Spatially organized striatal neuromodulator release encodes trajectory errors.

Goal-directed navigation requires animals to continuously evaluate their current direction and speed of travel relative to landmarks to discern whether they are approaching or deviating from their goal. Striatal dopamine and acetylcholine are powerful modulators of goal-directed behavior, but it is unclear whether and how neuromodulator dynamics at landmarks incorporate relative motion for effective behavioral guidance. Using optical measurements in mice, we demonstrate that cue-evoked striatal dopamine release encodes bi-directional 'trajectory errors' reflecting relationships between ongoing speed and direction of locomotion and visual flow relative to optimal goal trajectories. Striatum-wide micro-fiber array recordings resolved an anatomical gradient of trajectory error signaling across the anterior-posterior axis, distinct from trajectory error independent cue signals. Dynamic regression modeling revealed that positive and negative trajectory error encoding emerges early and late respectively during learning and over different time courses in the medial and lateral striatum, enabling region specific contributions to learning. Striatal acetylcholine release also encodes trajectory errors, but encoding is more spatially restricted, opposite polarity, and delayed relative to dopamine, supporting distinct roles in modulating striatal output and behavior. Dopamine trajectory error signaling and task performance were reproduced in a reinforcement learning model incorporating a conjunctive state space representation, suggesting a potential neural substrate for trajectory error generation. Our results establish region specific neuromodulator signals positioned to guide the speed and direction of locomotion to reach goals based on environmental landmarks during navigation.

Spatially organized striatum-wide acetylcholine dynamics for the learning and extinction of Pavlovian cues and actions.

Striatal acetylcholine (ACh) has been linked to behavioral flexibility. A key component of flexibility is down-regulating responding as valued cues and actions become decoupled from positive outcomes. We used array fiber photometry in mice to investigate how ACh release across the striatum evolves during learning and extinction of Pavlovian associations. Changes in multi-phasic release to cues and consummatory actions were bi-directional and region-specific. Following extinction, increases in cue-evoked ACh release emerged in the anterior dorsal striatum (aDS) which preceded a down-regulation of anticipatory behavior. Silencing ACh release from cholinergic interneurons in the aDS blocked behavioral extinction. Dopamine release dipped below baseline for down-shifted cues, but glutamate input onto cholinergic interneurons did not change, suggesting an intrastriatal mechanism for the emergence of ACh increases. Our large-scale mapping of striatal ACh dynamics during learning pinpoints region-specific elevations in ACh release positioned to down-regulate behavior during extinction, a central feature of flexible behavior.

Targeted micro-fiber arrays for measuring and manipulating localized multi-scale neural dynamics over large, deep brain volumes during behavior.

Neural population dynamics relevant to behavior vary over multiple spatial and temporal scales across three-dimensional volumes. Current optical approaches lack the spatial coverage and resolution necessary to measure and manipulate naturally occurring patterns of large-scale, distributed dynamics within and across deep brain regions such as the striatum. We designed a new micro-fiber array approach capable of chronically measuring and optogenetically manipulating local dynamics across over 100 targeted locations simultaneously in head-fixed and freely moving mice, enabling the investigation of cell-type- and neurotransmitter-specific signals over arbitrary 3D volumes at a spatial resolution and coverage previously inaccessible. We applied this method to resolve rapid dopamine release dynamics across the striatum, revealing distinct, modality-specific spatiotemporal patterns in response to salient sensory stimuli extending over millimeters of tissue. Targeted optogenetics enabled flexible control of neural signaling on multiple spatial scales, better matching endogenous signaling patterns, and the spatial localization of behavioral function across large circuits.

Targeted micro-fiber arrays for measuring and manipulating localized multi-scale neural dynamics over large, deep brain volumes during behavior.

