Transgenic mouse models of tuberous sclerosis (TSC) develop renal cysts, cystadenomas, solid adenomas and carcinomas. Identification and characterisation of these lesions in vivo may help in TSC pre-clinical trials. This study was to evaluate T2 weighted MRI for assessment of renal lesions in two Tsc mouse models.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors in the mammalian genome. They are activated by a multitude of different ligands that elicit rapid intracellular responses to regulate cell function. Unsurprisingly, a large proportion of therapeutic agents target these receptors. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus are important mediators in homeostatic control. Many modulators of PVN/SON activity, including neurotransmitters and hormones act via GPCRs--in fact over 100 non-chemosensory GPCRs have been detected in either the PVN or SON. This review provides a comprehensive summary of the expression of GPCRs within the PVN/SON, including data from recent transcriptomic studies that potentially expand the repertoire of GPCRs that may have functional roles in these hypothalamic nuclei. We also present some aspects of the regulation and known roles of GPCRs in PVN/SON, which are likely complemented by the activity of 'orphan' GPCRs.

It has become widely accepted that the role of mast cells is not restricted to allergic processes. Thus, mast cells play an important role in innate and adaptive immune responses, but study of proteins related to differentiation of mast cells has not been done yet. Enolase 1 is a glycolytic enzyme expressed in most tissues and calreticulin, known as endoplasmic reticulum (ER) resident chaperon, has multifunctional responses. This study aimed to investigate the effects of these proteins on the differentiation and functions of mouse bone marrow-derived mast cells (BMMCs). To identify the target proteins related to the differentiation of BMMCs, we examined the protein expression pattern of BMMCs using 2-dimensional electrophoresis (2-DE) and MALDI-TOF analysis. Expressions of FcεRIα, surface molecules (c-kit, CD40, CD40L, VCAM-1), tryptase, and cytokines were examined in BMMCs using FACS analysis, Western blot, and RT-PCR respectively. Enolase 1 and calreticulin were transfected into BMMCs, and [Ca(2+)]i levels were determined by confocal microscope, while amounts of TNF-α and LTs were measured by ELISA. Eight proteins were identified by proteomic analysis. Enolase and calreticulin siRNA transfection inhibited the expressions of FcεRIα, surface molecules, tryptase, and cytokine mRNA, which are gradually enhanced during culture periods of BMMCs. Enolase 1 and calreticulin siRNA reduced the [Ca(2+)]i levels, amounts of total TNF-α, and the release of TNF-α and leukotrienes, all of which are increased in the BMMCs activated with antigen/antibody reaction. The data suggest that enolase 1 and calreticulin are important proteins in regulating the differentiation and functions of BMMCs.

The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide 3-kinase/AKT, signal transducer and activator of transcription 5 and extracellular signal-regulated kinase 1/2. In patients with CML, tyrosine kinase inhibitors (TKIs) are used to suppress the BCR-ABL tyrosine kinase, resulting in impressive response rates. However, resistance can occur, especially in acute-phase CML, through various mechanisms. Here, we show that the glucocorticoid-induced leucine zipper protein (GILZ) modulates imatinib and dasatinib resistance and suppresses tumor growth by inactivating the mammalian target of rapamycin complex-2 (mTORC2)/AKT signaling pathway. In mouse and human models, GILZ binds to mTORC2, but not to mTORC1, inhibiting phosphorylation of AKT (at Ser473) and activating FoxO3a-mediated transcription of the pro-apoptotic protein Bim; these results demonstrate that GILZ is a key inhibitor of the mTORC2 pathway. Furthermore, CD34(+) stem cells isolated from relapsing CML patients underwent apoptosis and showed inhibition of mTORC2 after incubation with glucocorticoids and imatinib. Our findings provide new mechanistic insights into the role of mTORC2 in BCR-ABL(+) cells and indicate that regulation by GILZ may influence TKI sensitivity.

