Tonic inhibition of accumbal spiny neurons by extrasynaptic 4 GABAA receptors modulates the actions of psychostimulants

Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/− or α4−/− mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/− mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the α4 deletion specific to D1-expressing neurons (α4D1−/−) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4−/− or α4D1−/− mice, blocked cocaine enhancement of CPP. In comparison, α4D2−/− mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward. Therefore, α4βδ GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors

The application of mHealth to mental health: opportunities and challenges

Recent advances in smartphones and wearable biosensors enable the gathering of ‘real-time’ psychological, behavioural and physiological data, in increasingly precise and unobtrusive ways. It is therefore now possible to collect moment-to-moment information about an individuals’ moods, cognitions and activities, as well as automated data about their whereabouts, behaviour and physiological states. In this paper, we discuss the potential of these new mobile digital technologies for transforming mental health research and clinical practice. By drawing on a recent research project, we illustrate how traditional boundaries between research and clinical practice are becoming increasingly blurred and how in turn, this is leading to exciting new developments in the assessment and management of common mental disorders. The potential risks and key challenges associated with applying mobile technology to mental health are also discussed

The relevance of ERTS-1 data to the state of Ohio

There are no author-identified significant results in this report

During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons

AbstractAs neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5α-pregnan-3α-ol-20-one (5α3α), the GABAAR-inactive 5α-dihydroprogesterone, (5α-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABAARs incorporating the α1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from α1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABAARs of L2/3 interneurons were modulated by native neurosteroids in a development-dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity

The changing of the guard: groupwork with people who have intellectual disabilities

This paper considers the impact of service systems on group activities. It describes an inter-professional groupwork project facilitated by a social worker and a community nurse. The project provided an emancipatory experience for a group of adults who had intellectual disabilities. The group was charged with the task of reviewing and updating the recruitment and interview processes used by a 'Learning Disability Partnership Board', when employing new support workers. The paper begins with a brief history of intellectual disability and provides a context to the underpinning philosophical belief that people should be encouraged and supported to inhabit valued social roles no matter what disability they may have. It then identifies the ways in which the sponsoring health, education and social care services impacted on the creation and development of a groupwork project. It might have been expected that the nature of the intellectual disability would have been the major influence on group process. However the paper reveals that organisational constraints had a significant impact on group functioning. Issues including, staffing budgets and transport contracts impacted on group process and function. The results of the project show how, with adequate support, people with intellectual disability can make important decisions that have long-reaching impacts on the services

Strategies for Investigating Early Mars Using Returned Samples

The 2011 Visions & Voyages Planeary Science Decadal Survey identified making significant progress toward the return of samples from Mars as the highest priority goal for flagship missions in next decade. Numerous scientific objectives have been identified that could be advanced through the potential return and analysis of martian rock, regolith, and atmospheric samples. The analysis of returned martian samples would be particularly valuable in in-creasing our understanding of Early Mars. There are many outstanding gaps in our knowledge about Early Mars in areas such as potential astrobiology, geochronology, planetary evolution (including the age, context, and processes of accretion, differentiation, magmatic, and magnetic history), the history of water at the martian surface, and the origin and evolution of the martian atmosphere. Here we will discuss scientific objectives that could be significantly advanced by Mars sample return

Effects of Increasing Standardized Ileal Digestible Lysine During Gestation on Growth and Reproductive Performance of Gilts and Sows Under Commercial Conditions

