Characterization of the effects of cannabinoid receptor deletion on energy metabolism in female C57BL mice.

Background: Despite the evidence that energy balance is regulated differently in females and that the endocannabinoid system is sexually dimorphic, previous studies on the endocannabinoid system and energy balance predominantly used male models. Here, we characterize the effects of cannabinoid receptor deletion on body weight gain and glucose metabolism in female C57BL mice. Methods: Female mice lacking the cannabinoid-1 receptor (CB1R-/-), cannabinoid-2 receptor (CB2R-/-), or both receptors (CB1R-/-/CB2R-/-) and wild-type (WT) mice were fed with a low (LFD; 10% of calories from fat) or high-fat diet (HFD; 45% of calories from fat) for six weeks. Results: Female WT mice fed with HFD gained significantly more weight than WT mice fed with LFD (p < 0.001). Similar pattern was observed for CB2/- mice fed with HFD compared to CB2R-/- mice fed with LFD (p < 0.001), but not for CB1R-/- fed with HFD vs. LFD (p = 0.22) or CB1R-/-/CB2R-/- fed with HFD vs. LFD (p = 0.96). Comparing the 4 groups on LFD, weight gain of CB1R-/- mice was greater than all other genotypes (p < 0.05). When fed with HFD, the deletion of CB1R alone in females did not attenuate weight gain compared to WT mice (p = 0.72). Female CB1R-/-/CB2R-/- mice gained less weight than WT mice when fed with HFD (p = 0.007) despite similar food intake and locomotor activity, potentially owing to enhanced thermogenesis in the white adipose tissue. No significant difference in weight gain was observed for female CB2R-/- and WT mice on LFD or HFD. Fasting glucose, however, was higher in CB2R-/- mice fed with LFD than all other groups (p < 0.05). Conclusion: The effects of cannabinoid receptor deletion on glucose metabolism in female mice were similar to previously published findings on male mice, yet the effects on body weight gain and thermogenesis were attenuated in CB1R-/- mice.

A cryptic natural variant allele of BYPASS2 suppresses the bypass1 mutant phenotype.

The Arabidopsis (Arabidopsis thaliana) BYPASS1 (BPS1) gene encodes a protein with no functionally characterized domains, and loss-of-function mutants (e.g. bps1-2 in Col-0) present a severe growth arrest phenotype that is evoked by a root-derived graft-transmissible small molecule that we call dalekin. The root-to-shoot nature of dalekin signaling suggests it could be an endogenous signaling molecule. Here, we report a natural variant screen that allowed us to identify enhancers and suppressors of the bps1-2 mutant phenotype (in Col-0). We identified a strong semi-dominant suppressor in the Apost-1 accession that largely restored shoot development in bps1 and yet continued to overproduce dalekin. Using bulked segregant analysis and allele-specific transgenic complementation, we showed that the suppressor is the Apost-1 allele of a BPS1 paralog, BYPASS2 (BPS2). BPS2 is one of four members of the BPS gene family in Arabidopsis, and phylogenetic analysis demonstrated that the BPS family is conserved in land plants and the four Arabidopsis paralogs are retained duplicates from whole genome duplications. The strong conservation of BPS1 and paralogous proteins throughout land plants, and the similar functions of paralogs in Arabidopsis, suggests that dalekin signaling might be retained across land plants.

Admission screening and cohort care decrease carbapenem resistant enterobacteriaceae in Vietnamese pediatric ICU's.

OBJECTIVES: To assess if admission screening for Carbapenem Resistant Enterobacteriaceae (CRE) and cohort care can reduce CRE acquisition (CRE colonization during hospital stay), Hospital Acquired Infections (HAI), hospital-stay, mortality, and costs in three Intensive Care Units (ICU's) at the Vietnamese National Children's Hospital. METHOD: CRE screening using rectal swabs and ChromIDCarbas elective culture at admission and if CRE negative, once weekly. Patients were treated in cohorts based on CRE colonization status. RESULTS: CRE colonization at baseline point-prevalence screening was 76.9% (103/134). Of 941 CRE screened at admission, 337 (35.8%) were CREpos. 694 patients met inclusion criteria. The 244 patients CRE negative at admission and screened > 2 times were stratified in 8 similar size groups (periods), based on time of admission. CRE acquisition decreased significant (OR - 3.2, p < 0.005) from 90% in period 2 (highest) to 48% in period 8 (last period). Patients with CRE acquisition compared to no CRE acquisition had a significantly higher rate of culture confirmed HAI, n = 20 (14%) vs. n = 2 (2%), longer hospital stays, 3.26 vs. 2.37 weeks, and higher total treatment costs, 2852 vs. 2295 USD. CONCLUSION: Admission CRE screening and cohort care in pediatric ICU's significantly decreased CRE acquisition, cases of HAI and duration of hospital-stay.

