The Neural Encoding of Reward in the Striatal-Pallidal Circuitry

Humans and animals are constantly exposed to external stimuli. The ability to process reward value of a stimulus is critical to guiding appropriate behavior and essential for survival. These processes are regulated by neuronal activity and neurochemical signaling in the reward circuitry, particularly in the nucleus accumbens (NAc). The NAc receives dopaminergic inputs from the midbrain ventral tegmental area (VTA) and sends GABAergic projections to the ventral pallidum (VP). Electrophysiological studies have characterized phasic neuronal responses in the NAc that differential encode appetitive and aversive taste stimuli. Exposure to an appetitive taste stimulus evoked predominantly phasic inhibitory responses in the NAc whereas a majority of responses to an aversive taste was excitation. The work presented here focused on investigating how activity in the NAc modulate reward encoding in downstream VP, and the role of dopamine signaling in regulating neuronal responses to reward in the NAc. Using electrophysiological recording techniques, we present evidence of neural encoding of reward information in the VP. VP neurons responded to appetitive and aversive taste stimuli with primarily inhibitory and excitatory responses, respectively. Furthermore, devaluation of the appetitive stimulus resulted from cocaine-induced taste aversion conditioning revealed that the encoding of sucrose shifted from inhibition to excitation, resembling that of an aversion response. These data suggest that the VP, similar to the NAc, also encode reward information neuronally. In a subsequent study, the influence of NAc on VP reward encoding was tested by pharmacologically manipulating activity in the NAc while monitoring the neuronal activity in the VP. We demonstrate that by inhibiting activity in the NAc with a GABAergic agonist, the neural encoding to sucrose in the VP was augmented, followed by increased sucrose consumption. These findings support the notion that at least some aspect of reward information processed in VP is modulated by NAc activity. In the final study, we show that chemogenetically suppressing activity of VTA dopamine neurons inverted the response profile to sucrose from inhibition to excitation in the NAc. This elimination of inhibitory reward encoding in the NAc was accompanied by a dampened motivational state, demonstrated by subjects terminating leverpress behavior for sucrose reward quicker in a progressive ratio test on day that dopamine signaling was chemogenetically suppressed but not in control condition. Taken together, results from these studies provide insights into how reward information is represented by physiological events in the reward circuitry. We demonstrate that neuronal responses in both the NAc and the VP encode reward and correlate strongly to reward-driven motivated behavior. Furthermore, we used a chemogenetic approach to show that suppressed NAc dopamine signaling models a low motivational state that is represented by altered neuronal responses in the NAc. This endeavor to better understand the neural representation of reward may help us better understand the physiology of both normal and diseased motivational and affective states

The Neural Encoding of Cocaine-Induced Devaluation in The Ventral Pallidum

Cocaine experience affects motivation structures such as the nucleus accumbens (NAc) and its major output target, the ventral pallidum (VP). Previous studies demonstrated that both NAc activity and hedonic responses change reliably as a taste cue comes to predict cocaine availability. Here we extended this investigation to examine drug-experience induced changes in hedonic encoding in the VP. VP activity was first characterized in adult male Sprague–Dawley rats in response to intraoral infusions of palatable saccharin and unpalatable quinine solutions. Next, rats received 7 daily pairings of saccharin that predicted either a cocaine (20 mg/kg, ip) or saline injection. Finally, the responses to saccharin and quinine were again assessed. Of 109 units recorded in 11 rats that received saccharin–cocaine pairings, 71% of responsive units significantly reduced firing rate during saccharin infusions and 64% increased firing rate during quinine exposure. However, as saccharin came to predict cocaine, and elicited aversive taste reactivity, VP responses changed to resemble quinine. After conditioning, 70% of saccharin-responsive units increased firing rate. Most units that encoded the palatable taste (predominantly reduced firing rate) were located in the anterior VP, while most units that were responsive to aversive tastes were located in the posterior VP. This study reveals an anatomical complexity to the nature of hedonic encoding in the VP

Future Frontiers in Small Molecule Inhibitors of Protein-Protein Interactions

Protein-protein interactions (PPIs) are ubiquitous in essential biological processes such as cell proliferation and differentiation, host-pathogen interactions, and signal transduction pathways [1]. Pioneering advances in the field of interactomics have uncovered new net-works of protein interactions within cells, with esti-mates for the size of the interactome ranging up to 650,000 PPIs [2]. However, targeting PPIs has histori-cally been considered to be a particularly challenging task due to their typically large size (>1,500 Å) and amorphous nature that lack well-defined crevices for recognition by small molecules. Not surprisingly, the pharmaceutical landscape over the last century has been dominated by programs for small molecule in-hibitors of enzymes (particularly kinases), G-protein-coupled receptors, protein transporters and ion chan-nels that account for the majority of known drugs

