Dopamine-dependent long-term plasticity is believed to be a cellular mechanism underlying reinforcement learning. In response to reward and reward-predicting cues, phasic dopamine activity ...potentiates the efficacy of corticostriatal synapses on spiny projection neurons (SPNs). Since phasic dopamine activity also encodes other behavioural variables, it is unclear how postsynaptic neurons identify which dopamine event is to induce long-term plasticity. Additionally, it is unknown how phasic dopamine released from arborised axons can potentiate targeted striatal synapses through volume transmission. To examine these questions we manipulated striatal cholinergic interneurons (ChIs) and dopamine neurons independently in two distinct in vivo paradigms. We report that long-term potentiation (LTP) at corticostriatal synapses with SPNs is dependent on the coincidence of pauses in ChIs and phasic dopamine activation, critically accompanied by SPN depolarisation. Thus, the ChI pause defines the time window for phasic dopamine to induce plasticity, while depolarisation of SPNs constrains the synapses eligible for plasticity.
Cholinergic interneurons have emerged as one of the key players controlling network functions in the striatum. Extracellularly recorded cholinergic interneurons acquire characteristic responses to ...sensory stimuli during reward-related learning, including a pause and subsequent rebound in spiking. However, the precise underlying cellular mechanisms have remained elusive. Here, we review recent advances in our understanding of the regulation of cholinergic interneuron activity. We discuss evidence of mechanisms that have been proposed to underlie sensory responses, including antagonistic actions by dopamine, recurrent inhibition via local interneurons, and an intrinsically generated membrane hyperpolarization in response to excitatory inputs. The review highlights outstanding questions and concludes with a model of the sensory responses and their downstream effects through dynamic acetylcholine receptor activation.
This volume, growing out of the celebrated turn toward history in literary criticism, showcases some of the best new historical work being done today in textual theory, literary history, and cultural ...criticism. The collection brings together for the first time key representativesfrom various schools of historicist scholarship, including leading critics whose work has helped define new historicism. The essays illuminate literary periods ranging from Anglo-Saxon to postmodern, a variety of literary texts that includes The Siege of Thebes, Macbeth, The Jazz Singer, and The Chosen Place, the Timeless People, and central issues that have marked new historicism: power, ideology, textuality, othering, marginality, exile, and liberation. The contributors are Janet Aikins, Lawrence Buell, Ralph Cohen, Margaret Ezell, Stephen Greenblatt, Terence Hoagwood, Jerome McGann, Robert Newman, Katherine O'Keeffe, Lee Patterson, Michael Rogin, Edward Said, and Hortense Spillers. The editors' introduction situates the various essays within contemporary criticism and explores the multiple, contestatory issues at stake within the historicist enterprise.
Plasticity at synapses between the cortex and striatum is considered critical for learning novel actions. However, investigations of spike-timing-dependent plasticity (STDP) at these synapses have ...been performed largely in brain slice preparations, without consideration of physiological reinforcement signals. This has led to conflicting findings, and hampered the ability to relate neural plasticity to behavior. Using intracellular striatal recordings in intact rats, we show here that pairing presynaptic and postsynaptic activity induces robust Hebbian bidirectional plasticity, dependent on dopamine and adenosine signaling. Such plasticity, however, requires the arrival of a reward-conditioned sensory reinforcement signal within 2 s of the STDP pairing, thus revealing a timing-dependent eligibility trace on which reinforcement operates. These observations are validated with both computational modeling and behavioral testing. Our results indicate that Hebbian corticostriatal plasticity can be induced by classical reinforcement learning mechanisms, and might be central to the acquisition of novel actions.Spike timing dependent plasticity (STDP) has been studied extensively in slices but whether such pairings can induce plasticity in vivo is not known. Here the authors report an experimental paradigm that achieves bidirectional corticostriatal STDP in vivo through modulation by behaviourally relevant reinforcement signals, mediated by dopamine and adenosine signaling.
