Restoration of Intrinsic Inhibition in the PFC to Prevent Relapse to Cocaine Seeking

Reward learning involves burst firing of midbrain dopamine neurons in the Ventral Tegmental Area (VTA). The resulting dopamine release from VTA terminals instructs regions like the prefrontal cortex (PFC) about rewards and reward-related cues. Glutamatergic PFC neurons initiate motivated behaviors via innervation of the nucleus accumbens. Chronic use of drugs of abuse such as cocaine disrupts this natural reward pathway, leading to enduring cellular adaptations in dopaminergic signaling that contribute to relapse vulnerability. However, how dopamine modulates activity in this circuitry is not known. We posit that dopamine release from VTA terminals gates intrinsic inhibition in the PFC via a dopamine D1 receptor mediated reduction in potassium channel function. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these receptors, increasing D1 receptor activation and the subsequent activation of intracellular signaling cascades. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, resulting in long–lasting reductions in intrinsic inhibition that contribute to drug-seeking in response to cues. We test this hypothesis using the extinction–reinstatement rodent model of cocaine addiction. This in vivo protocol resembles the human condition, in that exposure to drug-associated cues induces drug-seeking behavior. In combination with in situ electrophysiology, chemogenetics, optogenetics, and retrograde tracing, we show that activation of VTA terminals reduces intrinsic inhibition in accumbens core-projecting prelimbic (PL) PFC cells. Operant cocaine self-administration renders PL cells hypersensitive to depolarization via elevated D1 receptor signaling, resulting in calcium store dependent desensitization of inhibitory Kv7 potassium channels and an enduring reduction in intrinsic inhibition. The deficit in Kv7 function and intrinsic inhibition is overcome by pharmacological stabilization of Kv7 channels with retigabine, which when microinjected into the PL reduces cue-induced reinstatement of cocaine-seeking. These studies underscore the significance of dopamine modulation of intrinsic inhibition in accumbens-projecting PL neurons as a mediator of relapse to drug seeking, and offer Kv7 as a potential novel drug target for cocaine addiction

SU(N) quantum spin models: A variational wavefunction study

The study of SU(N) quantum spin models is relevant to a variety of physical systems including ultracold atoms in optical lattices, and also leads to insights into novel quantum phases and phase transitions of SU(2) spin models. We use Gutzwiller projected fermionic variational wavefunctions to explore the phase diagram and correlation functions of SU(N) spin models in the self-conjugate representation, with Heisenberg bilinear and biquadratic interactions. In 1D, the variational phase diagram of the SU(4) spin chain is constructed by examining instabilities of the Gutzwiller projected free fermion ground state to various broken symmetries, and it agrees well with exact results.The spin and dimer correlations of the Gutzwiller projected free fermion state with N flavors of fermions are also in good agreement with exact and 1/N calculations for the critical points of SU(N) spin chains. In 2D, the variational phase diagram on the square lattice is obtained by studying instabilities of the Gutzwiller projected pi-flux state. The variational ground state of the pure Heisenberg model is found to exhibit long range Neel order for N=2,4 and spin Peierls order for N > 4. For N=4 and 6, biquadratic interactions lead to a complex phase diagram which includes an extended valence bond crystal in both cases, as well as a stable pi-flux phase for N=6. The spin correlations of the projected pi-flux state at N=4 are in good agreement with 1/N calculations. We find that this state also shows strongly enhanced dimer correlations, in qualitative accord with the large-N results. We compare our results with a recent QMC study of the SU(4) Heisenberg model.Comment: 22 pages, 7 figs, added references to arxiv versio

Dopamine terminals from the ventral tegmental area gate intrinsic inhibition in the prefrontal cortex.

Spike frequency adaptation (SFA or accommodation) and calcium-activated potassium channels that underlie after-hyperpolarization potentials (AHP) regulate repetitive firing of neurons. Precisely how neuromodulators such as dopamine from the ventral tegmental area (VTA) regulate SFA and AHP (together referred to as intrinsic inhibition) in the prefrontal cortex (PFC) remains unclear. Using whole cell electrophysiology, we measured intrinsic inhibition in prelimbic (PL) layer 5 pyramidal cells of male adult rats. Results demonstrate that bath application of dopamine reduced intrinsic inhibition (EC50: 25.0 μmol/L). This dopamine action was facilitated by coapplication of cocaine (1 μmol/L), a blocker of dopamine reuptake. To evaluate VTA dopamine terminals in PFC slices, we transfected VTA dopamine cells of TH::Cre rats in vivo with Cre-dependent AAVs to express channelrhodopsin-2 (ChR2) or designer receptors exclusively activated by designer drugs (DREADDS). In PFC slices from these animals, stimulation of VTA terminals with either blue light to activate ChR2 or bath application of clozapine-N-oxide (CNO) to activate Gq-DREADDs produced a similar reduction in intrinsic inhibition in PL neurons. Electrophysiological recordings from cells expressing retrograde fluorescent tracers showed that this plasticity occurs in PL neurons projecting to the accumbens core. Collectively, these data highlight an ability of VTA terminals to gate intrinsic inhibition in the PFC, and under appropriate circumstances, enhance PL neuronal firing. These cellular actions of dopamine may be important for dopamine-dependent behaviors involving cocaine and cue-reward associations within cortical-striatal circuits

EUV ionization of pure He nanodroplets: Mass-correlated photoelectron imaging, Penning ionization and electron energy-loss spectra

