severe cognitive, affective, and behavioral consequences. TBIs typically result in a relatively rapid inflammatory and neuroinflammatory response. A major component of the neuroinflammatory response is astrocytes, a type of glial cell in the brain. Astrocytes are important in maintaining the integrity of neuronal functioning, and it is possible that astrocyte hypertrophy after TBIs might contribute to pathogenesis. The hippocampus is a unique brain region, because neurogenesis persists in adults. Accumulating evidence supports the functional importance of these newborn neurons and their associated astrocytes. Alterations to either of these cell types can influence neuronal functioning. To determine if hypertrophied astrocytes might negatively influence immature neurons in the dentate gyrus, astrocyte and newborn neurons were analyzed at 30 days following a TBI in mice. The results demonstrate a loss of radial glial-like processes extending through the granule cell layer after TBI, as well as ectopic growth and migration of immature dentate neurons. The results further show newborn neurons in close association with hypertrophied astrocytes, suggesting a role for the astrocytes in aberrant neurogenesis. Future studies are needed to determine the functional significance of these alterations to the astrocyte/immature neurons after TBI.

Traumatic Brain Injury (TBI) is the most frequent cause of death and disability in young adults and children in the developed world, occurring in over 1.7 million persons and resulting in 50,000 deaths in the United States alone. The Centers for Disease Control and Prevention estimate that between 3.2 and 5.3 million persons in the United States live with a TBI-related disability, including several neurocognitive disorders and functional limitations. Following the primary mechanical injury in TBI, literature suggests the presence of a delayed secondary injury involving a variety of neuroinflammatory changes. In the hours to days following a TBI, several signaling molecules and metabolic derangements result in disruption of the blood-brain barrier (BBB), leading to an extravasation of immune cells and cerebral edema. The primary, sudden injury in TBI occurs as a direct result of impact and therefore cannot be treated, but the timeline and pathophysiology of the delayed, secondary injury allows for a window of possible therapeutic options. The goal of this review is to discuss the pathophysiology of the primary and delayed injury in TBI as well as present several preclinical studies that identify molecular targets in the potential treatment of TBI. Additionally, certain recent clinical trials are briefly discussed to demonstrate the current state of TBI investigation.

Gulf war illness (GWI) is a chronic multi-symptom disease that afflicts 25-33% of troops that were deployed in the 1990-1991 Gulf War. GWI symptoms include cognitive, behavioral and emotional deficits, as well as migraines and pain. It is possible that exposure to Gulf War agents and prophylactics contributed to the reported symptomology. Pyridostigmine bromide (PB) and permethrin (PER) were given to protect from nerve gas attacks and insect vector born disease, respectively. Previous studies have demonstrated that 10 days of exposure to these chemicals can cause symptoms analogous to those observed in GWI, including impairment of long-term memory in mice. Other studies using this model have shown chronic neuroinflammation, and chronic neuroinflammation can lead to altered nociceptive sensitivity. At 10-weeks after the 10-day PB and PER exposure paradigm, we observed lowered nociceptive threshold on the Von Frey test that was no longer evident at 28 weeks and 38 weeks post-exposure. We further determined that vagus nerve stimulation, initiated at 38 weeks after exposure, restores the lowered nociceptive sensitivity. Therefore, stimulating the vagus nerve appears to influence nociception. Future studies are need to elucidate possible mechanisms of this effect.

