Striatum
striatum
Prof Stephanie Cragg
Dopamine and astrocyte biology in health and Parkinson's disease. The Cragg Group at the University of Oxford are conducting an MRC-funded research project to explore the role of astrocytes in the regulation of striatal dopamine function in health and parkinsonism. We are now seeking to appoint a Postdoctoral Research Scientist with an interest in astrocyte biology to join us for this exciting project. The post-holder will explore striatal dopamine transmission, its regulation and dysregulation by activity in astrocytes, related circuits and signalling molecules in mouse brain. For advert and how to apply see: https://www.jobs.ac.uk/job/CPC368/post-doctoral-research-scientist-in-dopamine-and-astrocyte-biology-in-health-and-parkinsons-disease
Prof Ian Oldenburg
The Oldenburg lab combines optics, multiphoton optogenetics, calcium imaging, and computation to understand the motor system. The overall goal of the Oldenburg Lab is to understand the causal relationship between neural activity and motor actions. We use advanced optical techniques such as multiphoton holographic optogenetics to control neural activity with an incredible degree of precision, writing complex patterns of activity to distributed groups of cells. Only by writing activity into the brain at the scale in which it naturally occurs (individual neurons firing distinct patterns of action potentials) can we test theories of what population activity means. We read out the effects of these precise manipulations locally with calcium imaging, in neighboring brain regions with electrophysiology, and at the 'whole animal level' through changes in behavior. We are looking for curious motivated, and talented people with a wide range of skill sets to join our group at all levels from Technician to Postdoc.
Mark Humphries
A 4-year fully-funded PhD studentship project with Professor Mark Humphries and Professor Stephen Coombes is available for October 2024 start, through the University of Nottingham's BBSRC Doctoral Training Programme. The striatum is central to an extraordinary range of disorders, from Parkinson's disease to OCD, but our best models for its function are outdated and contradicted by recent data. In this project, we will test the hypothesis that the striatum is a special class of recurrent neural networks (RNNs) that use purely inhibitory connections. We will build and analyse this class of networks, deriving predictions for the computations that striatum performs, and for the activity of neuron populations in the striatum. We will then test these predictions in two large-scale datasets of population recordings from striatum in freely-exploring mice from the studies of Klaus et al (Neuron, 2017) and Markowitz et al (Cell, 2018). The DTP offers 2 lab rotations and wide-ranging training modules. If successful, the PhD student will join the Humphries' lab and be part of the School of Psychology's extensive postgraduate support network.
SWEBAGS conference 2024: The involvement of the striatum in autism spectrum disorder
Decomposing motivation into value and salience
Humans and other animals approach reward and avoid punishment and pay attention to cues predicting these events. Such motivated behavior thus appears to be guided by value, which directs behavior towards or away from positively or negatively valenced outcomes. Moreover, it is facilitated by (top-down) salience, which enhances attention to behaviorally relevant learned cues predicting the occurrence of valenced outcomes. Using human neuroimaging, we recently separated value (ventral striatum, posterior ventromedial prefrontal cortex) from salience (anterior ventromedial cortex, occipital cortex) in the domain of liquid reward and punishment. Moreover, we investigated potential drivers of learned salience: the probability and uncertainty with which valenced and non-valenced outcomes occur. We find that the brain dissociates valenced from non-valenced probability and uncertainty, which indicates that reinforcement matters for the brain, in addition to information provided by probability and uncertainty alone, regardless of valence. Finally, we assessed learning signals (unsigned prediction errors) that may underpin the acquisition of salience. Particularly the insula appears to be central for this function, encoding a subjective salience prediction error, similarly at the time of positively and negatively valenced outcomes. However, it appears to employ domain-specific time constants, leading to stronger salience signals in the aversive than the appetitive domain at the time of cues. These findings explain why previous research associated the insula with both valence-independent salience processing and with preferential encoding of the aversive domain. More generally, the distinction of value and salience appears to provide a useful framework for capturing the neural basis of motivated behavior.
Neuromodulation of striatal D1 cells shapes BOLD fluctuations in anatomically connected thalamic and cortical regions
Understanding how macroscale brain dynamics are shaped by microscale mechanisms is crucial in neuroscience. We investigate this relationship in animal models by directly manipulating cellular properties and measuring whole-brain responses using resting-state fMRI. Specifically, we explore the impact of chemogenetically neuromodulating D1 medium spiny neurons in the dorsomedial caudate putamen (CPdm) on BOLD dynamics within a striato-thalamo-cortical circuit in mice. Our findings indicate that CPdm neuromodulation alters BOLD dynamics in thalamic subregions projecting to the dorsomedial striatum, influencing both local and inter-regional connectivity in cortical areas. This study contributes to understanding structure–function relationships in shaping inter-regional communication between subcortical and cortical levels.