Neural population dynamics relevant for behavior vary over multiple spatial and temporal scales across 3-dimensional volumes. Current optical approaches lack the spatial coverage and resolution necessary to measure and manipulate naturally occurring patterns of large-scale, distributed dynamics within and across deep brain regions such as the striatum. We designed a new micro-fiber array and imaging approach capable of chronically measuring and optogenetically manipulating local dynamics across over 100 targeted locations simultaneously in head-fixed and freely moving mice. We developed a semi-automated micro-CT based strategy to precisely localize positions of each optical fiber. This highly-customizable approach enables investigation of multi-scale spatial and temporal patterns of cell-type and neurotransmitter specific signals over arbitrary 3-D volumes at a spatial resolution and coverage previously inaccessible. We applied this method to resolve rapid dopamine release dynamics across the striatum volume which revealed distinct, modality specific spatiotemporal patterns in response to salient sensory stimuli extending over millimeters of tissue. Targeted optogenetics through our fiber arrays enabled flexible control of neural signaling on multiple spatial scales, better matching endogenous signaling patterns, and spatial localization of behavioral function across large circuits.

The antiparkinson drug ropinirole inhibits movement in a Parkinson's disease mouse model with residual dopamine neurons.

The dopamine (DA) D2-like receptor (D2R) agonist ropinirole is often used for early and middle stage Parkinson's disease (PD). However, this D2-like agonism-based strategy has a complicating problem: D2-like agonism may activate D2 autoreceptors on the residual DA neurons in the PD brain, potentially inhibiting these residual DA neurons and motor function. We have examined this possibility by using systemic and local drug administration in transcription factor Pitx3 null mutant (Pitx3Null) mice that mimic the DA denervation in early and middle stage PD and in DA neuron tyrosine hydroxylase (TH) gene knockout (KO) mice that mimic the severe DA loss in late stage PD. We found that in Pitx3Null mice with residual DA neurons and normal mice with normal DA system, systemically injected ropinirole inhibited locomotion, whereas bilateral dorsal striatal-microinjected ropinirole stimulated movement in Pitx3Null mice; bilateral microinjection of ropinirole into the ventral tegmental area also inhibited movement in Pitx3Null mice; we further determined that ropinirole inhibited nigral DA neuron spike firing in WT mice. In contrast, both systemically and striatum-locally administered ropinirole increased movements in TH KO mice, but produced relatively more dyskinesia than L-dopa. Although requiring confirmation in non-human primates and PD patients, these data suggest that while activating D2-like receptors in striatal projection neurons and hence stimulating movements, D2-like agonists can inhibit residual DA neurons and cause akinesia when the residual DA neurons and motor functions are still substantial, and this motor-inhibitory effect disappears when almost all DA neurons are lost such as in late stage PD.

Cyclic AMP-producing chemogenetic activation of indirect pathway striatal projection neurons and the downstream effects on the globus pallidus and subthalamic nucleus in freely moving mice.

The indirect pathway striatal medium spiny projection neurons (iMSNs) are critical to motor and cognitive brain functions. These neurons express a high level of cAMP-increasing adenosine A2a receptors. However, the potential effects of cAMP production on iMSN spiking activity have not been established, and recording identified iMSNs in freely moving animals is challenging. Here, we show that in the transgenic mice expressing cAMP-producing G protein Gs -coupled designer receptor exclusively activated by designer drug (Gs-DREADD) in iMSNs, the baseline spike firing in MSNs is normal, indicating DREADD expression does not affect the normal physiology of these neurons. Intraperitoneal injection of the DREADD agonist clozapine-N-oxide (CNO; 2.5 mg/kg) increased the spike firing in 50% of the recorded MSNs. However, CNO did not affect MSN firing in Gs-DREADD-negative mice. We also found that CNO injection inhibited the spike firing of globus pallidus external segment (GPe) neurons in Gs-DREADD-positive mice, further indicating CNO excitation of iMSNs. Temporally coincident with these effects on spiking firing in the indirect pathway, CNO injection selectively inhibited locomotion in D2 Gs-DREADD mice. Taken together, our results strongly suggest that cAMP production in iMSNs can increase iMSN spiking activity and cause motor inhibition, thus addressing a long-standing question about the cellular functions of the cAMP-producing adenosine A2a receptors in iMSNs. Cover Image for this issue: doi: 10.1111/jnc.14181.

Consequences of manganese intoxication on the circadian rest-activity rhythms in the rat.

