A Midbrain Circuit that Mediates Headache Aversiveness in Rats.

Migraines are a major health burden, but treatment is limited because of inadequate understanding of neural mechanisms underlying headache. Imaging studies of migraine patients demonstrate changes in both pain-modulatory circuits and reward-processing regions, but whether these changes contribute to the experience of headache is unknown. Here, we demonstrate a direct connection between the ventrolateral periaqueductal gray (vlPAG) and the ventral tegmental area (VTA) that contributes to headache aversiveness in rats. Many VTA neurons receive monosynaptic input from the vlPAG, and cranial nociceptive input increases Fos expression in VTA-projecting vlPAG neurons. Activation of PAG inputs to the VTA induces avoidance behavior, while inactivation of these projections induces a place preference only in animals with headache. This work identifies a distinct pathway that mediates cranial nociceptive aversiveness

Interaction between Family History of Alcoholism and Locus of Control in the Opioid Regulation of Impulsive Responding under the Influence of Alcohol

Naltrexone (NTX) is an opioid antagonist indicated for the treatment of alcoholism, which is not universally effective. Thus, identifying individual predictors of NTX’s behavioral effects is critical to optimizing its therapeutic use. Moreover, given the high rate of relapse during treatment for alcoholism, understanding NTX’s behavioral effects when combined with moderate ethanol intake is important. Our previous study of abstinent alcoholics and control subjects showed that a more internal Locus of Control score predicted increased impulsive choice on NTX (Mitchell et al., 2007). Here we tested whether this predictive relationship remains in the context of moderate alcohol intake

Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for Kras(G12D)-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and Kras(G12D)-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted Kras(G12D)-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression

Now or Later? An fMRI study of the effects of endogenous opioid blockade on a decision-making network

Previously, we found that distinct brain areas predict individual selection bias in decisions between small immediate (“Now”) and larger delayed rewards (“Later”). Furthermore, such selection bias can be manipulated by endogenous opioid blockade. To test whether blocking endogenous opioids with Naltrexone (NTX) alters brain activity during decision-making in areas predicting individual bias, we compared fMRI BOLD signal correlated with Now versus Later decision-making after acute administration of NTX (50 mg) or placebo. We tested abstinent alcoholics and control subjects in a double-blind two-session design. We defined regions of interest (ROI) centered on activation peaks predicting Now versus Later selection bias. NTX administration significantly increased BOLD signal during decision-making in the right lateral orbital gyrus ROI, an area where enhanced activity during decision-making predicts Later bias. Exploratory analyses identified additional loci where BOLD signal during decision-making was enhanced (left orbitofrontal cortex, left inferior temporal gyrus, and cerebellum) or reduced (right superior temporal pole) by NTX. Additional analyses identified sites, including the right lateral orbital gyrus, in which NTX effects on BOLD signal predicted NTX effects on selection bias. These data agree with opioid receptor expression in human frontal and temporal cortices, and suggest possible mechanisms of NTX’s therapeutic effects

Cultural Resources Investigations Along Whiteoak Bayou, Harris County, Texas

In 1986, cultural resources investigations were carried out to prepare a synthesis of the archeology of the Whiteoak Bayou area in western Harris County, Texas, and to conduct subsurface testing at prehistoric sites that may be affected by the U.S. Army Corps of Engineers Upper Whiteoak Bayou Flood Damage Reduction Project. The tasks undertaken during these investigations are: (1) background research into the environment and archeology of the area; (2) historic/archival research and reconnaissance survey to summarize the historical development of Whiteoak Bayou and to identify any important sites in the project area; (3) intensive survey of Vogel Creek, a tributary to Whiteoak Bayou, to assess the potential for intact cultural remains; (4) National Register testing and assessment of nine aboriginal sites; (5) geoarcheological investigations to establish the geological context of the archeological remains, to identify the depositional environments represented, and to establish an alluvial sequence for the project area; and (6) analysis of a large collection of artifacts from 46 Whiteoak Bayou sites made prior to 1986 by members of the Houston Archeological Society, as well as the materials recovered during 1986. The nine archeological sites tesLed during this project are 41HR241, 4lHR259, 41HR273, 41HR278, 41HR279, 41HR283, 41HR290, 41HR298, and 41HR541. The testing showed that only three -- 41HR259, 41HR273, and 41HR541 -- have substantial, intact cultural deposits. Two of these -- 41HR273 and 41HR541 -- are judged to be eligible for listing on the National Register of Historic Places and for designation as State Archeological Landmarks. One site, 4lHR259, is currently listed on the National Register, although the remaining part of this site is judged to have a limited potential to yield additi0nal information. The other seven sites are judged to be ineligible for listing

Immediate Reward Bias in Humans: Fronto-Parietal Networks and a Role for the Catechol-O-Methyltransferase 158Val/Val Genotype

The tendency to choose lesser immediate benefits over greater long-term benefits characterizes alcoholism and other addictive disorders. However, despite its medical and socioeconomic importance, little is known about its neurobiological mechanisms. Brain regions that are activated when deciding between immediate or delayed rewards have been identified

Endogenous Opioid Activity in the Anterior Cingulate Cortex Is Required for Relief of Pain

Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α(2)-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness

Reliability in the Identification of Midbrain Dopamine Neurons

Brain regions typically contain intermixed subpopulations of neurons with different connectivity and neurotransmitters. This complicates identification of neuronal phenotypes in electrophysiological experiments without using direct detection of unique molecular markers. A prime example of this difficulty is the identification of dopamine (DA) neurons in the midbrain ventral tegmental area (VTA). Although immunocytochemistry (ICC) against tyrosine hydroxylase (TH) is widely used to identify DA neurons, a high false negative rate for TH ICC following ex vivo electrophysiology experiments was recently reported, calling into question the validity of comparing DA and non-DA VTA neurons based on post-hoc ICC. However, in whole cell recordings from randomly selected rat VTA neurons we have found that TH labeling is consistently detected in ∼55% of neurons even after long recording durations (range: 2.5–150 min). This is consistent with our prior anatomical finding that 55% of VTA neurons are TH(+). To directly estimate a false negative rate for our ICC method we recorded VTA neurons from mice in which EGFP production is driven by the TH promoter. All 12 EGFP(+) neurons recorded with a K-gluconate internal solution (as used in our rat recordings) were strongly labeled by TH ICC (recording duration 16.6±1.8 min). However, using recording electrodes with an internal solution with high Cl− concentration reduced the intensity of TH co-labeling, in some cases to background (recording duration 16.7±0.9 min; n = 10). Thus TH is a highly reliable molecular marker for DA neurons in VTA patch clamp recordings provided compatible microelectrode solutions are used

The Majorana experiment: an ultra-low background search for neutrinoless double-beta decay

The observation of neutrinoless double-beta decay would resolve the Majorana nature of the neutrino and could provide information on the absolute scale of the neutrino mass. The initial phase of the Majorana experiment, known as the Demonstrator, will house 40 kg of Ge in an ultra-low background shielded environment at the 4850' level of the Sanford Underground Laboratory in Lead, SD. The objective of the Demonstrator is to determine whether a future 1-tonne experiment can achieve a background goal of one count per tonne-year in a narrow region of interest around the 76Ge neutrinoless double-beta decay peak.Comment: Presentation for the Rutherford Centennial Conference on Nuclear Physic