Dopamine and Acetylcholine waves in the striatum
Prefrontal top-down projections control context-dependent strategy selection
The rules governing behavior often vary with behavioral contexts. As a result, an action rewarded in one context may be discouraged in another. Animals and humans are capable of switching between behavioral strategies under different contexts and acting adaptively according to the variable rules, a flexibility that is thought to be mediated by the prefrontal cortex (PFC). However, how the PFC orchestrates the context-dependent switch of strategies remains unclear. Here we show that pathway-specific projection neurons in the medial PFC (mPFC) differentially contribute to context-instructed strategy selection. In mice trained in a decision-making task in which a previously established rule and a newly learned rule are associated with distinct contexts, the activity of mPFC neurons projecting to the dorsomedial striatum (mPFC-DMS) encodes the contexts and further represents decision strategies conforming to the old and new rules. Moreover, mPFC-DMS neuron activity is required for the context-instructed strategy selection. In contrast, the activity of mPFC neurons projecting to the ventral midline thalamus (mPFC-VMT) does not discriminate between the contexts, and represents the old rule even if mice have adopted the new one. Furthermore, these neurons act to prevent the strategy switch under the new rule. Our results suggest that mPFC-DMS neurons promote flexible strategy selection guided by contexts, whereas mPFC-VMT neurons favor fixed strategy selection by preserving old rules.
Mapping learning and decision-making algorithms onto brain circuitry
In the first half of my talk, I will discuss our recent work on the midbrain dopamine system. The hypothesis that midbrain dopamine neurons broadcast an error signal for the prediction of reward is among the great successes of computational neuroscience. However, our recent results contradict a core aspect of this theory: that the neurons uniformly convey a scalar, global signal. I will review this work, as well as our new efforts to update models of the neural basis of reinforcement learning with our data. In the second half of my talk, I will discuss our recent findings of state-dependent decision-making mechanisms in the striatum.
PPN inputs to striatum
Mechanisms and Roles of Fast Dopamine Signaling
Dopamine is a neuromodulator that codes information on various time scales. I will discuss recent progress on the identification of fast release mechanisms for dopamine in the mouse striatum. I will present data on triggering mechanisms of dopamine release and evaluate its roles in striatal regulation. In the long-term, our work will allow for a better understanding of the mechanisms and time scales of dopamine coding in health and disease.
Cell assembly activation coordinated by rhythmic oscillation in the prefrontal-ventral striatum-hippocampal network
Synaptic alterations in the striatum drive ASD-related behaviors in mice
Experience-dependent remapping of temporal encoding by striatal ensembles
Medium-spiny neurons (MSNs) in the striatum are required for interval timing, or the estimation of the time over several seconds via a motor response. We and others have shown that striatal MSNs can encode the duration of temporal intervals via time-dependent ramping activity, progressive monotonic changes in firing rate preceding behaviorally salient points in time. Here, we investigated how timing-related activity within striatal ensembles changes with experience. We leveraged a rodent-optimized interval timing task in which mice ‘switch’ response ports after an amount of time has passed without reward. We report three main results. First, we found that the proportion of MSNs exhibiting time-dependent modulations of firing rate increased after 10 days of task overtraining. Second, temporal decoding by MSN ensembles increased with experience and was largely driven by time-related ramping activity. Finally, we found that time-related ramping activity generalized across both correct and error trials. These results enhance our understanding of striatal temporal processing by demonstrating that time-dependent activity within MSN ensembles evolves with experience and is dissociable from motor- and reward-related processes.
What about antibiotics for the treatment of the dyskinesia induced by L-DOPA?
L-DOPA-induced dyskinesia is a debilitating adverse effect of treating Parkinson’s disease with this drug. New therapeutic approaches that prevent or attenuate this side effect is clearly needed. Wistar adult male rats submitted to 6-hydroxydopamine-induced unilateral medial forebrain bundle lesions were treated with L-DOPA (oral or subcutaneous, 20 mg kg-1) once a day for 14 days. After this period, we tested if doxycycline (40 mg kg-1, intraperitoneal, a subantimicrobial dose) and COL-3 (50 and 100 nmol, intracerebroventricular) could reverse LID. In an additional experiment, doxycycline was also administered repeatedly with L-DOPA to verify if it would prevent LID development. A single injection of doxycycline or COL-3 together with L-DOPA attenuated the dyskinesia. Co-treatment with doxycycline from the first day of L-DOPA suppressed the onset of dyskinesia. The improved motor responses to L-DOPA remained intact in the presence of doxycycline or COL-3, indicating the preservation of L-DOPA-produced benefits. Doxycycline treatment was associated with decreased immunoreactivity of FosB, cyclooxygenase-2, the astroglial protein GFAP and the microglial protein OX-42 which are elevated in the basal ganglia of rats exhibiting dyskinesia. Doxycycline also decreased metalloproteinase-2/-9 activity, metalloproteinase-3 expression and reactive oxygen species production. Metalloproteinase-2/-9 activity and production of reactive oxygen species in the basal ganglia of dyskinetic rats showed a significant correlation with the intensity of dyskinesia. The present study demonstrates the anti-dyskinetic potential of doxycycline and its analog compound COL-3 in hemiparkinsonian rats. Given the long-established and safe clinical use of doxycycline, this study suggests that these drugs might be tested to reduce or to prevent L-DOPA-induced dyskinesia in Parkinson’s patients.