The ionization dynamics of pure He nanodroplets irradiated by EUV radiation is studied using Velocity-Map Imaging PhotoElectron-PhotoIon COincidence (VMI-PEPICO) spectroscopy. We present photoelectron energy spectra and angular distributions measured in coincidence with the most abundant ions He+, He2+, and He3+. Surprisingly, below the autoionization threshold of He droplets we find indications for multiple excitation and subsequent ionization of the droplets by a Penning-like process. At high photon energies we evidence inelastic collisions of photoelectrons with the surrounding He atoms in the droplets

Penning ionization of doped helium nanodroplets following EUV excitation

Helium nanodroplets are widely used as a cold, weakly interacting matrix for spectroscopy of embedded species. In this work we excite or ionize doped He droplets using synchrotron radiation and study the effect onto the dopant atoms depending on their location inside the droplets (rare gases) or outside at the droplet surface (alkali metals). Using photoelectron-photoion coincidence imaging spectroscopy at variable photon energies (20-25 eV), we compare the rates of charge-transfer to Penning ionization of the dopants in the two cases. The surprising finding is that alkali metals, in contrast to the rare gases, are efficiently Penning ionized upon excitation of the (n=2)-bands of the host droplets. This indicates rapid migration of the excitation to the droplet surface, followed by relaxation, and eventually energy transfer to the alkali dopants

Insulating charge density wave for a half-filled SU(N) Hubbard model with an attractive on-site interaction in one dimension

We study a one-dimensional SU(N) Hubbard model with an attractive on-site interaction and $N>2$ at half-filling on the bipartite lattice using density-matrix renormalization-group method and a perturbation theory. We find that the ground state of the SU(N) Hubbard model is a charge density wave state with two-fold degeneracy. All the excitations are found to be gapful, resulting in an insulating ground state, on contrary to that in the SU(2) case. Moreover, the charge gap is equal to the Cooperon gap, which behaves as $-2Nt^2/(N-1)U$ in the strong coupling regime. However, the spin gap $\Delta_{s}$ and the quasiparticle gap $\Delta_{1}$ as well open exponentially in the weak coupling region, while in the strong coupling region, they linearly depend on $U$ such that $\Delta_{s}\sim -U(N-1)$ and $\Delta_{1}\sim -U(N-1)/2$.Comment: 7 pages, 7 figure

A Proposed System for All Weather Attack on Moving Vehicles

Control Systems Laboratory changed its name to Coordinated Science LaboratoryContract DA-11-022-ORD-72

Random Convex Hulls and Extreme Value Statistics

In this paper we study the statistical properties of convex hulls of $N$ random points in a plane chosen according to a given distribution. The points may be chosen independently or they may be correlated. After a non-exhaustive survey of the somewhat sporadic literature and diverse methods used in the random convex hull problem, we present a unifying approach, based on the notion of support function of a closed curve and the associated Cauchy's formulae, that allows us to compute exactly the mean perimeter and the mean area enclosed by the convex polygon both in case of independent as well as correlated points. Our method demonstrates a beautiful link between the random convex hull problem and the subject of extreme value statistics. As an example of correlated points, we study here in detail the case when the points represent the vertices of $n$ independent random walks. In the continuum time limit this reduces to $n$ independent planar Brownian trajectories for which we compute exactly, for all $n$, the mean perimeter and the mean area of their global convex hull. Our results have relevant applications in ecology in estimating the home range of a herd of animals. Some of these results were announced recently in a short communication [Phys. Rev. Lett. {\bf 103}, 140602 (2009)].Comment: 61 pages (pedagogical review); invited contribution to the special issue of J. Stat. Phys. celebrating the 50 years of Yeshiba/Rutgers meeting

Chaperone use during intimate examinations in primary care: postal survey of family physicians

BACKGROUND: Physicians have long been advised to have a third party present during certain parts of a physical examination; however, little is known about the frequency of chaperone use for those specific intimate examinations regularly performed in primary care. We aimed to determine the frequency of chaperone use among family physicians across a variety of intimate physical examinations for both male and female patients, and also to identify the factors associated with chaperone use. METHODS: Questionnaires were mailed to a randomly selected sample of 500 Ontario members of the College of Family Physicians of Canada. Participants were asked about their use of chaperones when performing a variety of intimate examinations, namely female pelvic, breast, and rectal exams and male genital and rectal exams. RESULTS: 276 of 500 were returned (56%), of which 257 were useable. Chaperones were more commonly used with female patients than with males (t = 9.09 [df = 249], p < 0.001), with the female pelvic exam being the most likely of the five exams to be attended by a chaperone (53%). As well, male physicians were more likely to use chaperones for examination of female patients than were female physicians for the examination of male patients. Logistic regression analyses identified two independent factors – sex of physician and availability of a nurse – that were significantly associated with chaperone use. For female pelvic exam, male physicians were significantly more likely to report using a chaperone (adjusted Odds Ratio [OR] 40.62, 95% confidence interval [CI] 16.91–97.52). Likewise, having a nurse available also significantly increased the likelihood of a chaperone being used (adjusted OR 6.92, 95% CI 2.74–17.46). This pattern of results was consistent across the other four exams. Approximately two-thirds of respondents reported using nurses as chaperones, 15% cited the use of other office staff, and 10% relied on the presence of a family member. CONCLUSION: Clinical practice concerning the use of chaperones during intimate exams continues to be discordant with the recommendations of medical associations and medico-legal societies. Chaperones are used by only a minority of Ontario family physicians. Chaperone use is higher for examinations of female patients than of male patients and is highest for female pelvic exams. The availability of a nurse in the clinic to act as a chaperone is associated with more frequent use of chaperones