• Parkinson's disease
• Simulation Based Inference
• basal ganglia
• calcium image
• cell assembly
• network model
• pathology
• striatum

• Japan Science and Technology Corporation
• HORIZON EUROPE Framework Programme

• Animals
• Mice
• Dopamine
• Parkinson Disease/drug therapy
• Levodopa/pharmacology
• Levodopa/therapeutic use
• Corpus Striatum
• Neostriatum

• Consejo Nacional de Ciencia y Tecnología
• Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México

• R01 MH117111 NIMH NIH HHS
• R01 NS107539 NINDS NIH HHS

• L-DOPA induced dyskinesia
• Parkinson’s disease
• UMAP
• graph theory
• neural microcircuits
• neuronal ensembles
• recurrence analysis
• striatum

• dimensionality reduction
• graphical methods
• neuronal ensembles
• population vectors
• two-photon imaging
• two-photon optogenetics

Parkinson’s disease is a neurodegenerative ailment generated by the loss of dopamine in the basal ganglia, mainly in the striatum. The disease courses with increased striatal levels of acetylcholine, disrupting the balance among these modulatory transmitters. These modifications disturb the excitatory and inhibitory balance in the striatal circuitry, as reflected in the activity of projection striatal neurons. In addition, changes in the firing pattern of striatal tonically active interneurons during the disease, including cholinergic interneurons (CINs), are being searched. Dopamine-depleted striatal circuits exhibit pathological hyperactivity as compared to controls. One aim of this study was to show how striatal CINs contribute to this hyperactivity. A second aim was to show the contribution of extrinsic synaptic inputs to striatal CINs hyperactivity. Electrophysiological and calcium imaging recordings in Cre-mice allowed us to evaluate the activity of dozens of identified CINs with single-cell resolution in ex vivo brain slices. CINs show hyperactivity with bursts and silences in the dopamine-depleted striatum. We confirmed that the intrinsic differences between the activity of control and dopamine-depleted CINs are one source of their hyperactivity. We also show that a great part of this hyperactivity and firing pattern change is a product of extrinsic synaptic inputs, targeting CINs. Both glutamatergic and GABAergic inputs are essential to sustain hyperactivity. In addition, cholinergic transmission through nicotinic receptors also participates, suggesting that the joint activity of CINs drives the phenomenon; since striatal CINs express nicotinic receptors, not expressed in striatal projection neurons. Therefore, CINs hyperactivity is the result of changes in intrinsic properties and excitatory and inhibitory inputs, in addition to the modification of local circuitry due to cholinergic nicotinic transmission. We conclude that CINs are the main drivers of the pathological hyperactivity present in the striatum that is depleted of dopamine, and this is, in part, a result of extrinsic synaptic inputs. These results show that CINs may be a main therapeutic target to treat Parkinson’s disease by intervening in their synaptic inputs.

• Consejo Nacional de Ciencia y Tecnología

• Parkinson's disease
• basal ganglia
• dopamine
• striatum
• turning

• 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology
• Animals
• Corpus Striatum/metabolism
• Dopamine
• Dopamine Agonists
• Interneurons/physiology
• Mice
• Neurons/physiology
• Receptors, Dopamine D1/metabolism

• R01 NS094754 NINDS NIH HHS
• R15 NS115032 NINDS NIH HHS

Multi-recording techniques show evidence that neurons coordinate their firing forming ensembles and that brain networks are made by connections between ensembles. While “canonical” microcircuits are composed of interconnected principal neurons and interneurons, it is not clear how they participate in recorded neuronal ensembles: “groups of neurons that show spatiotemporal co-activation”. Understanding synapses and their plasticity has become complex, making hard to consider all details to fill the gap between cellular-synaptic and circuit levels. Therefore, two assumptions became necessary: First, whatever the nature of the synapses these may be simplified by “functional connections”. Second, whatever the mechanisms to achieve synaptic potentiation or depression, the resultant synaptic weights are relatively stable. Both assumptions have experimental basis cited in this review, and tools to analyze neuronal populations are being developed based on them. Microcircuitry processing followed with multi-recording techniques show temporal sequences of neuronal ensembles resembling computational routines. These sequences can be aligned with the steps of behavioral tasks and behavior can be modified upon their manipulation, supporting the hypothesis that they are memory traces. In vitro, recordings show that these temporal sequences can be contained in isolated tissue of histological scale. Sequences found in control conditions differ from those recorded in pathological tissue obtained from animal disease models and those recorded after the actions of clinically useful drugs to treat disease states, setting the basis for new bioassays to test drugs with potential clinical use. These findings make the neuronal ensembles theoretical framework a dynamic neuroscience paradigm.