Theory, methods, and operational results of the Young Women's Health History Study: a study of young-onset breast cancer incidence in Black and White women.

PURPOSE: The etiology of young-onset breast cancer (BC) is poorly understood, despite its greater likelihood of being hormone receptor-negative with a worse prognosis and persistent racial and socioeconomic inequities. We conducted a population-based case-control study of BC among young Black and White women and here discuss the theory that informed our study, exposures collected, study methods, and operational results. METHODS: Cases were non-Hispanic Black (NHB) and White (NHW) women age 20-49 years with invasive BC in metropolitan Detroit and Los Angeles County SEER registries 2010-2015. Controls were identified through area-based sampling from the U.S. census and frequency matched to cases on study site, race, and age. An eco-social theory of health informed life-course exposures collected from in-person interviews, including socioeconomic, reproductive, and energy balance factors. Measured anthropometry, blood (or saliva), and among cases SEER tumor characteristics and tumor tissue (from a subset of cases) were also collected. RESULTS: Of 5,309 identified potentially eligible cases, 2,720 sampled participants were screened and 1,812 completed interviews (682 NHB, 1140 NHW; response rate (RR): 60%). Of 24,612 sampled control households 18,612 were rostered, 2,716 participants were sampled and screened, and 1,381 completed interviews (665 NHB, 716 NHW; RR: 53%). Ninety-nine% of participants completed the main interview, 82% provided blood or saliva (75% blood only), and SEER tumor characteristics (including ER, PR and HER2 status) were obtained from 96% of cases. CONCLUSIONS: Results from the successfully established YWHHS should expand our understanding of young-onset BC etiology overall and by tumor type and identify sources of racial and socioeconomic inequities in BC.

COVID-19 related muscle denervation atrophy.

COVID-19 has presented with a variety of manifestations including peripheral neurological symptoms. The most commonly associated peripheral neuropathies described with COVID-19 are Guillain-Barre syndrome and its variants as well as critical illness polyneuropathy. We report in this paper the distinct MRI findings of an unusual case of peripheral neuropathy associated with COVID-19. These findings are similar to those seen in Guillain-Barre syndrome or one of its variants, although differing from the classic condition in certain key clinical and radiological features.

Complexation by cysteine and iron mineral adsorption limit cadmium mobility during metabolic activity of Geobacter sulfurreducens.

Cadmium (Cd) adversely affects human health by entering the food chain via anthropogenic activity. In order to mitigate risk, a better understanding of the biogeochemical mechanisms limiting Cd mobility in the environment is needed. While Cd is not redox-active, Cd speciation varies (i.e., aqueous, complexed, adsorbed), and influences mobility. Here, the cycling of Cd in relation to initial speciation during the growth of Geobacter sulfurreducens was studied. Either fumarate or ferrihydrite (Fh) was provided as an electron acceptor and Cd was present as: (1) an aqueous cation, (2) an aqueous complex with cysteine, which is often present in metal stressed soil environments, or (3) adsorbed to Fh. During microbial Fe(iii) reduction, the removal of Cd was substantial (∼80% removal), despite extensive Fe(ii) production (ratio Fe(ii)total : Fetotal = 0.8). When fumarate was the electron acceptor, there was higher removal from solution when Cd was complexed with cysteine (97-100% removal) compared to aqueous Cd (34-50%) removal. Confocal laser scanning microscopy (CLSM) demonstrated the formation of exopolymeric substances (EPS) in all conditions and that Cd was correlated with EPS in the absence of Fe minerals (r = 0.51-0.56). Most notable is that aqueous Cd was more strongly correlated with Geobacter cells (r = 0.72) compared to Cd-cysteine complexes (r = 0.51). This work demonstrates that Cd interactions with cell surfaces and EPS, and Cd solubility during metabolic activity are dependent upon initial speciation. These processes may be especially important in soil environments where sulfur is limited and Fe and organic carbon are abundant.

Regulation of lipid metabolism in pancreatic beta cells by interferon gamma: A link to anti-viral function.

