Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice.

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.

Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model.

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We use quantitative mass spectrometry to carry out deep, unbiased proteomic profiling of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared with controls, SCZ and BP synapses show substantial and similar proteomic alterations. Network analyses reveal upregulation of proteins associated with autophagy and certain vesicle transport pathways and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. Some of the same pathways are similarly dysregulated in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered shared risk gene for SCZ and BP. Our work provides biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these disorders.

Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients.

Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disability [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? We monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. Grin2a and Akap11 mutants exhibited increased resting gamma power, attenuated auditory steady-state responses (ASSR) at gamma frequencies, and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. The EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients.

Daily rewiring of a neural circuit generates a predictive model of environmental light.

Behavioral responsiveness to external stimulation is shaped by context. We studied how sensory information can be contextualized, by examining light-evoked locomotor responsiveness of Drosophila relative to time of day. We found that light elicits an acute increase in locomotion (startle) that is modulated in a time-of-day-dependent manner: Startle is potentiated during the nighttime, when light is unexpected, but is suppressed during the daytime. The internal daytime-nighttime context is generated by two interconnected and functionally opposing populations of circadian neurons-LNvs generating the daytime state and DN1as generating the nighttime state. Switching between the two states requires daily remodeling of LNv and DN1a axons such that the maximum presynaptic area in one population coincides with the minimum in the other. We propose that a dynamic model of environmental light resides in the shifting connectivities of the LNv-DN1a circuit, which helps animals evaluate ongoing conditions and choose a behavioral response.

Obstetric and neonatal outcomes in women with epilepsy in Poland - a two-centre study.

AIM OF THE STUDY: To report pregnancy, delivery and perinatal outcomes in women with epilepsy seen in university clinics in Poland. Clinical rationale for the study. Women with epilepsy are reported to be at increased risk of adverse pregnancy and foetal outcomes. MATERIALS AND METHODS: The following data was collected in 171 pregnant women seen in two university epilepsy clinics: epilepsy characteristics and treatment, seizure frequency, pregnancy outcomes, perinatal outcomes, and feeding method. RESULTS: The mean age of patients at the time of delivery was 28.8 years, and most women were nulliparous. Almost 80% of patients were on monotherapy and the majority were prescribed antiepileptic drugs with low teratogenic potential. 53.8% of patients were seizure-free during pregnancy. Half of the cohort delivered by caesarean section and the majority delivered in term. Nearly all newborns scored > 7 Apgar points. Major congenital malformation was diagnosed in only one foetus. Any adverse pregnancy/neonatal outcome was found in 13% of patients. Two thirds of women reported breastfeeding at any time. CONCLUSIONS AND CLINICAL IMPLICATIONS: Almost 90% of women continued antiepileptic therapy during pregnancy. 46% of patients had epileptic seizures during pregnancy. Any adverse pregnancy/neonatal outcome was found in 13% of women with epilepsy. The majority of patients delivered healthy babies. Further studies are needed to find risk factors for adverse pregnancy/neonatal outcomes in women with epilepsy in Poland.

Ten-year follow-up after combined coronary artery bypass grafting and transmyocardial laser revascularization in patients with disseminated coronary atherosclerosis.

Coronary artery disease involving heavily calcified lesions has been associated with worse short- and long-term outcomes including increased mortality. This paper aims to evaluate long-term survival benefit when CABG + transmyocardial laser revascularization (TMLR) are performed on the hearts of patients with disseminated coronary atherosclerosis (DCA). This novel retrospective study was conducted between 1997 and 2002 and followed 86 patients with ischemic heart disease and severe DCA who underwent TMLR using a Holmium:YAG laser and/or CABG. There were 46 patients who had CABG plus TMLR on at least one heart wall ("combined therapy group") and 40 patients who had CABG or TMLR separately on at least one heart wall ("single therapy group"). For the whole group, actuarial survival at 10 years was 78.3% in the combined group compared to 72.5% in the single therapy group (p = 0.535). Ten-year survival in the combined vs. single therapy group for the anterior heart walls was 100 vs. 72.2% (p = 0.027). For the lateral and posterior heart walls were 73.7 vs. 73.3% (p = 0.97) and 84.2 vs. 72% (p = 0.27), respectively. Kaplan-Meier survival analysis showed benefit only for the anterior heart wall (F Cox test, p = 0.103). Single therapy procedures on all heart walls (odds ratio 1.736, p = 0.264) or on the anterior heart wall only (odds ratio 3.286, p = 0.279) were found to be predictors of 10-year late mortality. Combined therapy (TMLR + CABG) provides benefit for perioperative mortality and long-term survival only when provided on the anterior heart wall. For patients with disseminated coronary atherosclerosis, cardiac mortality was found to be increased when followed up 6 years later, regardless of the therapy applied.

