Biology subjects

Magill, P. J.

Publications and source records attributed to Magill, P. J..

13 recordsLinked to original sources

bioRxiv2025

Selective innervation of subpopulations of striatal neurons by distinct sets of neurons of the external globus pallidus

The striatum, the primary input nucleus of the basal ganglia, contains diverse populations of projection neurons and interneurons, each with distinct roles in motor processing. The external globus pallidus contains distinct populations of inhibitory neurons that are highly interconnected with other regions of the basal ganglia. How pallidal neurons innervate different populations of striatal neurons is critical for our understanding of their role in motor processing. Here we use monosynaptic viral tracing in transgenic mice to quantitively define the organization of pallidostriatal connectivity. We show that FoxP2-expressing arkypallidal neurons provide the greatest input to the striatum, primarily targeting indirect pathway spiny projection neurons and cholinergic interneurons. In contrast, prototypic pallidal neurons, defined by Nkx2-1 expression, preferentially innervate parvalbumin- and somatostatin-expressing interneurons. These data reveal a structured and selective organization of pallidostriatal projections, suggesting that distinct classes of pallidal neurons modulate striatal circuits through complementary pathways. Mapping these connections is key to understanding how basal ganglia networks coordinate motor control.

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bioRxiv2024

Rapid modulation of striatal cholinergic interneurons and dopamine release by satellite astrocytes

Astrocytes are increasingly thought to have underestimated and important roles in modulating neuronal circuits. Astrocytes in striatum can regulate dopamine transmission by governing the extracellular tone of axonal neuromodulators, including GABA and adenosine. However, here we reveal that striatal astrocytes occupy a cell type-specific anatomical and functional relationship with cholinergic interneurons (ChIs), through which they rapidly excite ChIs and govern dopamine release via nicotinic acetylcholine receptors on subsecond timescales. We identify that ChI somata are in unexpectedly close proximity to astrocyte somata, in mouse and human, forming a "soma-to-soma" satellite-like configuration not typically observed for other striatal neurons. Transient depolarization of astrocytes in mouse striatum reversibly regulated ChI excitability by decreasing extracellular calcium. These findings reveal a privileged satellite astrocyte-interneuron interaction for striatal ChIs operating on subsecond timescales via regulation of extracellular calcium dynamics to shape downstream striatal circuit activity and dopamine signaling.

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bioRxiv2024

Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensemble.

Defining spatial synchronization of pathological beta oscillations is important, given that many theories linking them to parkinsonian symptoms propose a reduction in the dimensionality of the coding space within and/or across cortico-basal ganglia structures. Such spatial synchronization could arise from a single process, with widespread entrainment of neurons to the same oscillation. Alternatively, the partially segregated structure of cortico-basal ganglia loops could provide a substrate for multiple ensembles that are independently synchronized at beta frequencies. Addressing this question requires an analytical approach that identifies groups of signals with a statistical tendency for beta synchronisation, which is unachievable using standard pairwise measures. Here, we utilized such an approach on multichannel recordings of background unit activity (BUA) in the external globus pallidus (GP) and subthalamic nucleus (STN) in parkinsonian rats. We employed an adapted version of a principle and independent component analysis-based method commonly used to define assemblies of single neurons (i.e., neurons that are synchronized over short timescales). This analysis enabled us to define whether changes in the power of beta oscillations in local ensembles of neurons (i.e., the BUA recorded from single contacts) consistently covaried over time, forming a "beta ensemble". Multiple beta ensembles were often present in single recordings and could span brain structures. Membership of a beta ensemble predicted significantly higher levels of short latency (<5ms) synchrony in the raw BUA signal and phase synchronization with cortical beta oscillations, suggesting that they comprised clusters of neurons that are functionally connected at multiple levels, despite sometimes being non-contiguous in space. Overall, these findings suggest that beta oscillations do not comprise a single synchronization process, but rather multiple independent activities that can bind both spatially contiguous and non-contiguous pools of neurons within and across structures. As previously proposed, such ensembles provide a substrate for beta oscillations to constrain the coding space of cortico-basal ganglia circuits.

