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Alzheimer's disease (AD) is the most prevalent form of dementia. Key AD symptoms include memory and cognitive decline; however, comorbid symptoms such as depression and sensory‐perceptual dysfunction are often reported. Among these, a deterioration of olfactory sensation is observed in approximately 90% of AD patients. However, the precise pathophysiological basis underlying olfactory deficits because of AD remains elusive. The olfactory glomeruli in the olfactory bulb (OB) receive sensory information in the olfactory processing pathway. Maintaining the structural and functional integrity of the olfactory glomerulus is critical to olfactory signalling. Herein, we conducted an in‐depth histopathological assessment to reveal detailed structural alterations in the olfactory glomeruli in AD patients. Fresh frozen post‐mortem OB specimens obtained from six AD patients and seven healthy age‐matched individuals were examined. We used combined immunohistochemistry and stereology to assess the gross morphology and histological alterations, such as those in the expression of Aβ protein, microglia, and neurotransmitters in the OB. Electron microscopy was employed to study the ultrastructural features in the glomeruli. Significant accumulation of Aβ, morphologic damage, altered neurotransmitter levels, and microgliosis in the olfactory glomeruli of AD patients suggests that glomerular damage could affect olfactory function. Moreover, greater neurodegeneration was observed in the ventral olfactory glomeruli of AD patients. The synaptic ultrastructure revealed distorted postsynaptic densities and a decline in presynaptic vesicles in AD specimens. These findings show that the primary olfactory pathway is affected by the pathogenesis of AD, and may provide clues to identifying the mechanism involved in olfactory dysfunction in AD. [ABSTRACT FROM AUTHOR]

The hypothalamus contains catecholaminergic neurons marked by the expression of tyrosine hydroxylase (TH). As multiple chemical messengers coexist in each neuron, we determined if hypothalamic TH‐immunoreactive (ir) neurons express vesicular glutamate or GABA transporters. We used Cre/loxP recombination to express enhanced GFP (EGFP) in neurons expressing the vesicular glutamate (vGLUT2) or GABA transporter (vGAT), then determined whether TH‐ir neurons colocalized with native EGFPVglut2‐ or EGFPVgat‐fluorescence, respectively. EGFPVglut2 neurons were not TH‐ir. However, discrete TH‐ir signals colocalized with EGFPVgat neurons, which we validated by in situ hybridization for Vgat mRNA. To contextualize the observed pattern of colocalization between TH‐ir and EGFPVgat, we first performed Nissl‐based parcellation and plane‐of‐section analysis, and then mapped the distribution of TH‐ir EGFPVgat neurons onto atlas templates from the Allen Reference Atlas (ARA) for the mouse brain. TH‐ir EGFPVgat neurons were distributed throughout the rostrocaudal extent of the hypothalamus. Within the ARA ontology of gray matter regions, TH‐ir neurons localized primarily to the periventricular hypothalamic zone, periventricular hypothalamic region, and lateral hypothalamic zone. There was a strong presence of EGFPVgat fluorescence in TH‐ir neurons across all brain regions, but the most striking colocalization was found in a circumscribed portion of the zona incerta (ZI)—a region assigned to the hypothalamus in the ARA—where every TH‐ir neuron expressed EGFPVgat. Neurochemical characterization of these ZI neurons revealed that they display immunoreactivity for dopamine but not dopamine β‐hydroxylase. Collectively, these findings indicate the existence of a novel mouse hypothalamic population that may signal through the release of GABA and/or dopamine. [ABSTRACT FROM AUTHOR]

Objectives: To determine the phenotype of the ventrolateral part of the periaqueductal gray matter neurons after bladder stimulation. Methods: In the experimental group, electrical stimulation of the bladder was carried out under freely moving condition by a bipolar stimulation electrode implanted in the bladder wall. Thereafter, the brain sections were processed for immunohistochemical analysis using antibodies against c‐Fos (neuronal activation marker) together with one of the following: tyrosine hydroxylase (dopaminergic cell marker), vesicular glutamate transporter (glutamatergic cell marker), serotonin, glutamate decarboxylase (glutamate decarboxylase 67, gamma‐aminobutyric acid cell marker) and neuronal nitric oxide synthase. We used design‐based confocal stereological analysis to quantify the immunohistochemically stained sections. Results: A significant increase in the number of c‐Fos‐positive cells in the ventrolateral part of the periaqueductal gray matter after stimulation was found. Furthermore, the ratio of c‐Fos cells double labeled with vesicular glutamate transporter was significantly higher in the ventrolateral part of the periaqueductal gray matter region in the stimulated compared with the sham group. Quantitative analysis of the other four cell types did not show any significant difference. Conclusion: These findings suggest that glutamatergic neurotransmission in the ventrolateral part of the periaqueductal gray matter is seemingly the main pathway to be activated after receiving sensory signals from the bladder. [ABSTRACT FROM AUTHOR]

Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60-7550, a selective phosphodiesterase type 2 inhibitor ( PDE2-I), presents memory-enhancing and anxiolytic-like properties. The behavioral effects of BAY 60-7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate ( cAMP) and cyclic guanosine monophosphate ( cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2-I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion ( BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze ( EZM), object location task ( OLT) and forced swim test ( FST). The effects of BAY 60-7550 were evaluated on neuronal nuclei (NeuN), caspase-9, cAMP response element-binding protein ( CREB), phosphorylated CREB ( pCREB) and brain-derived neurotrophic factor ( BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus-dependent cognitive function and induced despair-like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase-9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with BAY 60-7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, BAY 60-7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity. [ABSTRACT FROM AUTHOR]

With the growing use of selective serotonin reuptake inhibitor medications (SSRIs) for the treatment of depression during the perinatal period, questions have been raised about the longterm impact of these medications on development. We aimed to investigate how developmental SSRI exposure may alter affect-related behaviors and associated molecular processes in offspring using a rodent model of maternal stress and depression. For this purpose, prenatally stressed or non-stressed male offspring were exposed to fluoxetine (5 mg/kg/day) or vehicle, via lactation, until weaning. Primary results show that postnatal fluoxetine exposure differentially altered anxiety-like behavior by increasing anxiety in non-stressed offspring and decreasing anxiety in prenatally stressed offspring. In the hippocampus, developmental fluoxetine exposure decreased BDNF IV and TrkB mRNA expression. Prenatal stress alone also decreased escape behaviors and decreased hippocampal BDNF IV mRNA expression. These data provide important evidence for the long-term programming effects of early-life exposure to SSRIs on brain and behavior. [ABSTRACT FROM AUTHOR]

ABSTRACT Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 315-327, 2016. [ABSTRACT FROM AUTHOR]

The generation of complex three-dimensional bioengineered scaffolds that are capable of mimicking the molecular and topographical cues of the extracellular matrix found in native tissues is a field of expanding research. The systematic development of such scaffolds requires the characterisation of cell behaviour in response to the individual components of the scaffold. In the present investigation, we studied cell-substrate interactions between purified populations of Schwann cells and three-dimensional fibrin hydrogel scaffolds, in the presence or absence of multiple layers of highly orientated electrospun polycaprolactone nanofibres. Embedded Schwann cells remained viable within the fibrin hydrogel for up to 7 days (the longest time studied); however, cell behaviour in the hydrogel was somewhat different to that observed on the two-dimensional fibrin substrate: Schwann cells failed to proliferate in the fibrin hydrogel, whereas cell numbers increased steadily on the two-dimensional fibrin substrate. Schwann cells within the fibrin hydrogel developed complex process branching patterns, but, when presented with orientated nanofibres, showed a strong tendency to redistribute themselves onto the nanofibres, where they extended long processes that followed the longitudinal orientation of the nanofibres. The process length along nanofibre-containing fibrin hydrogel reached near-maximal levels (for the present experimental conditions) as early as 1 day after culturing. The ability of this three-dimensional, extracellular matrix-mimicking scaffold to support Schwann cell survival and provide topographical cues for rapid process extension suggest that it may be an appropriate device design for the bridging of experimental lesions of the peripheral nervous system. [ABSTRACT FROM AUTHOR]

