The brain was placed in 30% sucrose solution for 48–72 hr and was coronally sliced in 30 μm thick sections using a vibratome. The sections were stained with fluorescent Nissl dye (Neurotrace) and mounted onto a slide. The brain sections were viewed under a confocal microscope and digital pictures of the slices were acquired. For visualizing the recorded locations, photographed slices were fit and overlaid

onto slices from a standard mouse brain (www.brainmaps.org). The tips of the tetrodes were identified visually and marked with red dots (Figure S4). All statistical measures were performed using R statistical software. Unpaired Student’s t tests were used for all inter-group comparisons and paired Student’s t tests were used for all intra-group comparisons. The error bars indicate standard error of means (SEM). For statistical significance p < 0.01 (∗∗) and p < 0.05 (∗) were Rapamycin used, t values

indicate values from two-tailed t test with alpha set to 0.5. Plots were made on R software and Excel spreadsheets. We would like to thank Deqi Yin for maintenance of HCN1 lines and Drs. Isabel Muzzio and Josh Dudman for their help and advice in initial experiments. We thank Pierre Trifilieff for help with histology and Raymond Skjerpeng for help with autocorrelation functions. We thank Edvard Moser, May-Britt Moser, and Charlotte Boccara for their invaluable help in training S.A.H., and E.M., M.M., Lisa Giocomo, and Pablo Jercog for their inputs to this manuscript. HIF-1 pathway This study was funded by grant MH80745 from the NIH, the Mathers Charitable Foundation and HHMI. S.A.H., S.A.S., and E.R.K. planned

the main experiments and science analyses. S.A.H. performed the in vivo experiments and their analyses. S.J.T. and K.A.K. designed the ex vivo experiments and analyses. K.A.K. performed the ex vivo experiments and their analyses. S.A.H. wrote the manuscript with inputs from K.A.K., S.J.T., S.A.S., and E.R.K. Discussion was jointly written by S.A.H., S.A.S., and E.R.K. “
“Systems-level neuroscience has progressively advanced from descriptive approaches toward those that provide a more mechanistic understanding of the relationship between neural activity and behavior. A paradigmatic example is the characterization of a reward prediction error (RPE) emitted by dopaminergic activity, which provides the strongest link yet between computational explanations of behavior and neural data (Schultz et al., 1997). RPE theory derives from computational accounts of reinforcement learning that specify how an agent comes to learn the values of different actions and stimuli in a complex environment (Sutton and Barto, 1998). One such account, temporal difference (TD) learning, describes how predictive stimuli are associated with later rewards via the propagation of an error function through successive states, or time steps.

Spine

volumes, densities, and turnover rates were analyzed in 3D using custom software. Because spine addition rates can vary between cultures and experimental Doxorubicin price days, spine addition rates are reported as a percent of matched controls (calculated using all spines gained in the three posttreatment time points). Absolute spine addition and loss rates for all experiments are documented in Table S1. We prepared 1,000× stocks by dissolving MG132 (A.G. Scientific) and KN-93 (Tocris) in DMSO and bicuculline (Tocris), lactacystin (EMD Biochemicals), myristoylated PKI 14–22 amide (Tocris), Rp-cAMPS (Tocris), and CPP (Sigma) in water. Vehicle controls were matched in identity and volume to that in which the inhibitor was dissolved. When two drugs were applied, the vehicle consisted of the sum of the vehicles for both drugs. Slices were imaged at 30°C in magnesium-free ACSF containing 5 mM MNI-caged-glutamate. Image stacks were acquired immediately before and after the uncaging stimulus, which consisted of 50 pulses (720 nm, ∼12 mW at the sample) of 4 ms duration delivered at 5 Hz by parking

the beam at a point ∼0.5 μm from the edge of a secondary or tertiary apical dendrite. No more than four uncaging trials were performed on the same neuron. The success rate of de novo spine outgrowth was determined by two blind evaluators. Comparison of success rate across conditions was made by Fisher’s selleck exact test. Error bars represent standard error of the mean and significance was set at p = 0.05 (two-tailed t test, unless otherwise noted). All statistics were calculated across cells. ∗p < 0.05 and ∗∗p <

0.001. We thank Judy Callis, Aldrin Gomes, and Jim Trimmer for advice and reagents; Lauren Boudewyn, Julie Heiner, and Sarah Mikula for help with experiments and analysis; and Elva Diaz, Jim Trimmer, and Georgia Woods for critical reading of the manuscript. This work was supported by a Burroughs Wellcome Career Award in the Biomedical Sciences (K.Z.), an NSF CAREER Award (0845285 K.Z. and H.V.R.), and the NIH (T32GM007377 A.M.H.; MARC-GM083894 H.V.R.; NS062736 K.Z., A.M.H., Sitaxentan and H.V.R.; NS054732 G.N.P.; AG017502 J.W.H. and I.S.S.). H.V.R. was a participant in the BUSP Program (supported by NIH-IMSD GM056765, HHMI 52005892). “
“Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG expansion in exon 1 of the huntingtin gene (Huntington’s Disease Collaborative Research Group, 1993). This mutation translates into an elongated glutamine tract in the N terminus of the huntingtin protein. Patients with HD display progressive movement dysfunction, including hyperkinetic involuntary movements, chorea, and dystonia, as well as cognitive impairments. Presently, there is no effective treatment for HD. The majority of potential therapies now under development are aimed at ameliorating symptoms of one of several proposed molecular consequences of mutant huntingtin, i.e.