We report a systems genetic analysis of high density lipoprotein (HDL) levels in an F2 intercross between inbred strains CAST/EiJ and C57BL/6J. We previously showed that there are dramatic differences in HDL metabolism in a cross between these strains, and we now report co-expression network analysis of HDL that integrates global expression data from liver and adipose with relevant metabolic traits. Using data from a total of 293 F2 intercross mice, we constructed weighted gene co-expression networks and identified modules (subnetworks) associated with HDL and clinical traits. These were examined for genes implicated in HDL levels based on large human genome-wide associations studies (GWAS) and examined with respect to conservation between tissue and sexes in a total of 9 data sets. We identify genes that are consistently ranked high by association with HDL across the 9 data sets. We focus in particular on two genes, Wfdc2 and Hdac3, that are located in close proximity to HDL QTL peaks where causal testing indicates that they may affect HDL. Our results provide a rich resource for studies of complex metabolic interactions involving HDL. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

The gene repertoire regulating vertebrate biomineralization is poorly understood. Dental enamel, the most highly mineralized tissue in mammals, differs from other calcifying systems in that the formative cells (ameloblasts) lack remodeling activity and largely degrade and resorb the initial extracellular matrix. Enamel mineralization requires that ameloblasts undergo a profound functional switch from matrix-secreting to maturational (calcium transport, protein resorption) roles as mineralization progresses. During the maturation stage, extracellular pH decreases markedly, placing high demands on ameloblasts to regulate acidic environments present around the growing hydroxyapatite crystals. To identify the genetic events driving enamel mineralization, we conducted genome-wide transcript profiling of the developing enamel organ from rat incisors and highlight over 300 genes differentially expressed during maturation. Using multiple bioinformatics analyses, we identified groups of maturation-associated genes whose functions are linked to key mineralization processes including pH regulation, calcium handling, and matrix turnover. Subsequent qPCR and Western blot analyses revealed that a number of solute carrier (SLC) gene family members were up-regulated during maturation, including the novel protein Slc24a4 involved in calcium handling as well as other proteins of similar function (Stim1). By providing the first global overview of the cellular machinery required for enamel maturation, this study provide a strong foundation for improving basic understanding of biomineralization and its practical applications in healthcare.

Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC(50) in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs.

Using resting state (RS) functional magnetic resonance imaging (fMRI), the connectivity patterns of the default mode (DMN), frontoparietal, executive, and salience networks were explored in 13 Alzheimer's disease (AD) patients, 12 amnestic mild cognitive impairment (aMCI) patients, and 13 healthy controls. Compared with controls and aMCI, AD was associated with opposing connectivity effects in the DMN (decreased) and frontal networks (enhanced). The only RS abnormality found in aMCI patients compared with controls was a precuneus connectivity reduction in the DMN. RS fMRI group differences were only partly related to gray matter atrophy. In AD patients, the mean executive network connectivity was positively associated with frontal-executive and language neuropsychological scores. These results suggest that AD is associated with an alteration of large-scale functional brain networks, which extends well beyond the DMN. In AD, the limited resources of the DMN may be paralleled, in an attempt to maintain cognitive efficiency, by an increased prefrontal connectivity. A medial parietal RS fMRI signal change seems to be present since the early phase of AD.

A high prevalence of intersex or testicular oocytes (TO) in male smallmouth bass within the Potomac River drainage has raised concerns as to the health of the river. Studies were conducted to document biomarker responses both temporally and spatially to better understand the influence of normal physiological cycles, as well as water quality and land-use influences. Smallmouth bass were collected over a 2-year period from three tributaries of the Potomac River: the Shenandoah River, the South Branch Potomac and Conococheague Creek, and an out-of-basin reference site on the Gauley River. The prevalence of TO varied seasonally with the lowest prevalence observed in July, post-spawn. Reproductive maturity and/or lack of spawning the previous spring, as well as land-use practices such as application of manure and pesticides, may influence the seasonal observations. Annual, seasonal, and site differences were also observed in the percentage of males with measurable concentrations of plasma vitellogenin, mean concentration of plasma vitellogenin in females, and plasma concentrations of 17β-estradiol and testosterone in both sexes. Bass collected in the South Branch Potomac (moderate to high prevalence of TO) had less sperm per testes mass with a lower percentage of those sperm being motile when compared to those from the Gauley River (low prevalence of TO). An inverse relationship was noted between TO severity and sperm motility. An association between TO severity and wastewater treatment plant flow, percent of agriculture, total number of animal feeding operations, the number of poultry houses, and animal density within the catchment was observed.