Interferons (IFN) have been shown to alter lipid metabolism in immune and some non-hematopoietic cells and this affects host cell response to pathogens. In type 1 diabetes, IFNγ acts as a proinflammatory cytokine that, along with other cytokines, is released during pancreatic beta cell autoinflammation and contributes to immune response and beta cell dysfunction. The hypothesis tested herein is that IFN modifies beta cell lipid metabolism and this is associated with enhanced anti-viral response and beta cell stress. Treatment of INS-1 cells with IFNγ for 6 to 24 h led to a dynamic change in TAG and lipid droplet (LD) levels, with a decrease at 6 h and an increase at 24 h. The later accumulation of TAG was associated with increased de novo lipogenesis (DNL), and impaired mitochondrial fatty acid oxidation (FAO). Gene expression results suggested that IFNγ regulates lipolytic, lipogenic, LD and FAO genes in a temporal manner. The changes in lipid gene expression are dependent on the classical Janus kinase (JAK) pathway. Pretreatment with IFNγ robustly enhanced anti-viral gene expression induced by the viral mimetic polyinosinic: polycytidylic acid (PIC), and this potentiating effect of IFNγ was markedly attenuated by inhibitors of DNL. The IFNγ-induced accumulation of lipid, however, was insufficient to cause endoplasmic reticulum (ER) stress. These studies demonstrated a non-canonical effect of IFNγ in regulation of pancreatic beta cell lipid metabolism that is intimately linked with host cell defense and might alter cellular function early in the progression to type 1 diabetes.

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model.

Aberrant expression of miRNAs in pancreatic islets is closely related to the development of type 1 diabetes (T1D). The aim of this study was to identify key miRNAs dysregulated in pancreatic islets during T1D progression and to develop a theranostic approach to modify their expression using an MRI-based nanodrug consisting of iron oxide nanoparticles conjugated to miRNA-targeting oligonucleotides in a mouse model of T1D. Isolated pancreatic islets were derived from NOD mice of three distinct age groups (3, 8 and 18-week-old). Total RNA collected from cultured islets was purified and global miRNA profiling was performed with 3D-Gene global miRNA microarray mouse chips encompassing all mouse miRNAs available on the Sanger miRBase V16. Of the miRNAs that were found to be differentially expressed across three age groups, we identified one candidate (miR-216a) implicated in beta cell proliferation for subsequent validation by RT-PCR. Alterations in miR-216a expression within pancreatic beta cells were also examined using in situ hybridization on the frozen pancreatic sections. For in vitro studies, miR-216a mimics/inhibitors were conjugated to iron oxide nanoparticles and incubated with beta cell line, ßTC-6. Cell proliferation marker Ki67 was evaluated. Expression of the phosphatase and tensin homolog (PTEN), which is one of the direct targets of miR-216a, was analyzed using western blot. For in vivo study, the miR-216a mimics/inhibitors conjugated to the nanoparticles were injected into 12-week-old female diabetic Balb/c mice via pancreatic duct. The delivery of the nanodrug was monitored by in vivo MRI. Blood glucose of the treated mice was monitored post injection. Ex vivo histological analysis of the pancreatic sections included staining for insulin, PTEN and Ki67. miRNA microarray demonstrated that the expression of miR-216a in the islets from NOD mice significantly changed during T1D progression. In vitro studies showed that treatment with a miR-216a inhibitor nanodrug suppressed proliferation of beta cells and increased the expression of PTEN, a miR-216a target. In contrast, introduction of a mimic nanodrug decreased PTEN expression and increased beta cell proliferation. Animals treated in vivo with a mimic nanodrug had higher insulin-producing functionality compared to controls. These observations were in line with downregulation of PTEN and increase in beta cell proliferation in that group. Our studies demonstrated that miR-216a could serve as a potential therapeutic target for the treatment of diabetes. miR-216a-targeting theranostic nanodrugs served as exploratory tools to define functionality of this miRNA in conjunction with in vivo MR imaging.

Diet-Induced Obesity in Cannabinoid-2 Receptor Knockout Mice and Cannabinoid Receptor 1/2 Double-Knockout Mice.

