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Identification of Rat Ventral Tegmental Area GABAergic Neurons
The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain ventral tegmental area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABA(B) receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.
Journal Article
Sensitivity potential to a light flavor-changing scalar boson with DUNE and NA64μ
In this work, we report on the sensitivity potential of complementary muon-on-target experiments to new physics using a scalar boson benchmark model associated with charged lepton flavor violation. The NA64
μ
experiment at CERN uses a 160-GeV energy muon beam with an active target to search for excess events with missing energy and momentum as a probe of new physics. At the same time, the proton beam at Fermilab, which is used to produce the neutrino beam for the Deep Underground Neutrino Experiment (DUNE), will also produce a high-intensity muon beam dumped in an absorber. Combined with the liquid argon near detector, the system could be used to search for similar scalar boson particles with a lower-energy but higher-intensity beam. We find that both NA64
μ
and DUNE could cover new, unexplored parts of the parameter space of the same benchmark model, providing a complementary way to search for new physics.
Journal Article
Rice : global networks and new histories
\"Global Networks and New Histories Rice today is food to half the world's population. Its history is inextricably entangled with the emergence of colonialism, the global networks of industrial capitalism, and the modern world economy. The history of rice is currently a vital and innovative field of research attracting serious attention, but no attempt has yet been made to write a history of rice and its place in the rise of capitalism from a global and comparative perspective. Rice is a first step toward such a history. The fifteen chapters, written by specialists on Africa, the Americas, and several regions of Asia, are premised on the utility of a truly international approach to history. Each one brings a new approach that unsettles prevailing narratives and suggests new connections. Together they cast new light on the significant roles of rice as crop, food, and commodity and shape historical trajectories and interregional linkages in Africa, the Americas, Europe, and Asia\"-- Provided by publisher.
Book
Mu Opioid Receptor Actions in the Lateral Habenula
Increased activity of lateral habenula (LHb) neurons is correlated with aversive states including pain, opioid abstinence, rodent models of depression, and failure to receive a predicted reward. Agonists at the mu opioid receptor (MOR) are among the most powerful rewarding and pain relieving drugs. Injection of the MOR agonist morphine directly into the habenula produces analgesia, raising the possibility that MOR acts locally within the LHb. Consequently, we examined the synaptic actions of MOR agonists in the LHb using whole cell patch clamp recording. We found that the MOR selective agonist DAMGO inhibits a subset of LHb neurons both directly and by inhibiting glutamate release onto these cells. Paradoxically, DAMGO also presynaptically inhibited GABA release onto most LHb neurons. The behavioral effect of MOR activation will thus depend upon both the level of intrinsic neuronal activity in the LHb and the balance of activity in glutamate and GABA inputs to different LHb neuronal populations.
Journal Article
Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry
Relief of pain is rewarding. Using a model of experimental postsurgical pain we show that blockade of afferent input from the injury with local anesthetic elicits conditioned place preference, activates ventral tegmental dopaminergic cells, and increases dopamine release in the nucleus accumbens. Importantly, place preference is associated with increased activity in midbrain dopaminergic neurons and blocked by dopamine antagonists injected into the nucleus accumbens. The data directly support the hypothesis that relief of pain produces negative reinforcement through activation of the mesolimbic reward-valuation circuitry.
Journal Article
Unmasking the tonic-aversive state in neuropathic pain
Tonic pain, a chief clinical problem, is difficult to study in rodent models that measure threshold changes of evoked reactions to acutely applied stimuli. These authors used conditioned place preference to assess tonic pain in rats and measure the efficacy of agents that relieve it.
Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.
Journal Article
Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity
Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.
Journal Article