SnapShot: Circadian Clock.

Most creatures on this planet possess an ability to anticipate upcoming events in the environment, courtesy of their circadian clocks. This allows them to prepare for those changes instead of being caught by surprise, which could mean the difference between life and death. In this SnapShot, we describe the basics of how the clock ticks.

How to predict the risk of postoperative complications after coronary artery bypass grafting in patients under 50 and over 80 years old. A retrospective cross-sectional study.

BACKGROUND: Coronary artery disease (CAD) remains the leading cause of death in developed countries, and there is an increasing number of both young and elderly patients requiring surgical treatment. Despite improvement of conventional risk stratification scores (EuroSCORE II, STS risk score), all of the calculations are estimated based on the typical population and the studies emphasise that the scales may need further investigation and modernisation because demographic changes of the population suffering from CAD are unavoidable. AIM: To characterise two increasing and challenging cohorts of patients undergoing coronary artery bypass grafting (CABG) and to identify preoperative risk factors for postoperative complications. METHODS: In the retrospective cross-sectional study, we analysed 388 patients ≥ 80 years old and 190 patients ≤ 50 years old, who underwent CABG consecutively at our Institution. Data were obtained from medical records. RESULTS: The vast majority of studied patients had commonly described risk factors for cardiovascular diseases, regardless of the age group. Diabetes was present in almost twice as many individuals in the older cohort, when compared to the EuroSCORE population. A similar observation was made for hypertension, which was more frequent in both age groups. Summarising all of the postoperative complications, at least one occurred significantly more frequently among the older group (10% vs. 20.9%, p = 0.001). The vast majority of major adverse cardiac and cerebrovascular events (MACCE) in the older group led to death (79.4%). Among patients ≥ 80 years old, higher New York Heart Association (NYHA) class (p = 0.001, OR 2.05 [1.34-3.12] for every next class) and renal failure (p = 0.02, OR 2.47 [1.16-5.25]) increased the MACCE rate, whereas higher left ven-tricular ejection fraction (LVEF) (p = 0.002, OR 0.81 [0.7-0.93] for every 5%) decreased the risk. Emergent admission was the only factor increasing the occurrence of any postoperative complications among patients ≤ 50 years old (p = 0.007, OR 3.63, 95% CI 1.37-9.62). On the other hand, among patients ≥ 80 years old, emergent admission was not associated with any postoperative complications. CONCLUSIONS: Young and old patients requiring CABG differ from the standard EuroSCORE population. Postoperative complications are more common among older patients, and MACCE is usually fatal in this age group. Individuals with risk factors for MACCE (higher NYHA class, renal failure, lower LVEF) should be carefully evaluated and qualified, and closely monitored post-surgery.

The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn.

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception.

Minimally invasive direct coronary artery bypass (MIDCAB) ­ safety assessment in own material.

Introduction: Minimally invasive direct coronary artery bypass (MIDCAB) allows achieving similar safety and efficacy, with markedly reduced post-operative length of stay when compared to conventional surgical revascularization. Despite promising results, a small number of minimally invasive procedures are performed in Poland. The aim of the study is to assess short- and long-term outcome of MIDCAB revascularization in order to evaluate the safety of the procedure. Materials and Methods: Retrospective observational study analyzing 38 consecutive patients who underwent MIDCAB procedure between 2014 to 2016 in the Department of Cardiovascular Surgery and Transplantology at the John Paul II Hospital, Kraków. Perioperative data was obtained from patient medical records and the median follow-up period valued 17.3 months. Results: No postoperative deaths and only 1 case of postoperative myocardial infarction were observed. Throughout the follow-up period, the survival rate and freedom from MACCE rate valued 100%, with only 1 case of repeated revascularization. Conclusions: Minimally invasive revascularization is a safe procedure which can be performed with excellent short- and long-term outcome in low-risk patients.

Minimally invasive coronary artery bypass as a safe method of surgical revascularization. The step towards hybrid procedures.