OBJECTIVE: Evidence suggests that cannabinoid-1 receptor (CB1R) activation is associated with increased food intake and body weight gain. Human epidemiological studies, however, show decreased prevalence of obesity in cannabis users. Given the overlapping and complementary functions of the cannabinoid receptors (CB1R and CB2R), mice lacking CB2R and mice lacking both CB1R and CB2R were studied. METHODS: A high-fat diet was used to study metabolic changes in male mice lacking CB2R (CB2-/- ) or lacking both CB1R and CB2R (double-knockout [CB-DKO]) compared with wild-type mice. RESULTS: When CB2-/- mice were maintained on a high-fat diet, their weight gain was not different from wild-type mice (gaining 19 and 21 g, respectively), whereas CB-DKO mice gained only 5 g. There were no significant differences in food intake or locomotor activity between the three groups. Respiratory exchange rate and heat production were elevated in CB-DKO mice, with upregulation of adipose tissue thermogenic genes. Glucose tolerance test and insulin levels indicated increased insulin sensitivity in CB-DKO mice, whereas CB2-/- displayed signs of impaired glucose clearance. CONCLUSIONS: These results indicate that lacking both CB1R and CB2R protected mice from diet-induced obesity, possibly through the prominent role of CB1R in obesity or through an interactive effect of both receptors.

Use of NanoICE for Procurement Achieves Better Cooling of Liver Grafts.

BACKGROUND: Rapid cooling at procurement after cross-clamping has been the cornerstone of organ preservation. NanoICE is a new form of ice that has emerged in the food industry and is providing more efficient cooling and preservation than regular ice. We hypothesize that the use of NanoICE will accelerate the cooling process of the allograft and will be able to maintain a steady low temperature without causing any significant histologic damage. METHODS: In this randomized pilot study, 14 pigs were used to study the liver core/surface cooling in a non-survival organ procurement operation. Animals were randomly assigned to 1 of 2 groups, each arm involving 7 pigs: (1) crushed-iced normal saline cooling method (control group) and (2) NanoICE cooling method (study group). Surface and core temperatures were measured with temperature probes, and liver biopsies were obtained before cross-clamping and 15 hours after preservation to assess for any evidence and degree of freezing injury. RESULTS: NanoICE was able to reduce and sustain lower core temperatures at 30 minutes, 60 minutes, and 15 hours, compared with crushed ice. The degree of histologic damage (reflecting cold injury) at 15 hours after flushing was not significantly different between the 2 methods. CONCLUSIONS: NanoICE cools the deeper liver parenchyma more quickly and sustains a cooler temperature than regular crushed ice without causing significantly histologic damage. Future research should focus on whether the effect of NanoICE has any impact on graft function and survival.

Improved recovery from spinal cord injury in rats with chronic parvovirus serotype-1a infection.

OBJECTIVES: A vendor informed us that rats shipped to us and used by us in a spinal cord contusion injury experiment were infected by rat parvovirus type 1a (RPV-1a). Our aim was therefore to determine whether this infection may have altered locomotor recovery or tissue pathology. SETTING: Stockholm, Sweden. METHODS: We induced a moderate contusion injury of the spinal cord in rats received from an (unknown to us) RPV-1a-contaminated facility. We compared the hind limb locomotor function between RPV-1a-infected rats and non-infected controls with the same spinal cord lesions, obtained before (historical control), as well as after infection (future controls). Histologically, we assessed spinal tissue sparing, astrocyte reactivity and the amount of macrophages/activated microglia. RESULTS: RPV-1a-infected rats had significantly better hind limb locomotor recovery compared with both 'historical' and 'future' controls. We also observed significantly better tissue sparing and axonal sparing around the injury site, as well as significant reductions in macrophages/activated microglia and astrocyte reactivity in the spinal cords of RPV-1a-infected rats. CONCLUSION: The results stress the importance of knowing the health status of animals used to study central nervous system trauma and support the notion that acquired infections, even if asymptomatic, may alter response to injury in mammals. Furthermore, the results demonstrate that virus infections may have positive effects on functional recovery after spinal cord injury and indicate that RPV-1a infection may be neuroprotective by dampening secondary damage.

Impact of alogliptin and pioglitazone on lipid metabolism in islets of prediabetic and diabetic Zucker Diabetic Fatty rats.

Prolonged exposure of pancreatic beta (ß) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of ß cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, ß cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARγ and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARγ and increased incretin action working in concert to restore GL/FFA cycle in ß cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for ß cell failure.

Pediatric emergency care capabilities of Indian Health Service emergency medical service agencies serving American Indians/Alaska Natives in rural and frontier areas.