Multiple models of human neuropsychiatric pathologies have been generated during the last decades which frequently use chronic dosing. Unfortunately, some drug administration methods may result in undesirable effects creating analysis confounds hampering model validity and preclinical assay outcomes. Here, automated analysis of floating behaviour, a sign of a depressive-like state, revealed that mice, subjected to a three-week intraperitoneal injection regimen, had increased floating. In order to probe an alternative dosing design that would preclude this effect, we studied the efficacy of a low dose of the antidepressant imipramine (7 mg/kg/day) delivered via food pellets. Antidepressant action for this treatment was found while no other behavioural effects were observed. We further investigated the potential efficacy of chronic dosing via food pellets by testing the antidepressant activity of new drug candidates, celecoxib (30 mg/kg/day) and dicholine succinate (50 mg/kg/day), against standard antidepressants, imipramine (7 mg/kg/day) and citalopram (15 mg/kg/day), utilizing the forced swim and tail suspension tests. Antidepressant effects of these compounds were found in both assays. Thus, chronic dosing via food pellets is efficacious in small rodents, even with a low drug dose design, and can prevail against potential confounds in translational research within depression models applicable to adverse chronic invasive pharmacotherapies. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10mg/kg/day. Results show that a fluoxetine dose of 5mg/kg/day, but not 10mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5mg dose compared to a 10mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 1369–1386. The Goodpasture antigen-binding protein (GPBP) and its splice variant the ceramide transporter (CERT) are multifunctional proteins that have been found to play important roles in brain development and biology. However, the function of GPBP and CERT is controversial because of their involvement in two apparently unrelated research fields: GPBP was initially isolated as a protein associated with collagen IV in patients with the autoimmune disease Goodpasture syndrome. Subsequently, a splice variant lacking a serine-rich domain of 26 amino acids (GPBPΔ26) was found to mediate the cytosolic transport of ceramide and was therefore (re)named CERT. The two splice forms likely carry out different functions in specific sub-cellular localizations. Selective GPBP knockdown induces extensive apoptosis and tissue loss in the brain of zebrafish. GPBP/GPBPΔ26 knock-out mice die as a result of structural and functional defects in endoplasmic reticulum and mitochondria. Because both mitochondria and ceramide play an important role in many biological events that regulate neuronal differentiation, cellular senescence, proliferation and cell death, we propose that GPBP and CERT are pivotal in neurodegenerative processes. In this review, we discuss the current state of knowledge on GPBP and CERT, including the molecular and biochemical characterization of GPBP in the field of autoimmunity as well as the fundamental research on CERT in ceramide transport, biosynthesis, localization, metabolism and cell homeostasis. [ABSTRACT FROM AUTHOR]

The aim of the study was to compare the localization of the nitric oxide (NO)-cGMP pathway in hippocampus of mice and rats using cGMP- and soluble guanylyl cyclase (GC) immunocytochemistry and in situ hybridization of the cGMP-hydrolysing phosphodiesterase types 2, 5 and 9. In vitro incubation of hippocampus slices in the absence of a guanylyl cyclase stimulator or a phosphodiesterase inhibitor resulted in cGMP-positive astrocytes mainly in the CA1 area in mouse slices. In contrast, no cGMP immunoreactivity was observed under these conditions in the rat hippocampus. Treatment with an NO synthase inhibitor or inhibitors of soluble or particulate GC did not abolish cGMP immunoreactivity in astrocytes. Incubation with the NO donors sodium nitroprusside or diethylamino NONOate, or with the NO-independent activators of soluble GC, YC-1 and BAY41-2272, in combination with phosphodiesterase inhibitors, resulted in an increase in cGMP immunoreactivity in numerous astrocytes throughout the mouse hippocampus. In contrast, under these conditions cGMP immunoreactivity was primarily observed in varicose fibers in rat hippocampus. Comparison of the cellular localization of the β1 subunit of soluble GC and the mRNAs of PDE2, PDE5 and PDE9 revealed that in both species the β1 subunit was observed in pyramidal and granule cells, which also expressed the mRNAs of the three phosphodiesterase families. Although the β1 subunit was observed in astrocytes, none of the phosphodiesterases were detected in these cells. We conclude that, although the expression profiles of the soluble GC β1 subunit and cGMP-hydrolysing phosphodiesterase mRNAs were identical, the cellular patterns of cGMP immunoreactivity differ between rat and mouse hippocampus. [ABSTRACT FROM AUTHOR]