INTRODUCTION: Coronary artery disease is nowadays responsible for approximately 15% of hospitalizations in Poland. Minimally invasive coronary artery bypass (MIDCAB) represents an attractive alternative to a sternotomy, and at the same time provides better life quality and facilitates quick rehabilitation. AIM: To evaluate whether MIDCAB can be performed with similar early and mid-term results as off-pump coronary artery bypass (OPCAB) and therefore can be considered as a safe stage in hybrid revascularization. MATERIAL AND METHODS: In a retrospective cohort study, we analyzed 73 consecutive patients who underwent coronary artery bypass grafting (left internal mammary artery to left anterior descending artery) between 2013 and 2016 in the Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow. Thirty-eight (52.1%) MIDCAB and 35 (47.9%) OPCAB patients were enrolled. RESULTS: Short-term results did not significantly differ between groups and similar 30-day mortality was observed (MIDCAB 2.6% vs. OPCAB 2.9%, p = 1). The median follow-up period was 21 months. There were no statistical differences in terms of overall survival or cardiac mortality between groups (94.7% vs. 88.6%, p = 0.42; 2.6% vs. 2.9%, p = 1, respectively). The rate of hospitalization due to cardiac causes was similar in both groups (7.9% vs. 5.1%, p = 1) and there were no differences in current exacerbation of angina or heart failure, with median NYHA class I and CCS class I in both groups. CONCLUSIONS: Despite higher technical difficulty, MIDCAB procedures can be performed with similar safety results as OPCAB procedures. No differences in terms of mortality, repeat revascularization or recurrent angina are observed.

Risk factors for in-hospital mortality after coronary artery bypass grafting in patients 80 years old or older: a retrospective case-series study.

BACKGROUND: Age remains a significant and unmodifiable risk factor for cardiovascular diseases, and an increasing number of patients older than 80 years of age undergo Coronary Artery Bypass Grafting (CABG). Old age is also an independent risk factor for postoperative complications. The aim of this study is to describe the population of patients 80 years of age or older who underwent CABG procedure and to assess the mortality rate and risk factors for in-hospital mortality. METHODS: A retrospective case-series study analyzing 388 consecutive patients aged 80 years of age or older who underwent isolated CABG procedure between 2010 and 2014 in the Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow. RESULTS: In-hospital mortality stood at 7%, compared to 3.4% for all isolated CABG procedures at our Institution. In an univariate logistic regression analysis, risk factors for in-hospital mortality were as follows: NYHA class (p = 0.005, OR 1.95, 95% CI [1.23-3.1]), prolonged mechanical ventilation (p < 0.001, OR 7.08, 95% CI [2.47-20.3]), rethoracotomy (p = 0.04, OR 3.31, 95% CI [1.04-10.6]), duration of the procedure and ECC (for every 10 min p = 0.01, OR 1.01, 95% CI [1.0-1.01]; p = 0.03, OR 1.01, 95% CI [1.0-1.02], respectively), PRBC, FFP, and PLT transfusion (for every unit transfused p = 0.004, OR 1.42, 95% CI [1.12-1.8]; p = 0.002, OR 1.55, 95% CI [1.18-2.04]; p = 0.009, OR 1.93, 95% CI [1.18-3.14], respectively). Higher LVEF (p = 0.02, OR 0.97, 95% CI [0.94-0.99]) and LIMA graft implantation (p = 0.04, OR 0.36, 95% CI [0.13-0.98) decreased the in-hospital mortality. Death before discharge was more often observed in patients with multiple risk factors for cardiovascular diseases (0-2 -5.7%; 3-7.4%, 4-26.6%; p = 0.03). CONCLUSIONS: Older age is associated with higher in-hospital mortality after isolated CABG at our Institution. Risk stratification scores and individualized risk evaluation, centered on comorbidities, NYHA class and left ventricular function, should be assessed in all cases. Whenever suitable, LIMA grafts should be used. Prolonged procedure and ECC time worsen the short-term outcome. Elderly individuals should be closely monitored postoperatively and the care should be focused on excessive blood loss and respiratory failure.

Impact of Postoperative Bleeding on Short-Term Outcome in Patients After Orthotopic Heart Transplantation: A Retrospective Cohort Study.