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bioRxiv2024

Large-scale visualisation of α-synuclein oligomers in Parkinson's disease brain tissue

Parkinsons disease (PD) is a common neurodegenerative condition characterised by the presence in the brain of large intraneuronal aggregates, known as Lewy bodies and Lewy neurites, containing fibrillar -synuclein. According to the amyloid hypothesis, these large end-stage species form from smaller soluble protein assemblies, often termed oligomers, which are proposed as early drivers of pathogenesis. To date, however, this hypothesis has remained controversial, at least in part because it has not been possible to directly visualise oligomeric aggregates in human brain tissue. Therefore, their presence, abundance and distributions have remained elusive. Here, we present ASA-PD (Advanced Sensing of Aggregates - Parkinsons Disease), an imaging method to generate large-scale -synuclein oligomer maps in post-mortem human brain tissue. We combined autofluorescence suppression with single-molecule fluorescence methods, which together, enable the detection of nanoscale -synuclein aggregates. To demonstrate the utility of this platform, we captured [~]1.2 million oligomers from the anterior cingulate cortex in human post-mortem brain samples from PD and healthy control patients. Our data revealed a specific subpopulation of nanoscale oligomers that represent an early hallmark of the proteinopathy that underlies PD. We anticipate that quantitative information about oligomer distributions provided by ASA-PD will enable mechanistic studies to reveal the pathological processes caused by -synuclein aggregation.

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bioRxiv2023

Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging

LRRK2 mutations are the most common cause of dominantly inherited Parkinsons disease (PD). Here, we conducted PET imaging in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride. We interrogate presynaptic integrity and postsynaptic dopamine receptor availability, and compared these to non-transgenic rats. LRRK2 mutant rats displayed similar [18F]FDOPA uptake to non-transgenic animals, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, exhibiting regionally selective binding increase in the dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to the dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit observed in this genotype. These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, detecting upregulation of D2 receptors that parallels observations in early human sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

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bioRxiv2022

Distributional coding of associative learning within projection-defined populations of midbrain dopamine neurons

Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. While this teaching signal is often considered to be uniform, recent evidence instead supports diversity in dopamine signaling. However, it remains poorly understood how heterogeneous signals might be organized to facilitate the role of downstream circuits mediating distinct aspects of behavior. Here we investigated the organizational logic of dopaminergic signaling by recording and labeling individual midbrain dopamine neurons during associative behavior. We defined combinations of protein expression and cellular localization to sort recorded neurons according to the striatal regions they innervate. Our findings show that reward information and task variables are not only heterogeneously encoded, with multiplexing, but also differentially distributed across populations of dopamine neurons projecting to different regions of striatum. These data, supported by computational modelling, indicate that such distributional coding can maximize dynamic range and tailor dopamine signals to facilitate the specialized roles of different striatal regions.

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bioRxiv2021

Input zone-selective dysrhythmia in motor thalamus after dopamine depletion

The cerebral cortex, basal ganglia and motor thalamus form circuits important for purposeful movement. In Parkinsonism, basal ganglia neurons often exhibit dysrhythmic activity during, and with respect to, the slow ([~]1 Hz) and beta-band (15-30 Hz) oscillations that emerge in cortex in a brain state-dependent manner. There remains, however, a pressing need to elucidate the extent to which motor thalamus activity becomes similarly dysrhythmic after dopamine depletion relevant to Parkinsonism. To address this, we recorded single-neuron and ensemble outputs in the basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) of motor thalamus in anesthetized male dopamine-intact rats and 6-OHDA-lesioned rats during two brain states, respectively defined by cortical slow-wave activity and activation. Two forms of thalamic input zone-selective dysrhythmia manifested after dopamine depletion: First, BZ neurons, but not CZ neurons, exhibited abnormal phase-shifted firing with respect to cortical slow oscillations prevalent during slow-wave activity; secondly, BZ neurons, but not CZ neurons, inappropriately synchronized their firing and engaged with the exaggerated cortical beta oscillations arising in activated states. These dysrhythmias were not accompanied by the thalamic hypoactivity predicted by canonical firing rate-based models of circuit organization in Parkinsonism. Complementary recordings of neurons in substantia nigra pars reticulata suggested their altered activity dynamics could underpin the BZ dysrhythmias. Finally, pharmacological perturbations demonstrated that ongoing activity in the motor thalamus bolsters exaggerated beta oscillations in motor cortex. We conclude that BZ neurons are selectively primed to mediate the detrimental influences of abnormal slow and beta-band rhythms on circuit information processing in Parkinsonism.