Neurotoxicity is a major health problem in Africa: focus on Parkinson's / Parkinsonism
Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.
The Dopamine Synapse and Learning
The actions of dopamine within the striatum are central to the selection of cortical and perhaps thalamic inputs that mediate learning throughout life, including during operant conditioning, reward and avoidance learning and the establishment of motor patterns. Dysfunction of these synaptic circuits during maturation or aging underlies many neurological, psychiatric and neurodevelopment disorders. We will discuss the biological sequences by which these synapses are altered as an animal interacts with the environment.
Male songbirds turn off their self-evaluation systems when they sing to females
Attending to mistakes while practicing alone provides opportunities for learning but self-evaluation during audience-directed performance could distract from ongoing execution. It remains unknown how animals switch between practice and performance modes, and how evaluation systems process errors across distinct performance contexts. We recorded from striatal-projecting dopamine (DA) neurons as male songbirds transitioned from singing alone to singing female-directed courtship song. In the presence of the female, singing-related performance error signals were reduced or gated off and DA neurons were instead phasically activated by female vocalizations. Mesostriatal DA neurons can thus dynamically change their tuning with changes in social context.
Delineating Reward/Avoidance Decision Process in the Impulsive-compulsive Spectrum Disorders through a Probabilistic Reversal Learning Task
Impulsivity and compulsivity are behavioural traits that underlie many aspects of decision-making and form the characteristic symptoms of Obsessive Compulsive Disorder (OCD) and Gambling Disorder (GD). The neural underpinnings of aspects of reward and avoidance learning under the expression of these traits and symptoms are only partially understood. " "The present study combined behavioural modelling and neuroimaging technique to examine brain activity associated with critical phases of reward and loss processing in OCD and GD. " "Forty-two healthy controls (HC), forty OCD and twenty-three GD participants were recruited in our study to complete a two-session reinforcement learning (RL) task featuring a “probability switch (PS)” with imaging scanning. Finally, 39 HC (20F/19M, 34 yrs +/- 9.47), 28 OCD (14F/14M, 32.11 yrs ±9.53) and 16 GD (4F/12M, 35.53yrs ± 12.20) were included with both behavioural and imaging data available. The functional imaging was conducted by using 3.0-T SIEMENS MAGNETOM Skyra syngo MR D13C at Monash Biomedical Imaging. Each volume compromised 34 coronal slices of 3 mm thickness with 2000 ms TR and 30 ms TE. A total of 479 volumes were acquired for each participant in each session in an interleaved-ascending manner. " " The standard Q-learning model was fitted to the observed behavioural data and the Bayesian model was used for the parameter estimation. Imaging analysis was conducted using SPM12 (Welcome Department of Imaging Neuroscience, London, United Kingdom) in the Matlab (R2015b) environment. The pre-processing commenced with the slice timing, realignment, normalization to MNI space according to T1-weighted image and smoothing with a 8 mm Gaussian kernel. " " The frontostriatal brain circuit including the putamen and medial orbitofrontal (mOFC) were significantly more active in response to receiving reward and avoiding punishment compared to receiving an aversive outcome and missing reward at 0.001 with FWE correction at cluster level; While the right insula showed greater activation in response to missing rewards and receiving punishment. Compared to healthy participants, GD patients showed significantly lower activation in the left superior frontal and posterior cingulum at 0.001 for the gain omission. " " The reward prediction error (PE) signal was found positively correlated with the activation at several clusters expanding across cortical and subcortical region including the striatum, cingulate, bilateral insula, thalamus and superior frontal at 0.001 with FWE correction at cluster level. The GD patients showed a trend of decreased reward PE response in the right precentral extending to left posterior cingulate compared to controls at 0.05 with FWE correction. " " The aversive PE signal was negatively correlated with brain activity in regions including bilateral thalamus, hippocampus, insula and striatum at 0.001 with FWE correction. Compared with the control group, GD group showed an increased aversive PE activation in the cluster encompassing right thalamus and right hippocampus, and also the right middle frontal extending to the right anterior cingulum at 0.005 with FWE correction. " " Through the reversal learning task, the study provided a further support of the dissociable brain circuits for distinct phases of reward and avoidance learning. Also, the OCD and GD is characterised by aberrant patterns of reward and avoidance processing.