Worldwide feral pigs threaten native biodiversity, agricultural production and pose a risk to biosecurity as potential disease vectors. In New Zealand, the management of feral pigs has long been restricted to hunting, trapping, fencing and limited poisoning with 1080, warfarin and phosphorus. Sodium nitrite (NaNO2) is commonly used at very low concentrations in the food industry. At high doses, NaNO2 induces methaemoglobinaemia in mammals restricting the transport of oxygen by the red blood cell and in toxic doses leads to central nervous system anoxia, lethargy and death. Pen and field trials with pigs have been undertaken with an encapsulated formulation of NaNO2, designed to overcome the bitter taste of NaNO2 and mixed into a palatable paste bait. In pen trials, eight out of nine pigs consumed a lethal dose of paste bait. The average time to death was 59.5 min (±23.96 SD); symptoms lasted an average of 42.13 min (±19.12 SD) and included pale extremities, lethargy and ataxia. In a field trial, 12 radio-collared feral pigs were baited with the toxic paste bait formulation in prototype bait stations, where 11 of the 12 pigs consumed a lethal dose. Encapsulated NaNO2 has potential as an additional tool for the management of feral pigs, particularly when shooting and hunting is not practical or possible. Data in these studies were used to register this bait as a vertebrate toxic agent for feral pig management in New Zealand. This represents the first known registration of NaNO2 worldwide for use as a vertebrate toxic agent.

BACKGROUND: Invasive mammalian pests have inflicted substantial environmental and economic damage on a worldwide scale. RESULTS:Overthelast30yearstherehasbeenminimalinnovationinthedevelopmentofnewcontroltools.Thedevelopmentof new vertebrate pesticides, for example, has been largely restricted due to the costly and time-consuming processes associated with testing and registration. CONCLUSION: In this article we discuss recent progress and trends in a number of areas of research aimed to achieve long-term population suppression or eradication of mammalian pest species. The examples discussed here are emerging from research being conducted in New Zealand, where invasive mammalian pests are one of the greatest threats facing the national environment and economy. c � 2013 Society of Chemical Industry

Annually, there are over 2 million incidents of traumatic brain injury (TBI) and treatment options are non-existent. While many TBI studies have focused on the brain, peripheral contributions involving the digestive and immune systems are emerging as factors involved in the various symptomology associated with TBI. We hypothesized that TBI would alter hepatic function, including bile acid system machinery in the liver and brain. The results show activation of the hepatic acute phase response by 2 hours after TBI, hepatic inflammation by 6 hours after TBI and a decrease in hepatic transcription factors, Gli 1, Gli 2, Gli 3 at 2 and 24 hrs after TBI. Bile acid receptors and transporters were decreased as early as 2 hrs after TBI until at least 24 hrs after TBI. Quantification of bile acid transporter, ASBT-expressing neurons in the hypothalamus, revealed a significant decrease following TBI. These results are the first to show such changes following a TBI, and are compatible with previous studies of the bile acid system in stroke models. The data support the emerging idea of a systemic influence to neurological disorders and point to the need for future studies to better define specific mechanisms of action.

Author(s): Eason, Charles; Shapiro, Lee; Ross, James; Murphy, Elaine; Ogilvie, Shaun; MacMorran, Duncan; Jackson, Michael; Irie, Kenji; Inder, Shane; Clout, Mick; Rennison, David; Brimble, Margaret | Abstract: Internationally, over the last 20 years the number of tools available for the control of small mammals has declined. Through the efforts of research we have bucked this trend and retained and developed new tools. Three new toxins have been extensively researched and registered, namely para-aminopropiophenone (PAPP) in 2011 for stoats and feral cats; zinc phosphide for possums in 2012; and encapsulated sodium nitrite (ESN) in 2013, for possums and feral pigs. The development of PAPP and ESN, coined red blood cell toxins, developed for humaneness, represent the first new vertebrate pesticides registered for field control of mammalian pests anywhere in the world for g30 years. Research on rodenticides including diphacinone with the additive cholecalciferol (D+C) and a palatable form of norbormide continues. A New Zealand EPA application for D+C was filed in June 2015. More effective killing systems are being researched, and the first successful field trials of resetting toxin delivery devices for possum and stoat control were completed in 2013 and 2014. Improved deployment strategies, integration of humane and selective toxins, lures of greater potency, and improved killing devices aided by species’ recognition will transform ground control for endangered species protection. Sodium fluoroacetate (1080) and other important tools have been retained as new tools are emerging from a research and development pipeline. It is important for the future of New Zealand’s biodiversity that this focused research continues and we continue to learn and advance new technologies. Our goals are shifting to enable reduction in density of rat, stoat, and possum populations to zero over large scales (i.e., elimination at landscape scale), and to hold these at zero through detection and response, including the use of new technologies for perimeter control as part of barrier systems for conservation.