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bioRxiv2020

A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

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bioRxiv2020

State Dependency of Beta Oscillations in the Cortico-Basal-Ganglia Circuit and their Neuromodulation under Phase Locked Inputs

State-of-the-art therapeutic brain stimulation strategies are delivered open loop, using fixed parameters. However, brain states exhibit spontaneous fluctuations dependent upon different behavioural or disease states. Here, we use a model of the cortico-basal ganglia-thalamic circuit to demonstrate how connectivity underpins changes in subcortical beta oscillations - a commonly used control parameter for deep brain stimulation in Parkinsons disease. We show that recurrent cortical-subcortical loops involving either the cortico-subthalamic or pallido-subthalamic pathways can act in antagonism to modulate the expression of beta band activity (14-30 Hz). These pathways alter the relative timing of intermittent activity across the network, with increased pallido-subthalamic connectivity increasing the propensity of the circuit to enter a state of autonomous oscillation. We demonstrate that phase-locked stimulation can modulate these oscillations, with an efficacy that ultimately depends upon the connectivity across the circuit. This work outlines critical factors required to implement state-adaptive closed-loop brain stimulation. HighlightsO_LIConverging inputs to the subthalamic nucleus arriving via the external segment of globus pallidus and cortex act in antagonism and promote different beta rhythms. C_LIO_LIPhase locked stimulation has the capacity to selectively enhance or suppress a brain rhythm depending on the stimulation timing. C_LIO_LIThe efficacy of stimulation and the parameters required to deliver it, e.g. stimulation timing, effective sensing and stimulation locations, are functions of network state. C_LI

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bioRxiv2019

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

Striatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions. HighlightsO_LIGABA transporters set the level of GABA inhibition of DA output in dorsal striatum C_LIO_LIAstrocytes facilitate DA release levels by limiting tonic GABA inhibition C_LIO_LITonic inhibition of DA release is augmented in a mouse model of early parkinsonism C_LIO_LIDA and GABA co-release are reduced in a mouse model of early parkinsonism C_LI

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bioRxiv2018

Temporal evolution of beta bursts in the parkinsonian cortico-basal ganglia network

Prevalence and temporal dynamics of transient oscillations in the beta frequency band (15-35 Hz), referred to as beta bursts, are correlated with motor performance and tactile perception. Disturbance of these activities is a candidate mechanism for motor impairment in Parkinsons disease (PD), where the excessively long bursts correlate with symptom severity and are reduced by pharmacological and surgical treatments. To date, characterization of beta bursts in PD has been limited to the local field potentials in the subthalamic nucleus (STN) and cortical EEG. Here, we describe the changes that take place in spiking activity across the cortico-basal ganglia circuit, providing a unique insight into the network dynamics of these transient oscillations. Firstly, we demonstrate that rhythmic subthalamic spiking activity emerges at a fixed phase relationship with respect to cortical beta bursts in PD patients. Using multichannel recordings of ensembles of neurons in the 6-OHDA rat model of PD, we then dissect the beta burst dynamics across the sensorimotor cortex and several basal ganglia structures: striatum (Str), globus pallidus externus (GPe) and STN. Each subcortical structure exhibits enhanced rhythmic activity in the beta band locked to the onset of cortical beta bursts and longer cortical bursts lead to stronger subcortical rhythmicity. Crucially, enhanced subcortical rhythmic activity emerges at a fixed phase relationship with respect to the motor cortex, comparable to the relationship observed in PD patients. Striatal beta bursts terminate prior to the recruitment of those in the STN and GPe, suggesting that while they could play an important role in establishing synchrony in the beta band, they do not extensively contribute to its maintenance in other basal ganglia structures. Critically, changes in cortico-subcortical phase coupling precede the onset of a cortical beta burst, supporting the hypothesis that phase alignment across the cortico-basal ganglia network could recruit these structures into synchronous network oscillations. We provide a powerful approach that not only examines pathophysiology of PD across the motor circuit, but also offer insights that could aid in the design of novel neuromodulation strategies to manipulate the state of the motor system before pathological activities emerge.

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bioRxiv2018

Thalamocortical dynamics underlying spontaneous transitions in beta power in Parkinsonism

Parkinsons disease (PD) is a neurodegenerative condition in which aberrant oscillatory synchronization of neuronal activity at beta frequencies (15-35 Hz) across the cortico-basal ganglia-thalamocortical circuit is associated with debilitating motor symptoms, such as bradykinesia and rigidity. Mounting evidence suggests that the magnitude of beta synchrony in the parkinsonian state fluctuates over time, but the mechanisms by which thalamocortical circuitry regulates the dynamic properties of cortical beta in PD are poorly understood. Using the recently developed generic dynamic causal modelling framework, we recursively optimised a set of plausible models of the thalamocortical circuit (n=144) to infer the neural mechanisms that best explain the transitions between low and high beta power states observed in recordings of field potentials made in the motor cortex of anesthetized Parkinsonian rats. Bayesian model comparison suggests that upregulation of cortical rhythmic activity in the beta-frequency band results from changes in the coupling strength both between and within the thalamus and motor cortex. Specifically, our model indicates that high levels of cortical beta synchrony are mainly achieved by a delayed (extrinsic) input from thalamic relay cells to deep pyramidal cells and a fast (intrinsic) input from middle pyramidal cells to superficial pyramidal cells. We therefore hypothesize that beta synchronisation at the cortical level could selectively be modulated via interventions that are capable of finely regulating cortical excitability in a spatial (delivered to either the superficial or deep cortical laminae) and time specific manner.

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bioRxiv2017

Propagation of Beta/Gamma Rhythms in the Cortico-Basal Ganglia Circuits of the Parkinsonian Rat

Some motor impairments associated with Parkinsons disease are thought to arise from pathological activity in the neuronal networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in Parkinsonism, we investigated changes to the directed connectivity in these networks following dopamine depletion. We recorded local field potentials in the cortex and basal ganglia of anesthetized rats rendered Parkinsonian by injection of 6-hydroxydopamine (6-OHDA), with dopamine-intact rats as controls. We performed systematic analyses of the networks using a novel tool for estimation of directed neural interactions, as well as a conditioned variant which permits the analysis of the dependence of a connection upon a third reference signal. We find evidence of the dopamine dependency of both low beta (14-20 Hz) and high beta/low gamma (20-40 Hz) directed interactions within the BG and cortico-BG networks. Notably, 6-OHDA lesions were associated with enhancement of the cortical \"hyperdirect\" connection to the subthalamic nucleus (STN), as well the STNs feedback to the cortex and striatum. We find beta synchronization to be robust to conditioning using signals from any one structure. Conversely, we find that high beta/gamma drive from the cortex to subcortical regions is weakened by 6-OHDA lesions and is susceptible to conditioning. Furthermore, we provide evidence that gamma is routed from striatum in a pathway that is independent of STN. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in Parkinsonism.\n\nNew & NoteworthyWe present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aims of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinsons disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a \"short-circuiting\" of the network that gives rise to the conditions from which pathological synchronization may arise.

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