Trichothiodystrophy (TTD) is a rare, autosomal recessive nucleotide excision repair (NER) disorder caused by mutations in components of the dual functional NER/basal transcription factor TFIIH. TTD mice, carrying a patient-based point mutation in the Xpd gene, strikingly resemble many features of the human syndrome and exhibit signs of premature aging. To examine to which extent TTD mice resemble the normal process of aging, we thoroughly investigated the bone phenotype. Here, we show that female TTD mice exhibit accelerated bone aging from 39 weeks onwards as well as lack of periosteal apposition leading to reduced bone strength. Before 39 weeks have passed, bones of wild-type and TTD mice are identical excluding a developmental defect. Albeit that bone formation is decreased, osteoblasts in TTD mice retain bone-forming capacity as in vivo PTH treatment leads to increased cortical thickness. In vitro bone marrow cell cultures showed that TTD osteoprogenitors retain the capacity to differentiate into osteoblasts. However, after 13 weeks of age TTD females show decreased bone nodule formation. No increase in bone resorption or the number of osteoclasts was detected. In conclusion, TTD mice show premature bone aging, which is preceded by a decrease in mesenchymal stem cells/osteoprogenitors and a change in systemic factors, identifying DNA damage and repair as key determinants for bone fragility by influencing osteogenesis and bone metabolism.

Strontium (Sr) ralenate is a new agent used for the prevention and treatment of osteoporosis. As a bone-seeking element, 98% of Sr is deposited in the bone and teeth after oral ingestion. However, the effect of Sr treatment on bone microarchitecture and bone nanomechanical properties remains unclear. In this study, 18 osteoporotic goats were divided into four groups according to the treatment regimen: control, calcium alone (Ca), calcium and Sr at 24 mg/kg (Ca + 24Sr), and calcium and Sr at 40 mg/kg (Ca + 40Sr). The effects of Sr administration on bone microarchitecture and nanomechanical properties of trabecular bones were analyzed with micro-CT and nanoindentation test, respectively. Serum Sr levels increased six- and tenfold in the Ca + 24Sr and Ca + 40Sr groups, respectively. Similarly, Sr in the bone increased four- and sixfold in these two groups. Sr administration significantly increased trabecular bone volume fraction, trabecular thickness, and double-labeled new bone area. Sr administration, however, did not significantly change the nanomechanical properties of trabecular bone (elastic modulus and hardness). The data suggested that Sr administration increased trabecular bone volume and improved the microarchitecture while maintaining the intrinsic tissue properties in the osteoporotic goat model.

A progressive disintegration of the rest-activity rhythm has been observed in the R6/2 mouse model of Huntington's disease (HD). Rest-activity rhythm is controlled by a circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus, although SCN-independent oscillators such as the methamphetamine (MAP)-sensitive circadian oscillator (MASCO) can also control rhythmicity, even in SCN-lesioned animals. We aimed to test whether or not the administration of MAP could restore a normal rest-activity rhythm in R6/2 mice, via the activation of the MASCO. We administered chronic low doses of MAP to wild-type (WT) and presymptomatic (7-8 weeks) R6/2 mice, in constant darkness. As expected, ~40% of the WT mice expressed a rest-activity rhythm controlled by the MASCO, with a period of around 32 h. By contrast, the MASCO was missing from almost 95% of the R6/2 mice, even at early stages of disease. Interestingly, although the MASCO was deficient, initially MAP was able to stabilize the day/night activity ratio in R6/2 mice and delay the onset of disintegration of the rest-activity rhythm driven by the SCN. Furthermore, in presymptomatic R6/2 mice treated with L-DOPA, a MASCO-like component began to emerge, although this never became established. Our data show a major dysfunction of the MASCO in presymptomatic R6/2 mice that is likely to be due to an early abnormality of the catecholaminergic systems. We suggest that the dysfunction of the MASCO in humans could be partially responsible for circadian disturbances observed in HD patients, as well as patients with other neurological diseases in which both catecholaminergic and circadian abnormalities are present, such as Parkinson's disease and schizophrenia.