Cytokine Profile in Plasma Extracellular Vesicles of Parkinson's Disease and the Association with Cognitive Function

Plasma extracellular vesicles (EVs) containing various molecules, including cytokines, can reflect the intracellular condition and participate in cell-to-cell signaling, thus emerging as biomarkers for Parkinson’s disease (PD). Inflammation may be a crucial risk factor for PD development and progression. The present study investigated the role of plasma EV cytokines as the biomarkers of PD. This cross-sectional study recruited 113 patients with PD, with mild to moderate stage disease, and 48 controls. Plasma EVs were isolated, and the levels of cytokines, including pro-interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1, were evaluated. Patients with PD had significantly increased plasma EV pro-IL-1β and TNF-α levels compared with controls after adjustment for age and sex. Despite the lack of a significant association between plasma EV cytokines and motor symptom severity in patients with PD, cognitive dysfunction severity, assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment, was significantly associated with plasma EV pro-IL-1β, IL-6, IL-10, and TNF-α levels. This association was PD specific and not found in controls. Furthermore, patients with PD cognitive deficit (MMSE < 26) exhibited a distinguished EV cytokine profile compared to those without cognitive deficit. The findings support the concept of inflammatory pathogenesis in the development and progression of PD and indicate that plasma EV cytokines may serve as PD biomarkers in future

Basal Cell Carcinoma of the Head and Neck Region in Ethnic Chinese

Objectives. This study aims to report our experience in the management of HNBCC in ethnic Chinese over a 10-year period. Methods. A retrospective review of all ethnic Chinese patients with HNBCC treated in a tertiary centre from 1999 to 2009. Results. From 1999 to 2009, 225 patients underwent surgical excision for HNBCC. Majority were elderly female patients. Commonest presentation was a pigmented (76.2%) ulcer (64.8%) over the nose (31.6%). Median skin margin taken on tumour excision was 2.0 mm; primary skin closure was achieved in 51.8%. Postresection skin margin was clear in 75.4%. Of those with inadequate skin margins, 56.7% opted for further treatment, 43.4% for observation. Recurrence rates were 2.6% and 13.8%, respectively (P = 0.106). Overall recurrence rate was 5.5%. Conclusions. HNBCC commonly presented as pigmented ulcers over the nose of elderly female patients in our locality. Adequate tumour excision ± reconstruction offered the best chance of cure. Reexcision of those with inadequate skin margins improved local tumour control

Toll-like receptors, chemokine receptors and death receptor ligands responses in SARS coronavirus infected human monocyte derived dendritic cells

<p>Abstract</p> <p>Background</p> <p>The SARS outbreak in 2003 provides a unique opportunity for the study of human responses to a novel virus. We have previously reported that dendritic cells (DCs) might be involved in the immune escape mechanisms for SARS-CoV. In this study, we focussed on the gene expression of toll-like receptors (TLRs), chemokine receptors (CCRs) and death receptor ligands in SARS-CoV infected DCs. We also compared adult and cord blood (CB) DCs to find a possible explanation for the age-dependent severity of SARS.</p> <p>Results</p> <p>Our results demonstrates that SARS-CoV did not modulate TLR-1 to TLR-10 gene expression but significantly induced the expression of CCR-1, CCR-3, and CCR-5. There was also strong induction of TNF-related apoptosis-inducing ligand (TRAIL), but not Fas ligand gene expression in SARS-CoV infected DCs. Interestingly, the expressions of most genes studied were higher in CB DCs than adult DCs.</p> <p>Conclusion</p> <p>The upregulation of chemokines and CCRs may facilitate DC migration from the infection site to the lymph nodes, whereas the increase of TRAIL may induce lymphocyte apoptosis. These findings may explain the increased lung infiltrations and lymphoid depletion in SARS patients. Further explorations of the biological significance of these findings are warranted.</p

Gold-catalyzed cycloisomerization and Diels-Alder reaction of 1,4,9-Dienyne Esters to 3 a,6-Methanoisoindole Esters with pro-inflammatory cytokine antagonist activity