Numerous animal models of epileptogenesis demonstrate neuroplastic changes in the hippocampus. These changes occur not only for the mature neurons and glia, but also for the newly generated granule cells in the dentate gyrus. One of these changes, the sprouting of mossy fiber axons, is derived predominantly from newborn granule cells in adult rats with pilocarpine-induced temporal lobe epilepsy. Newborn granule cells also mainly contribute to another neuroplastic change, hilar basal dendrites (HBDs), which are synaptically targeted by mossy fibers in the hilus. Both sprouted mossy fibers and HBDs contribute to recurrent excitatory circuitry that is hypothesized to be involved in increased seizure susceptibility and the development of spontaneous recurrent seizures (SRS) that occur following the initial pilocarpine-induced status epilepticus. Considering the putative role of these neuroplastic changes in epileptogenesis, a critical question is whether similar anatomic phenomena occur after epileptogenic insults to the immature brain, where the proportion of recently born granule cells is higher due to ongoing maturation. The current study aimed to determine if such neuroplastic changes could be observed in a standardized model of neonatal seizure-inducing hypoxia that results in development of SRS. We used immunoelectron microscopy for the immature neuronal marker doublecortin to label newborn neurons and their HBDs following neonatal hypoxia. Our goal was to determine whether synapses form on HBDs from neurons born after neonatal hypoxia. Our results show a robust synapse formation on HBDs from animals that experienced neonatal hypoxia, regardless of whether the animals experienced tonic-clonic seizures during the hypoxic event. In both cases, the axon terminals that synapse onto HBDs were identified as mossy fiber terminals, based on the appearance of dense core vesicles. No such synapses were observed on HBDs from newborn granule cells obtained from sham animals analyzed at the same time points. This aberrant circuit formation may provide an anatomic substrate for increased seizure susceptibility and the development of epilepsy.

Neurogenesis occurs in the adult mammalian brain in discrete regions related to olfactory sensory signaling and integration. The olfactory receptor cell population is in constant turn-over through local progenitor cells. Also, newborn neurons are added to the olfactory bulbs through a major migratory route from the subventricular zone, the rostral migratory stream. The olfactory bulbs project to different brain structures, including: piriform cortex, amygdala, entorhinal cortex, striatum and hippocampus. These structures play important roles in odor identification, feeding behavior, social interactions, reproductive behavior, behavioral reinforcement, emotional responses, learning and memory. In all of these regions neurogenesis has been described in normal and in manipulated mammalian brain. These data are reviewed in the context of a sensory-behavioral hypothesis on adult neurogenesis that olfactory input modulates neurogenesis in many different regions of the brain.

The black reaction allowed Golgi to describe with amazing detail the morphology of glial cells as well as their proximal location and intimate connections with neurons and blood vessels. Based on this location, Golgi hypothesized that glial cells were functional units in the nervous system and were not merely a structural support medium. Relatively recent advances have confirmed the importance of glial cells in nervous system function and disease. The occurrence of gliosis is considered the hallmark of damaged tissue. Gliosis can differentially influence disease development and it is a prevailing characteristic of temporal lobe epilepsy. Its presence in the epileptic hippocampi might contribute to hyperexcitability, the development of aberrant neurogenic changes and inflammatory processes related to seizures. Considering the accumulating data regarding the pathological role of glial cells in epilepsy, novel therapeutic approaches that target glial cells are being explored. Such therapeutic approaches directed to glial cells present a novel perspective for the management of refractory pathologies.

S100B promotes development and maturation in the mammalian brain. However, prolonged or extensive exposure can lead to neurodegeneration. Two important functions of S100B in this regard, are its role in the development and plasticity of the serotonergic neurotransmitter system, and its role in the cascade of glial changes associated with neuroinflammation. Both of these processes are therefore accelerated towards degeneration in disease processes wherein S100B is increased, notably, Alzheimer's disease (AD) and Down syndrome (DS). In order to study the role of S100B in this context, we have examined S100B overexpressing transgenic mice. Similar to AD and DS, the transgenic animals show a profound change in serotonin innervation. By 28 weeks of age, there is a significant loss of terminals in the hippocampus. Similarly, the transgenic animals show neuroinflammatory changes analogous with AD and DS. These include decreased numbers of mature, stable astroglial cells, increased numbers of activated microglial cells and increased microglial expression of the cell surface receptor RAGE. Eventually, the S100B transgenic animals show neurodegeneration and the appearance of hyperphosphorylated tau structures, as seen in late stage DS and AD. The role of S100B in these conditions is discussed.

The Vagus Nerve is a major component, in conjunction with the spleen, in modulating the systemic anti-inflammatory response. Adrenergic fibers of the splenic nerve innervate the spleen, where they stimulate a distinct population of memory T cells. These memory T cells subsequently release ACh, thereby reducing macrophage activation and inhibiting TNFα. Therefore this pathway, as it relates to the spleen, is a two-neuron circuit: initiating first in the dorsal motor nucleus of the Vagus, subsequently synapsing at the celiac ganglion, and finally synapsing on the memory T cells. There are additional lines of evidence demonstrating cholinergic modulation of immune cells in the spleen. For example emerging evidence supports a regulating role of the vagus nerve in mobilizing marginal zone B cells and their subsequent secretion of antibodies, heralding an innate immune response. However, a direct link between splenic B cell number and the vagus nerve has not been previously established. Therefore, we assessed the effects of a left unilateral vagotomy on total splenocytes and MHCII+/CD11+ B cells in the spleen 3 days after vagotomy. Results The results indicate that at 3 days after left unilateral vagotomy, there is a significant decrease in the overall number of splenocytes. The results also show that this vagotomy results in a trend toward a significant reduction in MHCII+/CD11+ B cells in the spleen. Conclusions Our conclusions based upon these results show that there is a direct influence of left vagus nerve innervation on the number of splenic B cells and that left vagotomy results in an overall decrease in either the proliferation of splenocytes in general including the B-cells, or in cell death of splenocytes including the B cells.

Microglia are found throughout the central nervous system, respond rapidly to pathology and are involved in several components of the neuroinflammatory response. Iba1 is a marker for microglial cells and previous immunocytochemical studies have utilized this and other microglial-specific antibodies to demonstrate the morphological features of microglial cells at the light microscopic level. However, there is a paucity of studies that have used microglial-specific antibodies to describe the ultrastructural features of microglial cells and their processes. The goal of the present study is to use Iba1 immuno-electron microscopy to elucidate the fine structural features of microglial cells and their processes in the hilar region of the dentate gyrus of adult Sprague-Dawley rats. Iba1-labeled cell bodies were observed adjacent to neurons and capillaries, as well as dispersed in the neuropil. The nuclei of these cells had dense heterochromatin next to the nuclear envelope and lighter chromatin in their center. Iba1-immunolabeling was found within the thin shell of perikaryal cytoplasm that contained the usual organelles, including mitochondria, cisternae of endoplasmic reticulum and Golgi complexes. Iba1-labeled cell bodies also commonly displayed an inclusion body. Iba1-labeled cell bodies gave rise to processes that often had a small side branch arise within 5 mum of the microglial cell body. These data showing "resting" Iba-1 labeled microglial cells in the normal adult rat dentate gyrus provide a basis for comparison with the morphology of microglial cells in disease and injury models where they are activated or phagocytotic.