• Consejo Nacional de Ciencia y Tecnología
• Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México

Control of the timing of behavior is thought to require the basal ganglia (BG) and BG pathologies impair performance in timing tasks. Temporal interval discrimination depends on the ramping activity of medium spiny neurons (MSN) in the main BG input structure, the striatum, but the underlying mechanisms driving this activity are unclear. Here, we combine an MSN dynamical network model with an action selection system applied to an interval discrimination task. We find that when network parameters are appropriate for the striatum so that slowly fluctuating marginally stable dynamics are intrinsically generated, up and down ramping populations naturally emerge which enable significantly above chance task performance. We show that emergent population activity is in very good agreement with empirical studies and discuss how MSN network dysfunction in disease may alter temporal perception.

• Horizon 2020 Framework Programme

• Calcium imaging
• Dyskinetic striatal microcircuit
• Identification of antidyskinetic drugs actions
• L-DOPA-induced dyskinesia
• Neuronal ensembles

• Holographic optogenetics
• Memory engrams
• Neurobiology of memory
• Neuronal ensembles
• Pattern completion
• Pattern separation

• Neuronal ensembles
• microcircuits
• neuroimaging
• two-photon imaging

• K3 transgenic mice
• frontotemporal lobar degeneration
• goal-directed behavior
• habitual behavior
• tau protein
• whole cell patch clamp electrophysiology

• Antinociceptive
• Calcium imaging
• Dorsal horn
• Oxytocin

Behavioral studies have shown that the human motor system recycles motor parameters of previous actions, such as movement amplitude, when programming new actions. Shifting motor plans toward a new action forms a particularly severe problem for patients with Parkinson’s disease (PD), a disorder that, in its early stage, is dominated by basal ganglia dysfunction. Here, we test whether this action selection deficit in Parkinson’s patients arises from an impaired ability to recycle motor parameters shared across subsequent actions. Parkinson’s patients off dopaminergic medication (n = 16) and matched healthy controls (n = 16) performed a task that involved moving a handheld dowel over an obstacle in the context of a sequence of aiming movements. Consistent with previous research, healthy participants continued making unnecessarily large hand movements after clearing the obstacle (defined as “hand path priming effect”), even after switching movements between hands. In contrast, Parkinson’s patients showed a reduced hand path priming effect, i.e., they performed biomechanically more efficient movements than controls, but only when switching movements between hands. This effect correlated with disease severity, such that patients with more severe motor symptoms had a smaller hand path priming effect. We propose that the basal ganglia mediate recycling of movement parameters across subsequent actions.

• Parkinson’s disease
• basal ganglia
• motor efficiency
• motor planning
• priming

• Animals
• Brain Mapping
• Corpus Striatum/physiology
• Disease Models, Animal
• Disease Progression
• GABAergic Neurons/metabolism
• Homozygote
• Humans
• Huntingtin Protein/metabolism
• Huntington Disease/physiopathology
• Mice
• Mice, Transgenic
• Mutation
• Neurons/physiology
• Phenotype
• Radiosurgery

• 6-hydroxydopamine
• Biosensors
• Ca(2+) signaling
• ERK
• Förster resonance energy transfer
• Mouse
• Parkinson's disease
• Striatal projection neuron
• Striatum
• Two-photon microscopy
• cAMP signaling

For more than three decades it has been known, that striatal neurons become hyperactive after the loss of dopamine input, but the involvement of dopamine (DA) D1‐ or D2‐receptor‐expressing neurons has only been demonstrated indirectly. By recording neuronal activity using fluorescent calcium indicators in D1 or D2 eGFP‐expressing mice, we showed that following dopamine depletion, both types of striatal output neurons are involved in the large increase in neuronal activity generating a characteristic cell assembly of particular neurons that dominate the pattern. When we expressed channelrhodopsin in all the output neurons, light activation in freely moving animals, caused turning like that following dopamine loss. However, if the light stimulation was patterned in pulses the animals circled in the other direction. To explore the neuronal participation during this stimulation we infected normal mice with channelrhodopsin and calcium indicator in striatal output neurons. In slices made from these animals, continuous light stimulation for 15 s induced many cells to be active together and a particular dominant group of neurons, whereas light in patterned pulses activated fewer cells in more variable groups. These results suggest that the simultaneous activity of a large dominant group of striatal output neurons is intimately associated with parkinsonian symptoms.

