Altered neuronal activity in the ventromedial prefrontal cortex drives nicotine intake escalation.

Nicotine addiction develops after prolonged drug use and escalation of drug intake. However, because of difficulties in demonstrating escalation of nicotine use in rats, its underlying neuroadaptations still remain poorly understood. Here we report that access to unusually high doses of nicotine (i.e., from 30 µg to 240 µg/kg/injection) for self-administration precipitated a rapid and robust escalation of nicotine intake and increased the motivation for the drug in rats. This nicotine intake escalation also induced long-lasting changes in vmPFC neuronal activity both before and during nicotine self-administration. Specifically, after escalation of nicotine intake, basal vmPFC neuronal activity increased above pre-escalation and control activity levels, while ongoing nicotine self-administration restored these neuronal changes. Finally, simulation of the restoring effects of nicotine with in vivo optogenetic inhibition of vmPFC neurons caused a selective de-escalation of nicotine self-administration.

Vertical Organic Electrochemical Transistors and Electronics for Low Amplitude Micro-Organ Signals.

Electrical signals are fundamental to key biological events such as brain activity, heartbeat, or vital hormone secretion. Their capture and analysis provide insight into cell or organ physiology and a number of bioelectronic medical devices aim to improve signal acquisition. Organic electrochemical transistors (OECT) have proven their capacity to capture neuronal and cardiac signals with high fidelity and amplification. Vertical PEDOT:PSS-based OECTs (vOECTs) further enhance signal amplification and device density but have not been characterized in biological applications. An electronic board with individually tuneable transistor biases overcomes fabrication induced heterogeneity in device metrics and allows quantitative biological experiments. Careful exploration of vOECT electric parameters defines voltage biases compatible with reliable transistor function in biological experiments and provides useful maximal transconductance values without influencing cellular signal generation or propagation. This permits successful application in monitoring micro-organs of prime importance in diabetes, the endocrine pancreatic islets, which are known for their far smaller signal amplitudes as compared to neurons or heart cells. Moreover, vOECTs capture their single-cell action potentials and multicellular slow potentials reflecting micro-organ organizations as well as their modulation by the physiological stimulator glucose. This opens the possibility to use OECTs in new biomedical fields well beyond their classical applications.

Design of Potassium-Selective Mixed Ion/Electron Conducting Polymers.

An approach providing cation-selective poly-(3,4-ethylenedioxythiophene)(PEDOT):polyelectrolyte-mixed conductors is presented in this communication based on the structural modification of this ambivalent (ionic and electronic conductive) polymer complex. First, an 18-crown-6 moiety is integrated into the styrene sulfonate monomer structure as a specific metal cation scavenger particularly targeting K+ versus Na+ detection. This newly functionalized monomer is characterized by 1 H NMR titration to evaluate the ion selectivity. Aqueous PEDOT dispersion inks containing the polymeric ion-selective moieties are designed and their electrical and electrochemical properties analyzed. These biocompatible inks are the first proof-of-concept step towards ion selectivity in view of their interfacing with biological cells and microorgans of interest in the field of biosensors and physiology.

The glutamate receptor GluK2 contributes to the regulation of glucose homeostasis and its deterioration during aging.

OBJECTIVE: Islets secrete neurotransmitters including glutamate which participate in fine regulation of islet function. The excitatory ionotropic glutamate receptor GluK2 of the kainate receptor family is widely expressed in brain and also found in islets, mainly in α and γ cells. α cells co-release glucagon and glutamate and the latter increases glucagon release via ionotropic glutamate receptors. However, neither the precise nature of the ionotropic glutamate receptor involved nor its role in glucose homeostasis is known. As isoform specific pharmacology is not available, we investigated this question in constitutive GluK2 knock-out mice (GluK2-/-) using adult and middle-aged animals to also gain insight in a potential role during aging. METHODS: We compared wild-type GluK2+/+ and knock-out GluK2-/- mice using adult (14-20 weeks) and middle-aged animals (40-52 weeks). Glucose (oral OGTT and intraperitoneal IPGTT) and insulin tolerance as well as pyruvate challenge tests were performed according to standard procedures. Parasympathetic activity, which stimulates hormones secretion, was measured by electrophysiology in vivo. Isolated islets were used in vitro to determine islet ß-cell electrical activity on multi-electrode arrays and dynamic secretion of insulin as well as glucagon was determined by ELISA. RESULTS: Adult GluK2-/- mice exhibit an improved glucose tolerance (OGTT and IPGTT), and this was also apparent in middle-aged mice, whereas the outcome of pyruvate challenge was slightly improved only in middle-aged GluK2-/- mice. Similarly, insulin sensitivity was markedly enhanced in middle-aged GluK2-/- animals. Basal and glucose-induced insulin secretion in vivo was slightly lower in GluK2-/- mice, whereas fasting glucagonemia was strongly reduced. In vivo recordings of parasympathetic activity showed an increase in basal activity in GluK2-/- mice which represents most likely an adaptive mechanism to counteract hypoglucagonemia rather than altered neuronal mechanism. In vitro recording demonstrated an improvement of glucose-induced electrical activity of ß-cells in islets obtained from GluK2-/- mice at both ages. Finally, glucose-induced insulin secretion in vitro was increased in GluK2-/- islets, whereas glucagon secretion at 2 mmol/l of glucose was considerably reduced. CONCLUSIONS: These observations indicate a general role for kainate receptors in glucose homeostasis and specifically suggest a negative effect of GluK2 on glucose homeostasis and preservation of islet function during aging. Our observations raise the possibility that blockade of GluK2 may provide benefits in glucose homeostasis especially during aging.