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

The shape of the urine stream — from biophysics to diagnostics

We develop a new computational model of capillary-waves in free-jet flows, and apply this to the problem of urological diagnosis in this first ever study of the biophysics behind the characteristic shape of the urine stream as it exits the urethral meatus. The computational fluid dynamics model is used to determine the shape of a liquid jet issuing from a non-axisymmetric orifice as it deforms under the action of surface tension. The computational results are verified with experimental modelling of the urine stream. We find that the shape of the stream can be used as an indicator of both the flow rate and orifice geometry. We performed volunteer trials which showed these fundamental correlations are also observed in vivo for male healthy volunteers and patients undergoing treatment for low flow rate. For healthy volunteers, self estimation of the flow shape provided an accurate estimation of peak flow rate (+-2%). However for the patients, the relationship between shape and flow rate suggested poor meatal opening during voiding. The results show that self measurement of the shape of the urine stream can be a useful diagnostic tool for medical practitioners since it provides a non-invasive method of measuring urine flow rate and urethral dilation

Drug Predictive Cues Activate Aversion-Sensitive Striatal Neurons That Encode Drug Seeking

Drug-associated cues have profound effects on an addict’s emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, self-administration sessions were preceded by a taste cue that signaled delayed drug availability. Assessments of hedonic responses indicated that this delay cue became aversive during training. Both the self-administration behavior and the immediate cue were subsequently extinguished in the absence of cocaine. After extinction of self-administration behavior, the presentation of the aversive delay cue reinstated drug seeking. In vivo electrophysiology and voltammetry recordings in the nucleus accumbens measured the neural responses to both the delay and immediate drug cues after extinction. Interestingly, the presentation of the delay cue simultaneously decreased dopamine signaling and increased excitatory encoding of the immediate cue. Most importantly, the delay cue selectively enhanced the baseline activity of neurons that would later encode drug seeking. Together these observations reveal how cocaine cues can modulate not only affective state, but also the neurochemical and downstream neurophysiological environment of striatal circuits in a manner that promotes drug seeking

Space Time Foam: a ground state candidate for Quantum Gravity

A model of space-time foam, made by $N$ wormholes is considered. The Casimir energy leading to such a model is computed by means of the phase shift method which is in agreement with the variational approach used in Refs.[9-14]. The collection of Schwarzschild and Reissner-Nordstr\"{o}m wormholes are separately considered to represent the foam. The Casimir energy shows that the Reissner-Nordstr\"{o}m wormholes cannot be used to represent the foam.Comment: 6 pages.RevTeX with package epsf and two eps figures. To be submitted to the proceedings of the 4th Workshop of `Mysteries, Puzzles And Paradoxes In Quantum Mechanics' Gargnano (Italy), 27 August-1 September 200

Opposite Thermodynamic Arrows of Time

A model in which two weakly coupled systems maintain opposite running thermodynamic arrows of time is exhibited. Each experiences its own retarded electromagnetic interaction and can be seen by the other. The possibility of opposite-arrow systems at stellar distances is explored and a relation to dark matter suggested.Comment: To appear in Phys. Rev. Let

Yang-Mills gravity in biconformal space

We write a gravity theory with Yang-Mills type action using the biconformal gauging of the conformal group. We show that the resulting biconformal Yang-Mills gravity theories describe 4-dim, scale-invariant general relativity in the case of slowly changing fields. In addition, we systematically extend arbitrary 4-dim Yang-Mills theories to biconformal space, providing a new arena for studying flat space Yang-Mills theories. By applying the biconformal extension to a 4-dim pure Yang-Mills theory with conformal symmetry, we establish a 1-1, onto mapping between a set of gravitational gauge theories and 4-dim, flat space gauge theories.Comment: 27 pages; paper emphasis shifted to focus on gravity; references adde