Differential encoding of innate and learned behaviors in the sensorimotor striatum
COSYNE 2022
How does the dorsal striatum contribute to active choice rejection?
COSYNE 2022
Functional consequences of highly shared feedforward inhibition in the striatum
COSYNE 2023
Broadly-projecting mesolimbic dopamine neurons implement a distributional critic across the striatum
COSYNE 2025
Dopamine signaling for perceptual learning in the sensory striatum
COSYNE 2025
Hunger modulates exploration through dopamine signaling at the tail of striatum
COSYNE 2025
Layered, hierarchical behavioral control underlies dopamine signals across the striatum during decision-making
COSYNE 2025
A Multi-region, Multi-task RNN Model of How Dorsomedial Striatum Implements Flexible Behavior
COSYNE 2025
Sensory Prediction Error signals in Tail of the Striatum Dopamine
COSYNE 2025
Action-outcome based flexible behavior requires medial prefrontal cortex lead and its enhanced functional connectivity with dorsomedial striatum
FENS Forum 2024
Astrocyte-generated neurons functionally integrate into the lesioned striatum
FENS Forum 2024
Asymmetrical modulations of decision and movement speeds during self-paced foraging reveal the dorsal striatum selective contribution to effort sensitivity
FENS Forum 2024
BMAL1 in the dorsomedial striatum affects alcohol consumption, affective behavior, and motor function sex-specifically in mice
FENS Forum 2024
Cell-type specific auditory responses in the tail of the striatum shaped by feedforward inhibition
FENS Forum 2024
Cellular and circuit diversity within spiny projection neuron populations in the postnatal striatum arises from distinct embryonic progenitor pools
FENS Forum 2024
Mapping information flow between striatum and motor cortex during skill learning
FENS Forum 2024
Cognitive and motor regulation by the novel Pthlh interneuron population in the mouse striatum
FENS Forum 2024
Differential metabolism of serine enantiomers in the striatum of MPTP-lesioned monkeys and mice correlates with the severity of dopaminergic midbrain degeneration
FENS Forum 2024
Dopamine-acetylcholine interplay and neural activity motifs in the striatum: Insights from a mouse delayed-go reaching task
FENS Forum 2024
Dynamics of prefrontal cortex and dorsolateral striatum in the automation of reference memory
FENS Forum 2024
Effects of early exposure to NMDA receptor NR1-specific antibodies on the developing mouse striatum
FENS Forum 2024
Electroconvulsive therapy promotes reinnervation of the dopamine-depleted striatum in the 6-OHDA model of Parkinson’s disease
FENS Forum 2024
Expression profiling of the learning striatum
FENS Forum 2024
The impact of Shank3 postsynaptic protein deficiency on neuronal synaptic activity in the striatum of an autism-related mouse model
FENS Forum 2024
Increased fear-related behaviors following alpha-synuclein preformed fibrils injected into the basolateral amygdala or striatum in mice
FENS Forum 2024
Investigation of SynCAM 2 function at dopamine hub synapses of the mouse striatum
FENS Forum 2024
Learning-dependent functional increase in connectivity among the posterior striatum, lateral geniculate nucleus, and visual cortex in the visual discrimination task
FENS Forum 2024
Lesion-induced neuroblasts in the striatum are LGE-class interneurons and are not fated towards adult striatal neuron cell types
FENS Forum 2024
Logic of the spatial and functional organization of the cortico-striatal projections onto somatostatin and parvalbumin interneurons in the dorsal striatum of mice
FENS Forum 2024
Modelling determinants of region-specific dopamine dynamics in the striatum
FENS Forum 2024
Movement-related dopamine signaling in mouse dorsal striatum in health and parkinsonism
FENS Forum 2024
Neuronal taxonomy of the human dorsal striatum by single nuclei transcriptomics
FENS Forum 2024
Neuropathology of the striatum in X-linked dystonia parkinsonism
FENS Forum 2024
Optogenetic inhibition of parvalbumin interneurons in the medial striatum during a perceptual decision-making task
FENS Forum 2024
Planning-related activity in the primate prefrontal cortex and striatum during a board game
FENS Forum 2024
Role of the medial prefrontal cortex, striatum, and nucleus accumbens in the emission of 50-kHz ultrasonic vocalizations in hemiparkinsonian rats treated with dopaminergic drugs
FENS Forum 2024
Sparse and unique functional innervation of barrel cortex onto single projection neurons in dorsal striatum and its plasticity after sensorimotor learning
FENS Forum 2024
Temporal evolution of glial cell phenotype in the midbrain and striatum of A53T-alpha-synuclein transgenic mice: New disease-related mechanisms?
FENS Forum 2024
What role for the striatum in motor control? Insights from unilateral perturbation during foraging
FENS Forum 2024