Prior studies have documented a range of brain changes that occur as a result of healthy aging as well as neural alterations due to profound dysregulation in vascular health such as extreme hypertension, cerebrovascular disease and stroke. In contrast, little information exists about the more transitionary state between the normal and abnormal physiology that contributes to vascular disease and cognitive decline. Specifically, little information exists with regard to the influence of systemic vascular physiology on brain tissue structure in older individuals with low risk for cerebrovascular disease and with no evidence of cognitive impairment. We examined the association between resting blood pressure and diffusion tensor imaging (DTI) indices of white matter microstructure in 128 healthy older adults (43-87 years) spanning the normotensive to moderate-severe hypertensive range. Mean arterial blood pressure (MABP) was related to diffusion measures in several regions of the brain with greatest associations in the anterior corpus callosum and lateral frontal, precentral, superior frontal, lateral parietal and precuneus white matter. Associations between white matter integrity and blood pressure remained when controlling for age, when controlling for white matter lesions, and when limiting the analyses to only normotensive, pharmacologically controlled and pre-hypertensive individuals. Of the diffusion measures examined, associations were strongest between MABP and radial diffusivity which may indicate that blood pressure has an influence on myelin structure. Associations between MABP and white matter integrity followed spatial patterns resembling those often attributed to the effects of chronological age, suggesting that systemic cerebrovascular health may play a role in neural tissue degeneration classically ascribed to aging. These results demonstrate the importance of the consideration of vascular physiology in studies of cognitive and neural aging, and that this significance extends to even the normotensive and medically controlled population. These data additionally suggest that optimal management of blood pressure may require consideration of the more subtle influence of vascular health on neural health in addition to the primary goal of prevention of a major cerebrovascular event.

Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia. Mice were fasted for 12 hours and then administered intraperitoneal insulin to induce a blood glucose nadir of 50 mg/dL at 0.75 hour after injection that by 2 hours postinjection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference, and novel object recognition were subsequently examined. Mice made hypoglycemic showed depressive-like behaviors 24 hours after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 hours after its resolution. By 48 hours posthypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST, as did the antiadrenergic agents phentolamine, metoprolol, and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 hours postadministration that subsequently resolved by 48 hours. These data indicate that, in mice, acute hypoglycemia through adrenergic pathways caused depressive-like behaviors that exist well beyond the resolution of hypoglycemia.

The serotonin 5-HT(2A) receptor belongs to the G-protein-coupled receptors (GPCRs) superfamily and mediates the hypertrophic response to serotonin (5-HT) in cardiac myocytes. At present the regulatory mechanisms of 5-HT(2A) receptor-induced myocyte hypertrophy are not fully understood. The localization and the compartmentation of GPCRs within specialized membrane microdomains are known to modulate their signalling pathway. Therefore, we hypothesized that caveolae microdomains and caveolin-3, the predominant isoform of cardiac caveolae, might be regulators of 5-HT(2A) receptor signalling. We demonstrate that 5-HT(2A) receptors interact with caveolin-3 upon 5-HT stimulation and traffic into caveolae membrane microdomains. We provide evidence that caveolin-3 knockdown abolishes the redistribution of 5-HT(2A) receptors into caveolae and enhances 5-HT(2A) receptor-induced myocyte hypertrophic markers such as cell size, protein synthesis and ANF gene expression. Importantly, we demonstrate that caveolin-3 and caveolae structures are negative regulators of 5-HT(2A) receptor-induced nuclear factor of activated T cells (NFAT) transcriptional activation. Taken together, our data demonstrate that caveolin-3 and caveolae microdomains are important regulators of the hypertrophic response induced by 5-HT(2A) receptors. These findings thus open new insights to target heart hypertrophy under the enhanced serotonin system. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