Manganese (Mn) intoxication is associated with neurological dysfunctions collectively known as Parkinsonism or Manganism. Like in Parkinson's disease, Manganism is associated with motor disturbances, together with non-motor symptoms including cognitive and neuropsychiatric deficits. Although sleep dysfunctions are commonly reported among workers exposed to Mn, their underlying pathophysiology remains unknown. In this study, we investigated the rest-activity rhythms in rats treated daily with MnCl2 (10mg/kg, i.p) for 5weeks. Locomotor activity was assessed under a light-dark (LD) cycle, constant darkness (DD) and during adjustment to 6h shifts of the LD cycle. In LD conditions, Mn-treated rats exhibited a more fragmented and less stable rest-activity rhythm in addition to a reduction in the total 24-h amount of locomotor activity as well as in the activity confined to the active dark phase of the LD. Consequently, a significant decrease in the amplitude of the rest-activity rhythm was observed. These disturbances were displayed during and after Mn treatment. Furthermore, after the 6-h phase advance of the LD cycle, Mn-treated rats failed to re-adjust accurately their behavioral activity to the new shifted LD cycle. Upon release from LD into DD, Mn-treated rats expressed a normal and stable free-running period of their rest-activity rhythm (23.92±0.07h in Mn group vs. 24.01±0.04h in control rats). However, their rest-activity rhythm remained highly fragmented and less stable. Our results provide the first evidence that chronic Mn intoxication leads to impairment of rest-activity rhythms in addition to the motor and non-motor disturbances reported in Manganism.

Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission.

Manganese (Mn) is an essential element required for many physiological functions. While it is essential at physiological levels, excessive accumulation of Mn in the brain causes severe dysfunctions in the central nervous system known as manganism. Manganism is an extrapyramidal disorder characterized by motor disturbances associated with neuropsychiatric and cognitive disabilities similar to Parkinsonism. As the primary brain regions targeted by Mn are the basal ganglia, known to be involved in the pathophysiology of extrapyramidal disorders, this review will examine the impact of Mn exposure on the basal ganglia circuitry and neurotransmitters in relation to motor and non-motor disorders. The collected data from recent available studies in humans and experimental animal models provide new information about the mechanisms by which Mn affects behavior, neurotransmitters, and basal ganglia function observed in manganism. The effects of the alterations of metals on basal ganglia and neurochemical functioning are critical to develop effective modalities not only for the treatment of vulnerable populations (e.g., Mn-exposed workers) but also for understanding the etiology of neurodegenerative diseases where brain metal imbalances are involved, such as Parkinson's disease. We examine the impact of manganese (Mn) exposure on the basal ganglia circuitry and neurotransmitters in relation with motor and non-motor disorders. The collected data from available studies show that when accumulated in the globus pallidus, Mn influences the subthalamic (STN) and substantia nigra (SN) neurons, which are at the origin of changes in the thalamus and the cortex.

Manganese-induced atypical parkinsonism is associated with altered Basal Ganglia activity and changes in tissue levels of monoamines in the rat.

Manganese neurotoxicity is associated with motor and cognitive disturbances known as Manganism. However, the mechanisms underlying these deficits remain unknown. Here we investigated the effects of manganese intoxication on motor and non-motor parkinsonian-like deficits such as locomotor activity, motor coordination, anxiety and "depressive-like" behaviors. Then, we studied the impact of this intoxication on the neuronal activity, the globus pallidus (GP) and subthalamic nucleus (STN). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, norepinephrine and serotonin) has been determined. The experiments were carried out in adult Sprague-Dawley rats, daily treated with MnCl2 (10 mg/kg/, i.p.) for 5 weeks. We show that manganese progressively reduced locomotor activity as well as motor coordination in parallel with the manifestation of anxiety and "depressive-like" behaviors. Electrophysiological results show that, while majority of GP and STN neurons discharged regularly in controls, manganese increased the number of GP and STN neurons discharging irregularly and/or with bursts. Biochemical results show that manganese significantly decreased tissue levels of norepinephrine and serotonin with increased metabolism of dopamine in the striatum. Our data provide evidence that manganese intoxication is associated with impaired neurotransmission of monoaminergic systems, which is at the origin of changes in basal ganglia neuronal activity and the manifestation of motor and non-motor deficits similar to those observed in atypical Parkinsonism.