Astrocyte and microglial activation occurs following seizures and plays a role in epileptogenesis. However, the precise temporal and spatial response to seizures has not been fully examined. The pilocarpine model of temporal lobe epilepsy was selected to examine glial changes following seizures because morphological changes in the hippocampus closely mimic the human condition. Astrocytic and microglial changes in the hippocampus were examined during the first 5 days after pilocarpine-induced seizures in rats by analyzing GFAP, Iba1 and S100B-immunolabeling in CA1, CA3, and the hilus. Also, 3-dimensional reconstructions of microglial cells from the hilus and granule cell layer were analyzed. Lastly, astrocyte hypertrophy was examined in the hilus using electron microscopy. At 1 day after seizures and continuing throughout the 5 days examined, hypertrophied Iba1-labeled microglial cells and glial fibrillary acidic protein (GFAP)-labeled astrocytes were observed. At 1 and 2 days after seizures, significantly greater Iba1 immunolabeling was observed in CA1, CA3, and the hilus. In addition, both the area of Iba1 labeled processes and the number of their endings were increased in the hilus beginning at 1 day after seizures. S100B-immunolabeling was significantly elevated in CA3 at 1 day, in CA3 and CA1 at 2 days, and in all three hippocampal regions at 3 days after seizures. Electron microscopy confirmed astrocytic hypertrophy and demonstrated astrocytic cell bodies in the location where glial endfeet normally appear on capillaries. The differential response patterns of astrocytes and microglial cells following pilocarpine-induced seizures may signify their detrimental role in neuroinflammation after seizures.

Newly generated neurons are continuously added to the olfactory epithelium and olfactory bulbs of adult mammals. Studies also report newly generated neurons in the piriform cortex, the primary cortical projection site of the olfactory bulbs. The current study used BrdU-injection paradigms, and in vivo and in vitro DiI tracing methods to address three fundamental issues of these cells: their origin, migratory route and fate. The results show that 1 day after a BrdU-injection, BrdU/DCX double-labeled cells appear deep to the ventricular subependyma, within the white matter. Such cells appear further ventral and caudal in the ensuing days, first appearing in the rostral piriform cortex of mice at 2 days after the BrdU-injection, and at 4 days in the rat. In the caudal piriform cortex, BrdU/DCX labeled cells first appear at 4 days after the injection in mice and 7 days in rats. The time it takes for these cells to appear in the piriform cortex and the temporal distribution pattern suggest that they migrate from outside this region. DiI tracing methods confirmed a migratory route to the piriform cortex from the ventricular subependyma. The presence of BrdU/NeuN labeled cells as early as 7 days after a BrdU injection in mice and 10 days in the rat and lasting as long as 41 days indicates that some of these cells have extended survival durations in the adult piriform cortex.

Neurogenesis persists in the adult rodent olfactory epithelium and olfactory bulbs. Recent studies suggest that neurogenesis might also occur in the adult rodent piriform cortex, the primary cortical projection site of the olfactory bulbs. To determine whether olfactory enrichment influences neurogenesis in the mouse piriform cortex, olfactory enrichment was used in combination with bromodeoxyuridine labeling. Quantification of the number of bromodeoxyuridine-labeled cells in the piriform cortex that double label for either the immature neuronal marker, doublecortin, or the mature neuronal marker, neuronal nuclei or NeuN, showed that olfactory enrichment increases the survival of newborn neurons in the piriform cortex. These results confirm that neurogenesis occurs in the piriform cortex of rodents and suggest that it may play a neuroplastic role there.

Neurogenesis in the subgranular zone of the dentate gyrus persists throughout the lifespan of mammals, and the resulting newly born neurons are incorporated into existing hippocampal circuitry. Seizures increase the rate of neurogenesis in the adult rodent brain and result in granule cells in the dentate gyrus with basal dendrites. Using doublecortin (DCX) immunocytochemistry to label newly generated neurons the current study focuses on the electron microscopic features of DCX-labeled cell bodies and dendritic processes in the dentate gyrus of rats with pilocarpine-induced epilepsy. At the base of the granule cell layer clusters of cells that include up to six DCX-labeled cell bodies were observed. The cell bodies in these clusters lacked a one-to-one association with an astrocyte cell body and its processes, a relationship that is typical for newly born granule cells in control rats. Also, DCX-labeled basal dendrites in the hilus had immature synapses while those in control rats lacked synapses. These results indicate that increased neurogenesis after seizures alters the one-to-one relationship between astrocytes and DCX-labeled newly generated neurons at the base of the granule cell layer. The data also suggest that the synapses on DCX-labeled hilar basal dendrites contribute to the persistence of hilar basal dendrites on neurons born after pilocarpine-induced seizures.