BACKGROUND Orthotopic heart transplantation (HTX) remains the ultimate treatment option in patients with end-stage heart failure, endorsed by the European Society of Cardiology guidelines. The aim of the study is a complex evaluation of the postoperative bleeding after HTX and its influence on short-term outcome. MATERIAL AND METHODS A retrospective cohort study consisted of 53 patients (4 females and 49 males, median age 52.5 years, IQR 17 years) who underwent HTX in the Department of Cardiovascular Surgery and Transplantology of John Paul II Hospital in Krakow between 2007 and 2014. RESULTS The median chest tube output within first 24 hours after the surgery was 695 (550-870) mL. Bleeding decreased throughout the observation (p=0.000). The first postoperative hemoglobin level was a significant predictor of excessive blood loss (p=0.017). The volume of chest tube output increased the duration of mechanical ventilation (p=0.046) and the incidence of re-exploration after first 24 hours of observation (p=0.049). In patients with higher chest tube output, more packed red blood cells (PRBC), fresh frozen plasma (FFP), and platelet (PLT) transfusions were required (p=0.000, p=0.019, and p=0.000, respectively). Early rethoracotomy (within the first 24 hours post-surgery) increased the in-hospital mortality (p=0.021; OR 7.43 [1.36-40.64]). CONCLUSIONS The study demonstrates the importance of postoperative bleeding and bleeding complications for short-term outcome in our post-HTX cohort. Throughout the analysis, the first postoperative hemoglobin level was detected to be a significant predictor of postoperative blood loss.

Coronary Artery Disease in Young Adults: Who Needs Surgical Revascularization? A Retrospective Cohort Study.

BACKGROUND: Coronary artery disease (CAD) is a major cause of death and disability in developed countries. Despite the fact that prevalence accrues with age, an increasing number of young patients suffering from CAD is being observed worldwide. The aim of this study is to describe the population of young adults suffering from CAD and requiring coronary artery bypass grafting (CABG), and to assess early outcomes after the procedure. METHODS: A retrospective cohort study analyzed 190 consecutive patients aged ≤50 years old that underwent CABG between 2010 and 2014. Baseline characteristics and operative data were presented in the study. Postoperative complications, such as major adverse cardiac and cardiovascular events (MACCE), prolonged mechanical ventilation (>72 hours), bleeding requiring reexploration, sternal dehiscence, and others were assessed. RESULTS: A population comprising mostly overweight or obese males with a mean age of 46 ± 4.1 years was analyzed. Patients suffered mostly from three-vessel disease (81%), hypertension (74.7%), and had previous history of myocardial infarction (MI) (60%). The majority of patients had normal left ventricle ejection fraction (LVEF) (83.1%). 22.6% of cases were emergent procedures. Perioperative mortality was low (1%) and overall MACCE rate stood at 2.6%. Emergent surgery was associated with a higher incidence of postoperative complications (P = .007). The number of diseased vessels, LVEF, and CCS/NYHA class-on-admission was not associated with a higher incidence of postoperative complications (P > .05 for all). CONCLUSION: CAD in young patients remains an issue described insufficiently in the literature. Among our study cohort of younger patients undergoing CABG, the majority of the patients had multivessel disease and were slightly symptomatic with normal LVEF. Although the postoperative complication rate was low, the percentage of emergent surgeries was alarmingly high in this population. Consistent with the literature, we highlight the importance of CAD screening in the young population to detect subclinical disease, which might be treated therapeutically or operated electively.

Total arterial myocardial revascularization in patients over 70 years old - a new trend in coronary surgery in elderly.