INTRODUCTION: In the USA, the emergency medical services (EMS) system is vital for American Indians and Alaska Natives, who are disproportionately burdened by injuries and diseases and often live in rural areas geographically far from hospitals. In rural areas, where significant health disparities exist, EMS is often a primary source of healthcare providing a safety net for uninsured individuals or families who otherwise lack access to health-related services. EMS is frequently the first entry point for children and their families into the healthcare system. The Indian Health Service (IHS) supports the federally funded, tribally operated EMS agencies to help meet the affiliated American Indian and Alaska Natives' pre-hospital needs. While periodic assessments of state EMS agencies capabilities to care for children occur, it appears a systematic assessment of IHS EMS agencies in regards to children had not been previously conducted. METHODS: A consensus process, involving stakeholders, was used to identify topic areas for a survey for assessing the pediatric capabilities of IHS EMS. The survey was sent to 75 of 88 IHS EMS agency contacts. RESULTS: Sixty-one agencies (81%) responded. Nine agencies (15%) did not have a medical director. Agencies without a medical director were less likely to report the availability of online (p=0.1) or offline (p<0.01) pediatric medical direction. Half (51%) of the agencies had a mass casualties plan; however, 29% reported responding to a mass casualty incident, involving a large number of pediatric patients, that overwhelmed their service. Most agencies were well integrated with their state EMS system with almost all (95%) collecting EMS patient care data and 47% using national standard data elements. CONCLUSIONS: In some areas, IHS EMS agencies did not have the infrastructure to treat pediatric patients during day-to-day operations as well as disasters. Similar to operational challenges faced by rural EMS agencies, the IHS agencies lacked a medical director, were unable to provide pediatric continuing education, and were overwhelmed during mass casualty incidents. Moreover, the overall ratio of IHS EMS to service population is almost double that for other EMS agencies. In other areas, agencies were well integrated with their state EMS system. One possible solution to increase capabilities to care for pediatric patients is combining and sharing of common resources including medical directors with their state EMS systems and authorities.

The utility of imputed matched sets. Analyzing probabilistically linked databases in a low information setting.

OBJECTIVE: To compare results from high probability matched sets versus imputed matched sets across differing levels of linkage information. METHODS: A series of linkages with varying amounts of available information were performed on two simulated datasets derived from multiyear motor vehicle crash (MVC) and hospital databases, where true matches were known. Distributions of high probability and imputed matched sets were compared against the true match population for occupant age, MVC county, and MVC hour. Regression models were fit to simulated log hospital charges and hospitalization status. RESULTS: High probability and imputed matched sets were not significantly different from occupant age, MVC county, and MVC hour in high information settings (p > 0.999). In low information settings, high probability matched sets were significantly different from occupant age and MVC county (p < 0.002), but imputed matched sets were not (p > 0.493). High information settings saw no significant differences in inference of simulated log hospital charges and hospitalization status between the two methods. High probability and imputed matched sets were significantly different from the outcomes in low information settings; however, imputed matched sets were more robust. CONCLUSIONS: The level of information available to a linkage is an important consideration. High probability matched sets are suitable for high to moderate information settings and for situations involving case-specific analysis. Conversely, imputed matched sets are preferable for low information settings when conducting population-based analyses.

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Oral erlotinib, but not rapamycin, causes modest acceleration of bladder and hindlimb recovery from spinal cord injury in rats.

OBJECTIVES: Erlotinib and Rapamycin are both in clinical use and experimental inhibition of their respective molecular targets, EGFR and mTORC1, has improved recovery from spinal cord injury. Our aim was to determine if daily Erlotinib or Rapamycin treatment started directly after spinal contusion injury in rats improves locomotion function or recovery of bladder function. SETTING: Stockholm, Sweden. METHODS: Rats were subjected to contusion injuries and treated during the acute phase with either Erlotinib or Rapamycin. Recovery of bladder function was monitored by measuring residual urine volume and hindlimb locomotion assessed by open-field observations using the BBB rating scale as well as by automated registration of gait parameters. Body weights were monitored. To determine whether Erlotinib and Rapamycin inhibit the same signaling pathway, a cell culture system and western blots were used. RESULTS: Erlotinib accelerated locomotor recovery and slightly improved bladder recovery; however, we found no long-term improvements of locomotor function. Rapamycin did neither improved locomotor function nor bladder recovery. In vitro studies confirmed that Erlotinib and Rapamycin both inhibit the EGFR-mTORC1 signaling pathway. CONCLUSION: We conclude that none of these two drug regimes improved long-term functional outcome in our current model of spinal cord injury. Nevertheless, oral treatment with Erlotinib may offer modest temporary advantages, whereas treatment with Rapamycin does not.

Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons.

The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP-induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalo-cortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3mg/kg) on neural activation as reflected by transcriptional activation of c-fos in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-fos mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-fos mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-fos mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalo-cortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons.