scholarly journals The prediction-error hypothesis of schizophrenia: new data point to circuit-specific changes in dopamine activity

2021 ◽  
Author(s):  
Samuel J. Millard ◽  
Carrie E. Bearden ◽  
Katherine H. Karlsgodt ◽  
Melissa J. Sharpe
Keyword(s):  
Reinforcement Learning ◽  
Cognitive Deficits ◽  
Preclinical Models ◽  
Preclinical Research ◽  
Neutral Information ◽  
Learning Paradox ◽  
Midbrain Dopamine ◽  
Dopamine Circuits ◽  
New Research ◽  
Cohesive Framework

AbstractSchizophrenia is a severe psychiatric disorder affecting 21 million people worldwide. People with schizophrenia suffer from symptoms including psychosis and delusions, apathy, anhedonia, and cognitive deficits. Strikingly, schizophrenia is characterised by a learning paradox involving difficulties learning from rewarding events, whilst simultaneously ‘overlearning’ about irrelevant or neutral information. While dysfunction in dopaminergic signalling has long been linked to the pathophysiology of schizophrenia, a cohesive framework that accounts for this learning paradox remains elusive. Recently, there has been an explosion of new research investigating how dopamine contributes to reinforcement learning, which illustrates that midbrain dopamine contributes in complex ways to reinforcement learning, not previously envisioned. This new data brings new possibilities for how dopamine signalling contributes to the symptomatology of schizophrenia. Building on recent work, we present a new neural framework for how we might envision specific dopamine circuits contributing to this learning paradox in schizophrenia in the context of models of reinforcement learning. Further, we discuss avenues of preclinical research with the use of cutting-edge neuroscience techniques where aspects of this model may be tested. Ultimately, it is hoped that this review will spur to action more research utilising specific reinforcement learning paradigms in preclinical models of schizophrenia, to reconcile seemingly disparate symptomatology and develop more efficient therapeutics.

scholarly journals Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 647
Author(s):  
Allen PF Chen ◽  
Lu Chen ◽  
Thomas A. Kim ◽  
Qiaojie Xiong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neural Circuit ◽  
Selective Vulnerability ◽  
Dependent Manner ◽  
Memory Processing ◽  
Systems Neuroscience ◽  
Neuropsychiatric Diseases ◽  
Midbrain Dopamine ◽  
Dopamine Circuits

Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson’s, Schizophrenia, addiction, and Alzheimer’s disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA’s behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia’s dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA’s reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson’s disease, addiction, and Alzheimer’s Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA’s necessity and contribution to the functional plasticity of different striatal regions.

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 74
Author(s):  
Mónica Villarreal-Salazar ◽  
Astrid Brull ◽  
Gisela Nogales-Gadea ◽  
Antoni L. Andreu ◽  
Miguel A. Martín ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Autosomal Recessive Disorder ◽  
Glycogen Metabolism ◽  
Preclinical Models ◽  
Preclinical Research ◽  
Mcardle Disease ◽  
Invasive Techniques ◽  
Insight Into

McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.

scholarly journals UK consensus on pre-clinical vascular cognitive impairment functional outcomes assessment: Questionnaire and workshop proceedings

2020 ◽  
Vol 40 (7) ◽  
pp. 1402-1414
Author(s):  
Aisling McFall ◽  
Tuuli M Hietamies ◽  
Ashton Bernard ◽  
Margaux Aimable ◽  
Stuart M Allan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Functional Outcomes ◽  
Vascular Cognitive Impairment ◽  
Preclinical Models ◽  
Preclinical Research ◽  
Outcome Assessments ◽  
Consensus Statements ◽  
Functional Assessments ◽  
Research Centres ◽  
Assessment Questionnaire

Assessment of outcome in preclinical studies of vascular cognitive impairment (VCI) is heterogenous. Through an ARUK Scottish Network supported questionnaire and workshop (mostly UK-based researchers), we aimed to determine underlying variability and what could be implemented to overcome identified challenges. Twelve UK VCI research centres were identified and invited to complete a questionnaire and attend a one-day workshop. Questionnaire responses demonstrated agreement that outcome assessments in VCI preclinical research vary by group and even those common across groups, may be performed differently. From the workshop, six themes were discussed: issues with preclinical models, reasons for choosing functional assessments, issues in interpretation of functional assessments, describing and reporting functional outcome assessments, sharing resources and expertise, and standardization of outcomes. Eight consensus points emerged demonstrating broadly that the chosen assessment should reflect the deficit being measured, and therefore that one assessment does not suit all models; guidance/standardisation on recording VCI outcome reporting is needed and that uniformity would be aided by a platform to share expertise, material, protocols and procedures thus reducing heterogeneity and so increasing potential for collaboration, comparison and replication. As a result of the workshop, UK wide consensus statements were agreed and future priorities for preclinical research identified.

scholarly journals Instantiation of incentive value and movement invigoration by distinct midbrain dopamine circuits

2017 ◽  
Author(s):  
Benjamin T. Saunders ◽  
Jocelyn M. Richard ◽  
Elyssa B. Margolis ◽  
Patricia H. Janak
Keyword(s):  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Temporal Association ◽  
Conditioned Stimuli ◽  
Incentive Value ◽  
Pavlovian Learning ◽  
Midbrain Dopamine ◽  
Dopamine Circuits

Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals towards the acquisition of “rewards” (i.e., food) that are necessary for survival. Here, we test the fundamental role of midbrain dopamine neurons in conferring predictive or motivational properties to cues, independent of external rewards. We demonstrate that phasic optogenetic excitation of dopamine neurons throughout the midbrain, when presented in temporal association with discrete sensory cues, is sufficient to instantiate those cues as conditioned stimuli that subsequently both evoke dopamine neuron activity on their own, and elicit cue-locked conditioned behaviors. Critically, we identify highly parcellated behavioral functions for dopamine neuron subpopulations projecting to discrete regions of striatum, revealing dissociable mesostriatal systems for the generation of incentive value and movement invigoration. These results show that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to shape cue-controlled behavior.

Cannabinoids and Nausea

2017 ◽  
Author(s):  
Linda A. Parker
Keyword(s):  
Endocannabinoid System ◽  
Insular Cortex ◽  
Nausea And Vomiting ◽  
Preclinical Models ◽  
Cannabinoid System ◽  
Degrading Enzymes ◽  
New Research ◽  
Endogenous Cannabinoid ◽  
Endogenous Cannabinoid System

The treatment of nausea has lagged behind the treatment of chemotherapy-induced vomiting, despite its prevalence. The first recognized medicinal benefit of THC after its discovery was for chemotherapy-induced nausea and vomiting. Since the discovery of the endocannabinoid system, our understanding of the mechanisms by which cannabinoids reduce nausea and vomiting has been greatly improved. CB1 agonists reduce nausea in preclinical models. CBD and CBDA also show promise as non-psychoactive treatments. As well treatments that boost the endogenous cannabinoid system by inhibiting the degrading enzymes FAAH (elevating AEA) and MAGL (elevating 2-AG) or both have shown promise to treat nausea in preclinical models. New research identifies the interoceptive insular cortex as a region which may regulate the experience of nausea and its amelioration by 2-AG.

Perinatal Asphyxia: A Clinical Review, Including Research with Brain Hypothermia

2001 ◽  
Vol 20 (3) ◽  
pp. 31-40
Author(s):  
Nancy Ellen Flavin
Keyword(s):  
Cognitive Deficits ◽  
Perinatal Asphyxia ◽  
Clinical Manifestations ◽  
In Utero ◽  
Postnatal Period ◽  
Neurologic Injury ◽  
Newborn Animal ◽  
Neurologic Sequelae ◽  
New Research ◽  
Human Neonates

Perinatal asphyxia may occur in utero, during labor and delivery, or in the postnatal period. There are numerous causes, and the clinical manifestations vary. Infants who experience mild asphyxia may show no neurologic injury. Severe asphyxia may be fatal in utero, or immediately after birth, with survivors showing extensive neurologic sequelae, with or without cognitive deficits. Mild brain hypothermia appears promising in the prevention of further neurologic damage in encephalopathic infants following asphyxia. Recent research on newborn animal models has focused on the timing, duration, and depth of hypothermia. Promising new research is now under way in nurseries in the U.S. in an attempt to establish clinical protocols for use of hypothermia in human neonates.

Involvement of Midbrain Dopamine Neuron Activity in Negative Reinforcement Learning in Mice

2021 ◽  
Author(s):  
Zhijun Diao ◽  
Li Yao ◽  
Qiangqiang Cheng ◽  
Meilin Wu ◽  
Yuanyuan Di ◽  
...  
Keyword(s):  
Reinforcement Learning ◽  
Negative Reinforcement ◽  
Dopamine Neuron ◽  
Neuron Activity ◽  
Midbrain Dopamine

scholarly journals "Learning in reverse: Dopamine errors drive excitatory and inhibitory components of backward conditioning in an outcome-specific manner".

2022 ◽  
Author(s):  
Benjamin M Seitz ◽  
Ivy B Hoang ◽  
Aaron P Blaisdell ◽  
Melissa J Sharpe
Keyword(s):  
Reinforcement Learning ◽  
Dopamine Neurons ◽  
Prediction Errors ◽  
Learning Deficits ◽  
Backward Conditioning ◽  
Future Prediction ◽  
Midbrain Dopamine ◽  
Inhibitory Components ◽  
Complex Features ◽  
Dopamine Signal

For over two decades, midbrain dopamine was considered synonymous with the prediction error in temporal-difference reinforcement learning. Central to this proposal is the notion that reward-predictive stimuli become endowed with the scalar value of predicted rewards. When these cues are subsequently encountered, their predictive value is compared to the value of the actual reward received allowing for the calculation of prediction errors. Phasic firing of dopamine neurons was proposed to reflect this computation, facilitating the backpropagation of value from the predicted reward to the reward-predictive stimulus, thus reducing future prediction errors. There are two critical assumptions of this proposal: 1) that dopamine errors can only facilitate learning about scalar value and not more complex features of predicted rewards, and 2) that the dopamine signal can only be involved in anticipatory learning in which cues or actions precede rewards. Recent work has challenged the first assumption, demonstrating that phasic dopamine signals across species are involved in learning about more complex features of the predicted outcomes, in a manner that transcends this value computation. Here, we tested the validity of the second assumption. Specifically, we examined whether phasic midbrain dopamine activity would be necessary for backward conditioning- when a neutral cue reliably follows a rewarding outcome. Using a specific Pavlovian-to-Instrumental Transfer (PIT) procedure, we show rats learn both excitatory and inhibitory components of a backward association, and that this association entails knowledge of the specific identity of the reward and cue. We demonstrate that brief optogenetic inhibition of ventral tegmental area dopamine (VTA DA) neurons timed to the transition between the reward and cue, reduces both of these components of backward conditioning. These findings suggest VTA DA neurons are capable of facilitating associations between contiguously occurring events, regardless of the content of those events. We conclude that these data are in line with suggestions that the VTA DA error acts as a universal teaching signal. This may provide insight into why dopamine function has been implicated in a myriad of psychological disorders that are characterized by very distinct reinforcement-learning deficits.

scholarly journals Differentiation therapy of myeloid leukemia: four decades of development

Haematologica ◽  
2020 ◽  
pp. 1-13
Author(s):  
Vikas Madan ◽  
H. Phillip Koeffler
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Clinical Benefit ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Differentiation Therapy ◽  
Preclinical Models ◽  
Preclinical Research ◽  
Acute Myeloid

Acute myeloid leukemia is characterized by arrested differentiation, and agents that overcome this block are therapeutically useful, as shown by the efficacy of all-trans retinoic acid in acute promyelocytic leukemia. However, the early promise of differentiation therapy did not translate into clinical benefit for other subtypes of acute myeloid leukemia, in which cytotoxic chemotherapeutic regimens remained the standard of care. Recent advances, including insights from sequencing of acute myeloid leukemia genomes, have led to the development of targeted therapies, comprising agents that induce differentiation of leukemic cells in preclinical models and clinical trials, thus rejuvenating interest in differentiation therapy. These agents act on various cellular processes including dysregulated metabolic programs, signaling pathways, epigenetic machinery and the cell cycle. In particular, inhibitors of mutant IDH1/2 and FLT3 have shown clinical benefit, leading to approval by regulatory bodies of their use. Besides the focus on recently approved differentiation therapies, this review also provides an overview of differentiation- inducing agents being tested in clinical trials or investigated in preclinical research. Combinatorial strategies are currently being tested for several agents (inhibitors of KDM1A, DOT1L, BET proteins, histone deacetylases), which were not effective in clinical studies as single agents, despite encouraging anti-leukemic activity observed in preclinical models. Overall, recently approved drugs and new investigational agents being developed highlight the merits of differentiation therapy; and ongoing studies promise further advances in the treatment of acute myeloid leukemia in the near future.

scholarly journals Rethinking dopamine as generalized prediction error

2017 ◽  
Author(s):  
Matthew P.H. Gardner ◽  
Geoffrey Schoenbaum ◽  
Samuel J. Gershman
Keyword(s):  
Reinforcement Learning ◽  
Prediction Error ◽  
Dopamine Neurons ◽  
Prediction Errors ◽  
Model Free ◽  
Reward Prediction ◽  
Midbrain Dopamine ◽  
Sensory Prediction ◽  
Lines Of Evidence ◽  
Midbrain Dopamine Neurons

AbstractMidbrain dopamine neurons are commonly thought to report a reward prediction error, as hypothesized by reinforcement learning theory. While this theory has been highly successful, several lines of evidence suggest that dopamine activity also encodes sensory prediction errors unrelated to reward. Here we develop a new theory of dopamine function that embraces a broader conceptualization of prediction errors. By signaling errors in both sensory and reward predictions, dopamine supports a form of reinforcement learning that lies between model-based and model-free algorithms. This account remains consistent with current canon regarding the correspondence between dopamine transients and reward prediction errors, while also accounting for new data suggesting a role for these signals in phenomena such as sensory preconditioning and identity unblocking, which ostensibly draw upon knowledge beyond reward predictions.

Sign in / Sign up

Export Citation Format

Share Document