• Parkinson's disease
• assemblies
• basal ganglia
• calcium imaging
• optogenetics

• 6-OHDA
• dopamine
• drug-induced Parkinsonism
• firing patterns
• ion channels
• substantia nigra

• Gasping
• Intrinsic properties
• Long term facilitation
• Network topology
• Synaptic properties

• Mus Musculus
• 6-OHDA
• L-DOPA
• Parkinson's disease
• microcircuit analysis
• striatum

• Corticostriatal pathway
• Intrinsic properties
• Striatal interneurons
• Striatal projection neurons
• Striatum
• Synaptic integration
• Thalamostriatal pathway

• SPN
• VGCCs
• calcium imaging
• calcium-permeable AMPARs
• neuroinflammation

• Animals
• CX3C Chemokine Receptor 1/genetics
• CX3C Chemokine Receptor 1/metabolism
• Calcium/metabolism
• Calcium Channel Blockers/pharmacology
• Calcium Channels, L-Type/metabolism
• Cations, Divalent/metabolism
• Corpus Striatum/drug effects
• Corpus Striatum/metabolism
• Corpus Striatum/pathology
• Dopaminergic Neurons/drug effects
• Dopaminergic Neurons/metabolism
• Dopaminergic Neurons/pathology
• Female
• Inflammation/metabolism
• Inflammation/pathology
• Lipopolysaccharides
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia/drug effects
• Microglia/metabolism
• Microglia/pathology
• Receptors, AMPA/antagonists & inhibitors
• Receptors, AMPA/metabolism
• Receptors, Dopamine D1/genetics
• Receptors, Dopamine D1/metabolism
• Receptors, Dopamine D2/genetics
• Receptors, Dopamine D2/metabolism
• Tissue Culture Techniques
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism

• F31 NS092230 NINDS NIH HHS
• R01 NS083410 NINDS NIH HHS
• T32 NS041218 NINDS NIH HHS

Cell grafting has been considered a therapeutic approach for Parkinson’s disease (PD) since the 1980s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrement in dopamine release in the striatum. Consequently, the therapy of cell-transplantation for PD consists in grafting dopamine-producing cells directly into the brain to reestablish dopamine levels. Different cell sources have been shown to induce functional benefits on both animal models of PD and human patients. However, the observed motor improvements are highly variable between individual subjects, and the sources of this variability are not fully understood. The purpose of this review is to provide a general overview of the pioneering studies done in animal models of PD that established the basis for the first clinical trials in humans, and compare these with the latest findings to identify the most relevant aspects that remain unanswered to date. The main focus of the discussions presented here will be on the mechanisms associated with the survival and functionality of the transplants. These include the role of the dopamine released by the grafts and the capacity of the grafted cells to extend fibers and to integrate into the motor circuit. The complete understanding of these aspects will require extensive research on basic aspects of molecular and cellular physiology, together with neuronal network function, in order to uncover the real potential of cell grafting for treating PD.

• Parkinson’s disease
• Cell replacement
• Animal models
• Nigrostriatal pathway
• Striatum
• Dopaminergic loss

• calcium
• optogenetics
• two-photon

• Algorithms
• Animals
• Cocaine/pharmacology
• Corpus Striatum/cytology
• Corpus Striatum/drug effects
• Corpus Striatum/physiology
• Locomotion/drug effects
• Locomotion/physiology
• Machine Learning
• Mice
• Mice, Transgenic
• Neural Pathways/drug effects
• Neural Pathways/physiology
• Receptors, Dopamine D1/genetics
• Receptors, Dopamine D2/genetics

• ZIA DA000603-01 Intramural NIH HHS
• Z99 DA999999 Intramural NIH HHS
• R56 NS065110 NINDS NIH HHS
• ZIC DA000604-01 Intramural NIH HHS
• R01 NS065110 NINDS NIH HHS