An essential aim of biomedical research is to translate basic science information obtained from preclinical research using small and large animal models into clinical practice for the benefit of ...humans. Research on rodent models has enhanced our understanding of complex pathophysiology, thus providing potential translational pathways. However, the success of translating drugs from pre-clinical to clinical therapy has been poor, partly due to the choice of experimental model. The sheep model, in particular, is being increasingly applied to the field of biomedical research and is arguably one of the most influential models of human organ systems. It has provided essential tools and insights into cardiovascular disorder, orthopaedic examination, reproduction, gene therapy, and new insights into neurodegenerative research. Unlike the widely adopted rodent model, the use of the sheep model has an advantage over improving neuroscientific translation, in particular due to its large body size, gyrencephalic brain, long lifespan, more extended gestation period, and similarities in neuroanatomical structures to humans. This review aims to summarise the current status of sheep to model various human diseases and enable researchers to make informed decisions when considering sheep as a human biomedical model.
Highlights • The acute effect of LI-rMS on layer 5 pyramidal neurons was investigated in vitro. • LI-rMS does not alter passive membrane properties. • LI-rMS induced hyperpolarized action potential ...thresholds. • LI-rMS Increased evoked spike firing frequency.
Ultrasound-mediated blood-brain barrier (BBB) disruption has garnered focus as a method of delivering normally impenetrable drugs into the brain. Numerous studies have investigated this approach, and ...a diverse set of ultrasound parameters appear to influence the efficacy and safety of this approach. An understanding of these findings is essential for safe and reproducible BBB disruption, as well as in identifying the limitations and gaps for further advancement of this drug delivery approach. We aimed to collate and summarise protocols and parameters for achieving ultrasound-mediated BBB disruption in animal and clinical studies, as well as the efficacy and safety methods and outcomes associated with each. A systematic search of electronic databases helped in identifying relevant, included studies. Reference lists of included studies were further screened to identify supplemental studies for inclusion. In total, 107 articles were included in this review, and the following parameters were identified as influencing efficacy and safety outcomes: microbubbles, transducer frequency, peak-negative pressure, pulse characteristics, and the dosing of ultrasound applications. Current protocols and parameters achieving ultrasound-mediated BBB disruption, as well as their associated efficacy and safety outcomes, are identified and summarised. Greater standardisation of protocols and parameters in future preclinical and clinical studies is required to inform robust clinical translation.
Positive reinforcement helps to control the acquisition of learned behaviours. Here we report a cellular mechanism in the brain that may underlie the behavioural effects of positive reinforcement. We ...used intracranial self-stimulation (ICSS) as a model of reinforcement learning, in which each rat learns to press a lever that applies reinforcing electrical stimulation to its own substantia nigra. The outputs from neurons of the substantia nigra terminate on neurons in the striatum in close proximity to inputs from the cerebral cortex on the same striatal neurons. We measured the effect of substantia nigra stimulation on these inputs from the cortex to striatal neurons and also on how quickly the rats learned to press the lever. We found that stimulation of the substantia nigra (with the optimal parameters for lever-pressing behaviour) induced potentiation of synapses between the cortex and the striatum, which required activation of dopamine receptors. The degree of potentiation within ten minutes of the ICSS trains was correlated with the time taken by the rats to learn ICSS behaviour. We propose that stimulation of the substantia nigra when the lever is pressed induces a similar potentiation of cortical inputs to the striatum, positively reinforcing the learning of the behaviour by the rats.
Despite the importance of consumers in structuring communities, and the widespread assumption that consumption is strongest at low latitudes, empirical tests for global scale patterns in the ...magnitude of consumer impacts are limited. In marine systems, the long tradition of experimentally excluding herbivores in their natural environments allows consumer impacts to be quantified on global scales using consistent methodology. We present a quantitative synthesis of 613 marine herbivore exclusion experiments to test the influence of consumer traits, producer traits and the environment on the strength of herbivore impacts on benthic producers. Across the globe, marine herbivores profoundly reduced producer abundance (by 68% on average), with strongest effects in rocky intertidal habitats and the weakest effects on habitats dominated by vascular plants. Unexpectedly, we found little or no influence of latitude or mean annual water temperature. Instead, herbivore impacts differed most consistently among producer taxonomic and morphological groups. Our results show that grazing impacts on plant abundance are better predicted by producer traits than by large‐scale variation in habitat or mean temperature, and that there is a previously unrecognised degree of phylogenetic conservatism in producer susceptibility to consumption.
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