The granule cells of the dentate gyrus are a population of neurons continuously generated throughout life. In the rat, the morphological development of newly born granule cells generated in the adult share many similarities with granule cells generated during development. These include a specific migration pattern, orientation and progression of neurite outgrowth. It appears as though varied dendritic morphology occurs depending on the position of the granule cells within the granule cell layer. A hypothesis for granule cell migration and differentiation of their dendritic processes is proposed based on normal and epileptic rats. In this hypothesis, the granule cells are generated in the subgranular zone, and then they migrate into the granule cell layer. During this migration, the sequence of neurite outgrowth is described, where the newly born granule cell first sprouts rudimentary processes. One of these processes, the basal dendrite, is transiently present on developing rodent granule cells in rats. However, in seizure-induced rats the basal dendrite often fails to retract, which leads to the formation of hilar basal dendrites, and also perhaps, ectopic granule cells in the hilus. In this review, granule cell development is discussed with relevance to the creation of the recurrent excitatory circuitry in rodent models of temporal lobe epilepsy.

Previous studies showed that neurogenesis occurs in the dentate gyrus of the adult rodent. Recent evidence suggests that the resulting newly born neurons integrate into pre-existing hippocampal circuitry. Newly born neurons in the developing and adult dentate gyrus exhibit a transient basal dendrite. In adult pilocarpine-induced epileptic rats, basal dendrites persist and are ectopically located in the hilus where they receive synaptic input from mossy fiber axons. We hypothesize that these hilar basal dendrites are derived from newly born neurons that are born after the pilocarpine-induced seizures. To test this hypothesis, the length of basal dendrites from epileptic rats was compared with that from control rats using doublecortin immunocytochemistry, which labels newly born neurons and their processes for up to 3 weeks after their genesis. The data on hilar basal dendrites in pilocarpine animals indicate that those from newly born neurons are significantly longer than those found in the control rats. We also demonstrate that 20% of newly born neurons in the epileptic rat have a basal dendrite that enters the hilus at an angle greater than 30 degrees from its cell body as compared with2% in the control rats. Lastly, we provide evidence that the hilar basal dendrites in the epileptic rats are adjacent to glial fibrillary acidic protein-labeled astrocytic processes in the hilus and suggest that an ectopic glial scaffold in the hilus is involved with the formation of hilar basal dendrites. In conclusion, the data show that newly born neurons from epileptic rats have longer hilar basal dendrites and their formation might relate to gliosis which occurs as a result of hilar neuronal cell loss after status epilepticus.

S100B is a calcium-binding protein found within astroglial cells. When released, S100B has extracellular neurotrophic effects involving the neuronal cytoskeleton. The gene for S100B is located on chromosome 21 and levels of the protein are elevated in Down Syndrome (DS) and Alzheimer's Disease (AD). Thus, overexpression of S100B may be related to the cytoskeletal abnormalities seen in these disorders. Transgenic mice overexpressing human S100B were examined for cytoskeletal changes as young (70 days) and aged (200 days) adults, using immunochemical staining of the dendritic associated protein, MAP-2, the growth-associated protein-43 (GAP-43) and the dendritic spine marker, drebrin. As young adults, the S100B transgenic mice exhibited significantly greater MAP-2-immunoreactivity in the hippocampus, however as older adults, the animals exhibited less staining. In both the CD1 control animals and the S100B animals, the immunoreactivity of drebrin increased with age, however there were no significant between group differences. Finally, the older S100B animals showed more GAP-43 staining than the control animals, suggesting that synaptic remodeling could take place, possibly in response to the loss of MAP-2-ir dendrites. Overall, the data suggest that S100B overexpression leads to changes in cytoskeletal markers. The longitudinal effects of S100B overexpression are discussed with relevance to aging and pathology.