• Dyskinetic circuit
• Network properties
• Parkinsonian circuit
• Striatal microcircuit
• l-DOPA

• Algorithms
• Animals
• Computational Biology
• Corpus Striatum/physiology
• Mice
• Models, Neurological
• Nerve Net/physiology
• Neurons/physiology

• R01 NS078435 NINDS NIH HHS
• U01 NS094375 NINDS NIH HHS
• NS078435 NINDS NIH HHS
• R21 DA032259 NIDA NIH HHS
• MH101697 NIMH NIH HHS
• R01 MH101697 NIMH NIH HHS
• DA032259 NIDA NIH HHS
• NS094375 NINDS NIH HHS

• associative learning
• correlations
• single-unit recordings
• striatum

• Cell assemblies
• calcium imaging
• microelectrode arrays
• short-term synaptic plasticity
• whole cell recordings

• Parkinson's disease
• beta-band oscillation
• fast-spiking interneurons
• gap junctions
• striatal imbalance
• striatum

• MEA
• Memantine
• Network
• Up-down states

• Kreb's cycle
• SIDS
• gasping
• network analysis
• pre-Bötzinger complex

• Behavioral sensitization
• L-DOPA
• Parkinson’s disease
• dyskinesia
• medium spiny neuron
• striatum
• three-dimensional neuronal reconstruction

Fast-spiking interneurons (FSIs) play a central role in organizing the output of striatal neural circuits, yet functional interactions between these cells are still largely unknown. Here we investigated the interplay of action potential (AP) firing between electrically connected pairs of identified FSIs in mouse striatal slices. In addition to a loose coordination of firing activity mediated by membrane potential coupling, gap junctions (GJ) induced a frequency-dependent inhibition of spike discharge in coupled cells. At relatively low firing rates (2–20 Hz), some APs were tightly synchronized whereas others were inhibited. However, burst firing at intermediate frequencies (25–60 Hz) mostly induced spike inhibition, while at frequencies >50–60 Hz FSI pairs tended to synchronize. Spike silencing occurred even in the absence of GABAergic synapses or persisted after a complete block of GABA_A receptors. Pharmacological suppression of presynaptic spike afterhyperpolarization (AHP) caused postsynaptic spikelets to become more prone to trigger spikes at near-threshold potentials, leading to a mostly synchronous firing activity. The complex pattern of functional coordination mediated by GJ endows FSIs with peculiar dynamic properties that may be critical in controlling striatal-dependent behavior.

• GABA
• action potential
• fast-spiking interneurons
• gap junctions
• striatum

The question to solve in the present work is: what is the predominant action induced by the activation of cholinergic-nicotinic receptors (nAChrs) in the striatal network given that nAChrs are expressed by several elements of the circuit: cortical terminals, dopamine terminals, and various striatal GABAergic interneurons. To answer this question some type of multicellular recording has to be used without losing single cell resolution. Here, we used calcium imaging and nicotine. It is known that in the presence of low micromolar N-Methyl-D-aspartate (NMDA), the striatal microcircuit exhibits neuronal activity consisting in the spontaneous synchronization of different neuron pools that interchange their activity following determined sequences. The striatal circuit also exhibits profuse spontaneous activity in pathological states (without NMDA) such as dopamine depletion. However, in this case, most pathological activity is mostly generated by the same neuron pool. Here, we show that both types of activity are inhibited during the application of nicotine. Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs. Interestingly, inhibitory actions of nicotine were also blocked by the GABA_A-receptor antagonist bicuculline, in which case, the actions of nicotine on the circuit became excitatory and facilitated neuronal synchronization. We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons. This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

• GABAergic interneurons
• nicotine
• nicotinic receptors
• striatal microcircuit

• Dissociated culture
• dopamine receptors
• inhibitory collaterals
• striatum
• synaptic physiology

• R01 MH064797 NIMH NIH HHS

• Action Potentials/physiology
• Algorithms
• Animals
• Basal Ganglia/pathology
• Computational Biology/methods
• Computer Simulation
• Corpus Striatum/physiology
• Humans
• Inhibitory Postsynaptic Potentials
• Models, Neurological
• Neural Inhibition/physiology
• Neurons/metabolism
• Neurons/physiology
• Post-Synaptic Density/metabolism
• Reproducibility of Results
• Software
• Synaptic Transmission/physiology