Introduction: In modern society, civilization has extended the life expectancy of developed nations. The demographic analysis of Eurostat (European Statistical Office) predicts the increase of the population over 70 years old in Western Europe from 15.2% reported in 1995 to 19.5% in 2020. Undoubtedly, the incidence of cardiovascular diseases increases with age. Nowadays, they are the most commonly diagnosed disease, as well as the most common cause of death in patients over 70 years old. Therefore, a significant increase of surgeries in elderly patients, reaching up to 30%, is reported in cardiac surgery. As changes in operating technique are being observed, better outcomes of surgeries in elderly patients are being noted. With over 10 years of observation, more beneficial results are noted for arterial revascularization with usage of arterial grafts compared with venous ones. The aim of the study is to evaluate the safety of harvesting both internal mammary arteries and radial artery in CABG in patients over 70 years old and to analyze the incidence of major adverse cardiac and cerebrovascular events (MACCE) and other postoperative complications in this cohort. Materials and Methods: In a retrospective observational study we analyzed 101 cases, where TAMR was applied in patients aged 70 yo or older between 2003 to 2009 in the Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Kraków. Exclusion criteria included among others low left ventricular ejection fraction, high Euroscore, and accompanying valvular disease. Data was obtained from patient medical records. Baseline characteristics, intraoperative data and postoperative complications were assessed. All surgeries were performed in extracorporeal circulation and via median sternotomy. Results: In the study cohort, most patients suffered from multi-vessel disease (65.3%), and all required at least 2 bypass grafts. Left internal mammary artery (LIMA) was used in all cases, right internal mammary artery (RIMA) in 30.7%, and radial artery (RA) in 95% of surgeries. In 6.9% of individuals additional transmyocardial laser revascularization was applied due to disseminated coronary artery disease. The in-hospital mortality stood at 1.98%, however there were no cardiac deaths reported. The postoperative MACCE incidence was 6.94% due to 6 cases of myocardial infarction, and 1 case of acute stroke. The in-hospital mortality was 1.98%. Other postoperative complications occurred as follows: rethoracotomy (2.9%), blood products transfusions (69.3%), prolonged mechanical ventilation (9.9%), atrial fibrillation (15.8%), deep wound infection (3.96%), sternal dehiscence (1.98%). Conclusions: Technique of TAMR in coronary artery bypass grafting is a safe method in low-risk patients over 70 years old and can be performed with good short-term outcome. Further evaluation analyzing the long-term benefits in elderly patients of TAMR is warranted.

Nuclear Factor I-C acts as a regulator of hepatocyte proliferation at the onset of liver regeneration.

BACKGROUND & AIMS: Knockout studies of the murine Nuclear Factor I-C (NFI-C) transcription factor revealed abnormal skin wound healing and growth of its appendages, suggesting a role in controlling cell proliferation in adult regenerative processes. Liver regeneration following partial hepatectomy (PH) is a well-established regenerative model whereby changes elicited in hepatocytes lead to their rapid and phased proliferation. Although NFI-C is highly expressed in the liver, no hepatic function was yet established for this transcription factor. This study aimed to determine whether NFI-C may play a role in hepatocyte proliferation and liver regeneration. METHODS: Liver regeneration and cell proliferation pathways following two-thirds PH were investigated in NFI-C knockout (ko) and wild-type (wt) mice. RESULTS: We show that the absence of NFI-C impaired hepatocyte proliferation because of plasminogen activator I (PAI-1) overexpression and the subsequent suppression of urokinase plasminogen activator (uPA) activity and hepatocyte growth factor (HGF) signalling, a potent hepatocyte mitogen. This indicated that NFI-C first acts to promote hepatocyte proliferation at the onset of liver regeneration in wt mice. The subsequent transient down regulation of NFI-C, as can be explained by a self-regulatory feedback loop with transforming growth factor beta 1 (TGF-ß1), may limit the number of hepatocytes entering the first wave of cell division and/or prevent late initiations of mitosis. CONCLUSION: NFI-C acts as a regulator of the phased hepatocyte proliferation during liver regeneration.

Updating appetitive memory during reconsolidation window: critical role of cue-directed behavior and amygdala central nucleus.

When presented with a light cue followed by food, some rats simply approach the foodcup (Nonorienters), while others first orient to the light in addition to displaying the food-cup approach behavior (Orienters). Cue-directed orienting may reflect enhanced attentional and/or emotional processing of the cue, suggesting divergent natures of cue-information processing in Orienters and Nonorienters. The current studies investigate how differences in cue processing might manifest in appetitive memory retrieval and updating using a paradigm developed to persistently attenuate fear responses (Retrieval-extinction paradigm; Monfils et al., 2009). First, we examined whether the retrieval-extinction paradigm could attenuate appetitive responses in Orienters and Nonorienters. Next, we investigated if the appetitive memory could be updated using reversal learning (fear conditioning) during the reconsolidation window (as opposed to repeated unreinforced trials, i.e., extinction). Both extinction and new fear learning given within the reconsolidation window were effective at persistently updating the initial appetitive memory in the Orienters, but not the Nonorienters. Since conditioned orienting is mediated by the amygdala central nucleus (CeA), our final experiment examined the CeA's role in the retrieval-extinction process. Bilateral CeA lesions interfered with the retrieval-extinction paradigm-did not prevent spontaneous recovery of food-cup approach. Together, our studies demonstrate the critical role of conditioned orienting behavior and the CeA in updating appetitive memory during the reconsolidation window.

Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator.

The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer's, Parkinson's, Huntington's, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer's disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background and recurred on reintroduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds, indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.