Inhibitory and excitatory alcohol-seeking cues distinct roles in behavior, neurochemistry, and mesolimbic pathway in alcohol preferring (P) rats.

Cues associated with alcohol use can readily enhance self-reported cravings for alcohol, which increases the likelihood of reusing alcohol. Understanding the neuronal mechanisms involved in alcohol-seeking behavior is important for developing strategies to treat alcohol use disorder. In all experiments, adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS- associated with the absence of EtOH (extinction training), and a CS0, a neutral stimulus. The data indicated that presentation of an excitatory conditioned cue (CS+) can enhance EtOH- seeking while the CS- can inhibit EtOH-seeking under multiple test conditions. Presentation of the CS+ activates a subpopulation of dopamine neurons within the interfascicular nucleus of the posterior ventral tegmental area (posterior VTA) and basolateral amygdala (BLA). Pharmacological inactivation of the BLA with GABA agonists inhibits the ability of the CS+ to enhance EtOH-seeking but does not alter context-induced EtOH-seeking or the ability of the CS- to inhibit EtOH-seeking. Presentation of the conditioned odor cues in a non-drug-paired environment indicated that presentation of the CS+ increased dopamine levels in the BLA. In contrast, presentation of the CS- decreased both glutamate and dopamine levels in the BLA. Further analysis revealed that presentation of a CS+ EtOH-associated conditioned cue activates GABA interneurons but not glutamate projection neurons. Overall, the data indicate that excitatory and inhibitory conditioned cues can contrarily alter EtOH-seeking behaviors and that different neurocircuitries are mediating these distinct cues in critical brain regions. Pharmacotherapeutics for craving should inhibit the CS+ and enhance the CS- neurocircuits.

Electroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells.

Electroacupuncture (EA) performed in rats and humans using limb acupuncture sites, LI-4 and LI-11, and GV-14 and GV-20 (humans) and Bai-hui (rats) increased functional connectivity between the anterior hypothalamus and the amygdala and mobilized mesenchymal stem cells (MSCs) into the systemic circulation. In human subjects, the source of the MSC was found to be primarily adipose tissue, whereas in rodents the tissue sources were considered more heterogeneous. Pharmacological disinhibition of rat hypothalamus enhanced sympathetic nervous system (SNS) activation and similarly resulted in a release of MSC into the circulation. EA-mediated SNS activation was further supported by browning of white adipose tissue in rats. EA treatment of rats undergoing partial rupture of the Achilles tendon resulted in reduced mechanical hyperalgesia, increased serum interleukin-10 levels and tendon remodeling, effects blocked in propranolol-treated rodents. To distinguish the afferent role of the peripheral nervous system, phosphoinositide-interacting regulator of transient receptor potential channels (Pirt)-GCaMP3 (genetically encoded calcium sensor) mice were treated with EA acupuncture points, ST-36 and LIV-3, and GV-14 and Bai-hui and resulted in a rapid activation of primary sensory neurons. EA activated sensory ganglia and SNS centers to mediate the release of MSC that can enhance tissue repair, increase anti-inflammatory cytokine production and provide pronounced analgesic relief. Stem Cells 2017;35:1303-1315.

Regional variation in capture of fibrillating swine left ventricle during electrical stimulation.

INTRODUCTION: While it has been shown that electrical stimulation can capture a region of myocardium during ventricular fibrillation (VF), the ideal location to stimulate to maximize capture of the fibrillating in vivo left ventricle (LV) is not known. We previously demonstrated a mean directionality to the propagation of VF wavefronts in swine from posterior to anterior LV. We hypothesized that this directionality of VF wavefronts would affect capture of the LV epicardium while stimulating during VF. METHODS AND RESULTS: In seven open-chest swine, during different VF episodes, electrical stimulation was performed singly or simultaneously from two lines of 26 epicardial electrodes, one on the posterior LV adjacent to the posterior descending coronary artery and another on the anterior LV adjacent to the left anterior descending coronary artery. Mapping was performed between the line of stimulating electrodes with 768 recording electrodes 2-mm apart. The incidence and extent of epicardium captured by stimulation through the lines of stimulating electrodes were determined in the mapped region. Capture occurred during 67% of 78 VF episodes. Capture from the posterior LV line was achieved in 88% of the episodes and from the anterior LV line in 44% of the episodes (P = 0.001). The maximum amount of myocardium captured was also much greater for stimulating from the posterior as compared to the anterior LV line (232 +/- 168 mm(2) vs 64 +/- 124 mm(2), P = 0.003). A significant part of the variability in capture was related to the direction of the mean VF wavefront velocity vector in each animal (r = 0.84, P < 0.05). CONCLUSION: Electrical stimulation from the posterior LV resulted in a greater incidence and extent of LV capture than stimulation from the anterior LV. A significant component of the variability in capture is related to the mean direction of VF wavefronts.

Estimated global epicardial distribution of activation rate and conduction block during porcine ventricular fibrillation.

INTRODUCTION: A proposed mechanism of the maintenance of ventricular fibrillation (VF) determined by studying small hearts or segments of large hearts is that a single stable rotor exists at the site of maximal activation rate, which gives rise to activation fronts that propagate into slower activating regions where they frequently block. We wished to determine if two predictions of this hypothesized mechanism are true during VF in large hearts: (1) there is a single maximum in the distribution of activation rates with the activation rate decreasing with distance away from this maximum; and (2) the incidence of block is greater outside than inside the fastest activating region. METHODS AND RESULTS: Six 25-second episodes of VF from each of six pigs were recorded from 504 electrodes over the entire ventricular epicardium. The electrodes were divided into four zones: left ventricular base and apex (LVB and LVA) and right ventricular base and apex (RVB and RVA). A fast Fourier transform was performed on each electrogram, and the mean activation rate was estimated from the dominant (peak) frequency (DF) and block was estimated to be present during those time intervals when double peaks (DPs) were present in the power spectrum. The zones had statistically significant distributions of DF (LVB>LVA>RVA>RVB) and DP incidence (RVA>RVB>LVA>LVB). CONCLUSION: During VF, the LV base has the highest estimated activation rate and the lowest estimated block incidence, and the RV has the slowest rate but the highest block incidence. This is consistent with the concept of VF being maintained by activation fronts originating from the LV base.