NADPH oxidase has recently been identified as a promising new therapeutic target in ALS. Genetic deletion of NADPH oxidase (Nox2) in the transgenic SOD1(G93A) mutant mouse model of ALS was reported to increase survival remarkably by 97 days. Furthermore, apocynin, a widely used inhibitor of NADPH oxidase, was observed to dramatically extend the survival of the SOD1(G93A) ALS mice even longer to 113 days (Harraz et al. J Clin Invest 118: 474, 2008). Diapocynin, the covalent dimer of apocynin, has been reported to be a more potent inhibitor of NADPH oxidase. We compared the protection of diapocynin to apocynin in primary cultures of SOD1(G93A)-expressing motor neurons against nitric oxide-mediated death. Diapocynin, 10 μM, provided significantly greater protection compared to apocynin, 200 μM, at the lowest statistically significant concentrations. However, administration of diapocynin starting at 21 days of age in the SOD1(G93A)-ALS mouse model did not extend lifespan. Repeated parallel experiments with apocynin failed to yield protection greater than a 5-day life extension in multiple trials conducted at two separate institutions. The maximum protection observed was an 8-day extension in survival when diapocynin was administered at 100 days of age at disease onset. HPLC with selective ion monitoring by mass spectrometry revealed that both apocynin and diapocynin accumulated in the brain and spinal cord tissue to low micromolar concentrations. Diapocynin was also detected in the CNS of apocynin-treated mice. The failure to achieve significant protection with either apocynin or diapocynin raises questions about the utility for treating ALS patients.

The objectives were to assess the potential of long-term prophylactic administration of telmisartan, an angiotensin II receptor antagonist and a partial peroxisome proliferator activator receptor (PPAR)γ agonist, in preventing the development of hypertension and hyperglycemia and to demonstrate the alteration in gene expression associated with the development of hyperglycemia and insulin resistance in Cohen-Rosenthal diabetic hypertensive rat, a unique model of hypertension and type 2 diabetes mellitus comorbidity. Cohen-Rosenthal diabetic hypertensive rats were continuously treated with telmisartan (3 mg/[kg d]) starting at age 6 to 8 weeks before developing hypertension or diabetes. Weight changes, blood pressure, blood insulin, adiponectin, glucose tolerance, and insulin sensitivity were monitored. Fat, liver, and muscle messenger RNAs were examined for the expression of genes potentially involved in the onset of insulin resistance. In addition to the expected antihypertensive effect of prophylactic telmisartan, diabetes was blunted, evidenced at the end of the study by a significantly lower glucose level. This was accompanied by improved glucose tolerance, increased sensitivity to insulin, reduction in fasting insulin levels and homeostasis model assessment index, as well as an increase in serum adiponectin. Telmisartan also prevented the increase in serum triglycerides and the associated appearance of lipid droplets in the liver. Diabetes induced tissue-specific changes in messenger RNAs expression of the following selected genes, which were restored by telmisartan treatment: PPARγ, PPARδ, PPARγ coactivator 1α, adiponectin, adiponectin receptor 1, adiponectin receptor 2, phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, adenosine monophosphate kinase, and glucose translocator 4. Telmisartan blunted the development of hypertension, insulin resistance, and diabetes in prediabetic Cohen-Rosenthal diabetic hypertensive rats through pleiotropic activity, involving specific gene regulation of target organs.