A study was conducted on a commercial sow farm to evaluate the effects of increasing dietary standardized ileal digestible (SID) lysine (Lys) intake in gestation on sow performance and piglet birth weight. A total of 936 females (498 gilts, 438 sows; Camborough, PIC, Hendersonville, TN) were group-housed (approximately 275 females per pen) and individually fed with electronic sow feeders (ESF). Scales were located in the alleyway after the feeding stations returning into the pen. Females were moved from the breeding stall to pens on d 4 of gestation and were allotted to 1 of 4 dietary treatments on d 5. Dietary treatments included increasing SID Lys intake (11, 13.5, 16, and 18.5 g/d). Gilts and sows received 4.6 and 5.1 lb/d, respectively, (5.3 and 5.7 Mcal NE/d) of feed throughout the entire study. Dietary treatments were achieved by different blends of low (0.48% SID Lys) and high (0.88% SID Lys) Lys diets via ESF based on the females’ set feed allowance. Initial and final BW and backfat were obtained on d 4 and 112 of gestation. Individual piglet BW was obtained within 12 h of birth on litters from 895 females. Data were analyzed using the GLIMMIX procedure of SAS. Body weight at d 112 of gestation increased within each parity group (linear, P \u3c 0.001) as SID Lys increased with gilts and sows consuming 18.5 g/d SID Lys weighing 16 and 11 lb more, respectively, than gilts and sows consuming 11 g/d SID Lys. There was no evidence for differences in d 112 backfat depth. Average total born for gilts and sows was 15.3 and 16.0, respectively with no evidence for differences among treatments. However, the percentage of pigs born alive increased (P = 0.006) with increasing SID Lys intake for sows but not in gilts. This is explained by the treatment × parity group interaction (P = 0.043) for percentage of stillborn pigs. In gilts, there was no evidence for differences among treatments in the percentage of stillborn pigs; however, in sows, as dietary SID Lys intake increased, the percentage of stillborn pigs decreased (linear, P = 0.002). Increasing SID Lys intake during gestation did not affect the percentage of mummified fetuses, total born, or born alive piglet birth weight in this study. In addition, increasing SID Lys intake during gestation did not affect subsequent reproductive performance. In conclusion, increasing dietary SID Lys intake in gestation increased female BW, without changing backfat or total born litter weight, indicating these females are depositing more lean tissue. The impact on female reproductive performance suggests that increasing SID Lys intake may increase the percentage of piglets born alive by reducing the number of stillborns in sows, but not in gilts

Neural cognitive control moderates the association between insular risk processing and risk-taking behaviors via perceived stress in adolescents

Adolescence is a critical period for the initiation of risk-taking behaviors. We examined the longitudinal interplay between neural correlates of risk processing and cognitive control in predicting risk-taking behaviors via stress. The sample consisted of 167 adolescents (53% males) who were assessed twice (MAgeTime1 = 14.13, MAgeTime2 = 15.05). Neural risk processing was operationalized as blood-oxygen-level-dependent (BOLD) responses in the anterior insula during a lottery choice task and neural cognitive control as BOLD responses during an inhibitory control task. Adolescents reported on perceived stress and risk-taking behaviors. Structural equation modeling analyses indicated that low insular risk processing predicted increases in perceived stress, while perceived stress did not predict changes in insular risk processing across one year. Moreover, significant moderation by neural cognitive control indicated that low insular risk processing predicted increases in risk-taking behaviors via increases in perceived stress among adolescents with poor neural cognitive control, but not among adolescents with good neural cognitive control. The results suggest that risk processing in the anterior insular cortex plays an important role in stress experience and risk-taking behaviors particularly for vulnerable adolescents with poor neural cognitive control

Upstream Solutions: Does the Supplemental Security Income Program Reduce Disability in the Elderly?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72843/1/j.1468-0009.2007.00512.x.pd

GABA-Independent GABAA Receptor Openings Maintain Tonic Currents

Activation of GABA(A) receptors (GABA(A)Rs) produces two forms of inhibition: ‘phasic’ inhibition generated by the rapid, transient activation of synaptic GABA(A)Rs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of peri- or extrasynaptic GABA(A)Rs which can detect extracellular GABA. Such tonic GABA(A)R-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex-vivo hippocampal slices, tonic currents are predominantly generated by GABA-independent GABA(A) receptor openings. This tonic GABA(A)R conductance is resistant to the competitive GABA(A)R antagonist SR95531, which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker picrotoxin. When slices are perfused with 200 nM GABA, a concentration that is comparable to cerebrospinal fluid concentrations but is twice that measured by us in the hippocampus in vivo using zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABA(A)Rs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations