Age‐dependent differences in morphine‐induced taste aversions

Adolescence is a developmental period of particular importance given the host of neurobiological changes that occur during this stage of development. Drug use and abuse is said to be a function of the balance of its rewarding and aversive effects, and any age‐dependent differences in morphine's aversive effects could impact drug intake. The present experiments examined the ability of morphine sulfate (0, 3.2, 10, and 18 mg/kg) to induce taste aversions in adolescent and adult rats under high (20‐min fluid access each day; Experiment 1A/B) and low (50% of ad libitum access; Experiment 2A/B) deprivation conditions. In both studies, adolescent and adult rats were given a novel saccharin solution to drink and were subsequently injected with morphine. Independent of the deprivation condition, adults acquired stronger aversions than adolescents and did so at a faster rate. On a subsequent two‐bottle aversion test, all morphine‐injected subjects drank a significantly lower percentage of saccharin than vehicle‐injected controls with adults exhibiting stronger aversions than adolescents. These age‐dependent differences in morphine‐induced CTAs extend the findings with other drugs of abuse for which adolescents exhibit weaker aversions. The possible basis for and implications of these differences were discussed. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 415–428, 2013     

Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress

Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O₂), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mammalian target of rapamycin complex 1 (mTORC1) activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O₂. Specifically, we demonstrate that hypoxic Tsc2^−/− (tuberous sclerosis complex 2^−/−) cells deprived of serum lipids exhibit a magnified unfolded protein response (UPR) but fail to appropriately expand their endoplasmic reticulum (ER), leading to inositol-requiring protein-1 (IRE1)-dependent cell death that can be reversed by the addition of unsaturated lipids. UPR activation and apoptosis were also detected in Tsc2-deficient kidney tumors. Importantly, we observed this phenotype in multiple human cancer cell lines and suggest that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.     

Opposed hemodynamic responses following increased excitation and parvalbumin-based inhibition

Understanding cellular contributions to hemodynamic activity is essential for interpreting blood-based brain mapping signals. Optogenetic studies examining cell-specific influences on local hemodynamics have reported that excitatory activity results in cerebral perfusion and blood volume increase, while inhibitory activity contributes to both vasodilation and vasoconstriction. How specific subpopulations of interneurons regulate the brain’s blood supply is less examined. Parvalbumin interneurons are the largest subpopulation of GABAergic neurons in the brain, critical for brain development, plasticity, and long-distance excitatory neurotransmission. Despite their essential role in brain function, the contribution of parvalbumin neurons to neurovascular coupling has been relatively unexamined. Using optical intrinsic signal imaging and laser speckle contrast imaging, we photostimulated awake and anesthetized transgenic mice expressing channelrhodopsin under a parvalbumin promoter. Increased parvalbumin activity reduced local oxygenation, cerebral blood volume, and cerebral blood flow. These “negative” hemodynamic responses were consistent within and across mice and reproducible across a broad range of photostimulus parameters. However, the sign and magnitude of the hemodynamic response resulting from increased parvalbumin activity depended on the type and level of anesthesia used. Opposed hemodynamic responses following increased excitation or parvalbumin-based inhibition suggest unique contributions from different cell populations to neurovascular coupling.     

A Basomedial Amygdala to Intercalated Cells Microcircuit Expressing PACAP and Its Receptor PAC1 Regulates Contextual Fear

Trauma can cause dysfunctional fear regulation leading some people to develop disorders, such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased CFOS expression in mICCs, decreased fear recall, and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICC PACAPergic pathway produced EPSCs in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENT Traumatic stress can affect different aspects of fear behaviors, including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear, including acquisition, generalization, recall, and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.     

Comparison of Tc-99m MAA Planar Versus SPECT/CT Imaging for Lung Shunt Fraction Evaluation Prior to Y-90 Radioembolization: Are We Overestimating Lung Shunt Fraction?

CardioVascular and Interventional Radiology - To compare lung shunt fraction (LSF) prior to Y-90 radioembolization calculated using planar imaging versus SPECT/CT in patients with hepatocellular...     

Meta-analysis of Intraprocedural Comparative Effectiveness of Vascular Plugs Vs Coils in Proximal Splenic Artery Embolization and Associated Patient Radiation Exposure

PurposeTo compare vascular plugs to coil embolization of the proximal splenic artery and evaluate differences in radiation exposure to the patients.MethodsAn electronic literature search was performed for relevant studies from January 2000 to July 2018 that compared the efficacy of vascular plugs vs coils in splenic artery embolization. Only studies that investigated coil or vascular plug use, without combination with other embolic agents, were included. Meta-analysis was performed using a fixed effects model approach with the inverse variance-weighted average method to determine pooled differences in time to vessel occlusion, procedure time, fluoroscopy time, total number of devices used, and radiation exposure. Heterogeneity was assessed using the I square statistic. Pooled outcomes were compared, and quality assessments were evaluated using the Newcastle Ottawa Scale.ResultsEight studies met inclusion criteria. 81 patients were embolized with vascular plugs and 52 patients with coils only. The most common indication for splenic artery embolization was trauma. Time to vessel occlusion was shorter in the vascular plug group by 7.11 minutes (P = 0.003). Fluoroscopy time was shorter by 13.82 minutes in the vascular plug cohort, and these patients received less radiation (?439 mGy) compared to the coil group (P = 0.006 and P = 0.02, respectively). The number of devices was significantly fewer in the vascular plug group (?3.54; P < 0.001). Procedure time was not statistically significant.ConclusionOur data supports the vascular plug is superior to coils for embolization of the proximal splenic artery with respect to occlusion time, fluoroscopy time, patient radiation exposure, and number occlusive devices used.