Impacts of the Madden-Julian oscillation on Australian rainfall and circulation

Impacts of the Madden¿Julian oscillation (MJO) on Australian rainfall and circulation are examined during all four seasons. The authors examine circulation anomalies and a number of different rainfall metrics, each composited contemporaneously for eight MJO phases derived from the real-time multivariate MJO index. Multiple rainfall metrics are examined to allow for greater relevance of the information for applications. The greatest rainfall impact of the MJO occurs in northern Australia in (austral) summer, although in every season rainfall impacts of various magnitude are found in most locations, associated with corresponding circulation anomalies. In northern Australia in all seasons except winter, the rainfall impact is explained by the direct influence of the MJO's tropical convective anomalies, while in winter a weaker and more localized signal in northern Australia appears to result from the modulation of the trade winds as they impinge upon the eastern coasts, especially in the northeast. In extratropical Australia, on the other hand, the occurrence of enhanced (suppressed) rainfall appears to result from induced upward (downward) motion within remotely forced extratropical lows (highs), and from anomalous low-level northerly (southerly) winds that transport moisture from the tropics. Induction of extratropical rainfall anomalies by remotely forced lows and highs appears to operate mostly in winter, whereas anomalous meridional moisture transport appears to operate mainly in the summer, autumn, and to some extent in the sprin

Aversive Stimuli Drive Drug Seeking in a State of Low Dopamine Tone

Background Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF). Methods Combining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of intraoral quinine administration on nucleus accumbens dopamine signaling and hedonic expression in 21 male Sprague-Dawley rats. We tested the role of CRF in modulating aversion-induced changes in dopamine concentration and cocaine seeking by bilaterally infusing the CRF antagonist, CP-376395, into the ventral tegmental area (VTA). Results We found that quinine rapidly reduced dopamine signaling on two distinct time scales. We determined that CRF acted in the VTA to mediate this reduction on only one of these time scales. Further, we found that the reduction of dopamine tone and quinine-induced cocaine seeking were eliminated by blocking the actions of CRF in the VTA during the experience of the aversive stimulus. Conclusions These data demonstrate that stress-induced drug seeking can occur in a terminal environment of low dopamine tone that is dependent on a CRF-induced decrease in midbrain dopamine activity

Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

To restore function after injury to the CNS, axons must be stimulated to extend into denervated territory and, critically, must form functional synapses with appropriate targets. We showed previously that forced overexpression of the transcription factor Sox11 increases axon growth by corticospinal tract (CST) neurons after spinal injury. However, behavioral outcomes were not improved, raising the question of whether the newly sprouted axons are able to form functional synapses. Here we developed an optogenetic strategy, paired with single-unit extracellular recordings, to assess the ability of Sox11-stimulated CST axons to functionally integrate in the circuitry of the cervical spinal cord. Initial time course experiments established the expression and function of virally expressed Channelrhodopsin (ChR2) in CST cell bodies and in axon terminals in cervical spinal cord. Pyramidotomies were performed in adult mice to deprive the left side of the spinal cord of CST input, and the right CST was treated with adeno-associated virus (AAV)–Sox11 or AAV–EBFP control, along with AAV–ChR2. As expected, Sox11 treatment caused robust midline crossing of CST axons into previously denervated left spinal cord. Clear postsynaptic responses resulted from optogenetic activation of CST terminals, demonstrating the ability of Sox11-stimulated axons to form functional synapses. Mapping of the distribution of CST-evoked spinal activity revealed overall similarity between intact and newly innervated spinal tissue. These data demonstrate the formation of functional synapses by Sox11-stimulated CST axons without significant behavioral benefit, suggesting that new synapses may be mistargeted or otherwise impaired in the ability to coordinate functional output. SIGNIFICANCE STATEMENT As continued progress is made in promoting the regeneration of CNS axons, questions of synaptic integration are increasingly prominent. Demonstrating direct synaptic integration by regenerated axons and distinguishing its function from indirect relay circuits and target field plasticity have presented technical challenges. Here we force the overexpression of Sox11 to stimulate the growth of corticospinal tract axons in the cervical spinal cord and then use specific optogenetic activation to assess their ability to directly drive postsynaptic activity in spinal cord neurons. By confirming successful synaptic integration, these data illustrate a novel optogenetic-based strategy to monitor and optimize functional reconnection by newly sprouted axons in the injured CNS

The view from elsewhere: perspectives on ALife Modeling

Many artificial life researchers stress the interdisciplinary character of the field. Against such a backdrop, this report reviews and discusses artificial life, as it is depicted in, and as it interfaces with, adjacent disciplines (in particular, philosophy, biology, and linguistics), and in the light of a specific historical example of interdisciplinary research (namely cybernetics) with which artificial life shares many features. This report grew out of a workshop held at the Sixth European Conference on Artificial Life in Prague and features individual contributions from the workshop's eight speakers, plus a section designed to reflect the debates that took place during the workshop's discussion sessions. The major theme that emerged during these sessions was the identity and status of artificial life as a scientific endeavor