A synthetic method to prepare 3a,6-methanoisoindole esters efficiently by gold(I)-catalyzed tandem 1,2-acyloxy migration/Nazarov cyclization followed by Diels–Alder reaction of 1,4,9-dienyne esters is described. We also report the ability of one example to inhibit binding of tumor necrosis factor-α (TNF-α) to the tumor necrosis factor receptor 1 (TNFR1) site and TNF-α-induced nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation in cell at a half-maximal inhibitory concentration (IC50) value of 6.6 μM. Along with this is a study showing the isoindolyl derivative to exhibit low toxicity toward human hepatocellular liver carcinoma (HepG2) cells and its possible mode of activity based on molecular modeling analysis

Exogenous Expression of Human apoA-I Enhances Cardiac Differentiation of Pluripotent Stem Cells

The cardioprotective effects of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (apoA-I) are well documented, but their effects in the direction of the cardiac differentiation of embryonic stem cells are unknown. We evaluated the effects of exogenous apoA-I expression on cardiac differentiation of ESCs and maturation of ESC-derived cardiomyocytes. We stably over-expressed full-length human apoA-I cDNA with lentivirus (LV)-mediated gene transfer in undifferentiated mouse ESCs and human induced pluripotent stem cells. Upon cardiac differentiation, we observed a significantly higher percentage of beating embryoid bodies, an increased number of cardiomyocytes as determined by flow cytometry, and expression of cardiac markers including α-myosin heavy chain, β-myosin heavy chain and myosin light chain 2 ventricular transcripts in LV-apoA-I transduced ESCs compared with control (LV-GFP). In the presence of noggin, a BMP4 antagonist, activation of BMP4-SMAD signaling cascade in apoA-I transduced ESCs completely abolished the apoA-I stimulated cardiac differentiation. Furthermore, co-application of recombinant apoA-I and BMP4 synergistically increased the percentage of beating EBs derived from untransduced D3 ESCs. These together suggests that that pro-cardiogenic apoA-I is mediated via the BMP4-SMAD signaling pathway. Functionally, cardiomyocytes derived from the apoA-I-transduced cells exhibited improved calcium handling properties in both non-caffeine and caffeine-induced calcium transient, suggesting that apoA-I plays a role in enhancing cardiac maturation. This increased cardiac differentiation and maturation has also been observed in human iPSCs, providing further evidence of the beneficial effects of apoA-I in promoting cardiac differentiation. In Conclusion, we present novel experimental evidence that apoA-I enhances cardiac differentiation of ESCs and iPSCs and promotes maturation of the calcium handling property of ESC-derived cardiomyocytes via the BMP4/SMAD signaling pathway

Association Between Net Vertebral Artery Flow Volume and Non-AF Stroke: A Retrospective 2-Year Analysis

Objectives: Association between net vertebral artery flow volume (NVAFV) and stroke types remains unclear. We hypothesize NVAFV is low in patients with posterior circulation infarction (PCI) and an ideal cut-off value for discriminating PCI from anterior circulation infarction (ACI) and controls may be present.Materials and Methods: As study candidates, we retrospectively enrolled hospitalized patients with first-time non-AF stroke within 2-years period. Consecutive non-AF, non-stroke subjects were enrolled as the control group. We compared NVAFV values among the PCI, ACI, and control groups.Results: Overall, 866 candidates—213, 418, and 235 candidates in the PCI, ACI, and control groups, respectively—were enrolled. NVAFV (mean ± SD) values were 134.8 ± 52.7, 152.3 ± 59.2, and 172.0 ± 54.7 mL/min in the PCI, ACI, and control groups, respectively. Statistics revealed significant difference (p &lt; 0.001) among three groups. To use NVAFV as a diagnostic parameter, the AUC of any two groups should be between 0.58 and 0.69. Most (93.6%) of the controls had NVAFV above 100 mL/min. The odds ratio of any non-AF stroke is 3.48 if the NVAFV is below 100 mL/min.Conclusions: NVAFV is lowest in non-AF PCI group. Low NVAFV is associated with both non-AF ACI and PCI. No ideal cut-off value is available to discriminate PCI from other two conditions. We agree that an NVAFV of 100 mL/min is the lower limit of a normal value. Any value below 100 mL/min indicates high stroke risk and implies diffuse cerebral atherosclerosis and impaired cerebral perfusion