Neuroimaging studies have consistently shown functional brain abnormalities in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD). However, the extent to which these two disorders are associated with similar or distinct neural changes remains unclear. We conducted a systematic review of functional magnetic resonance imaging studies comparing BD and MDD patients to healthy participants using facial affect processing paradigms. Relevant spatial coordinates from twenty original studies were subjected to quantitative Activation Likelihood Estimation meta-analyses based on 168 BD and 189 MDD patients and 344 healthy controls. We identified common and distinct patterns of neural engagement for BD and MDD within the facial affect processing network. Both disorders were associated with increased engagement of limbic regions. Diagnosis-specific differences were observed in cortical, thalamic and striatal regions. Decreased ventrolateral prefrontal cortical engagement was associated with BD while relative hypoactivation of the sensorimotor cortices was seen in MDD. Increased responsiveness in the thalamus and basal ganglia were associated with BD. These findings were modulated by stimulus valence. These data suggest that whereas limbic overactivation is reported consistently in patients with mood disorders, future research should consider the relevance of a wider network of regions in formulating conceptual models of BD and MDD.

Mice with a dysfunctional myxovirus resistance-1 (dMx1) gene transport intranasally-instilled PR8 influenza virus to the olfactory bulb (OB) within 4 h post-infection. To determine if the presence of a functional Mx1 (fMx1) gene would influence this brain viral localization and/or disease, we infected mature C57BL/6 dMx1 and fMx1 mice under the same conditions and observed sickness behaviors, viral nucleoprotein (NP) RNA expression and innate immune mediator (IIM) mRNA expression in selected tissues at 15 and 96 h post-infection. Virus invaded the OB and lungs comparably in both sub-strains at 15 and 96 h as determined by nested PCR. In contrast, virus was present in blood and somatosensory cortex of dMx1, but not fMx1 mice at 96 h. At 15 h, sickness behaviors were comparable in both sub-strains. By 96 h dMx1, but not fMx1, were moribund. In both 15 and 96 h lungs, viral NP was significantly elevated in the dMx1 mice compared to the fMx1 mice, as determined by quantitative PCR. OB expression of most IIM mRNAs was similar at both time periods in both sub-strains. In contrast, lung IIM mRNAs were elevated in fMx1 at 15 h, but by 96 h were consistently reduced compared to dMx1 mice. In conclusion, functional Mx1 did not alter OB invasion by virus but attenuated illness compared to dMx1 mice. Inflammation was similar in OBs and lungs of both strains at 15 h but by 96 h it was suppressed in lungs, but not in OBs, of fMx1 mice.

To evaluate molecular signatures of an individual cell type in comparison to the associated region relevant towards understanding the pathogenesis of Alzheimer's disease (AD), CA1 pyramidal neurons and the surrounding hippocampal formation were microaspirated via laser capture microdissection (LCM) from neuropathologically confirmed AD and age-matched control (CTR) subjects as well as from wild type mouse brain using single population RNA amplification methodology coupled with custom-designed microarray analysis with real-time quantitative polymerase-chain reaction (qPCR) validation. CA1 pyramidal neurons predominantly displayed downregulation of classes of transcripts related to synaptic transmission in AD versus CTR. Regional hippocampal dissections displayed downregulation of several overlapping genes found in the CA1 neuronal population related to neuronal expression, as well as upregulation of select transcripts indicative of admixed cell types including glial-associated markers and immediate-early and cell death genes. Gene level distributions observed in CA1 neurons and regional hippocampal dissections in wild type mice paralleled expression mosaics seen in postmortem human tissue. Microarray analysis was validated in qPCR studies using human postmortem brain tissue and CA1 sector and regional hippocampal dissections obtained from a mouse model of AD/Down syndrome (Ts65Dn mice) and normal disomic (2N) littermates. Classes of transcripts that have a greater percentage of the overall hybridization signal intensity within single neurons tended to be genes related to neuronal communication. The converse was also found, as classes of transcripts such as glial-associated markers were under represented in CA1 pyramidal neuron expression profiles relative to regional hippocampal dissections. These observations highlight a dilution effect that is likely to occur in conventional regional microarray and qPCR studies. Thus, single population studies of specific neurons and intrinsic circuits will likely yield informative gene expression profile data that may be subthreshold and/or underrepresented in regional studies with an admixture of cell types.