Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input.

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions. However, the precise mechanisms underlying this process remain unclear. One way to study action selection is to understand how it breaks down in pathological states. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson's disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. We found this differential activation of TRAPed dMSNs is likely to be driven by higher dopamine receptor expression, dopamine-dependent excitability, and excitatory input from the motor cortex and thalamus. Together, these findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.

Overground versus treadmill walking in Parkinson's disease: Relationship between speed and spatiotemporal gait metrics.

BACKGROUND: Treadmills provide a safe and convenient way to study the gait of people with Parkinson's disease (PD), but outcome measures derived from treadmill gait may differ from overground walking. OBJECTIVE: To investigate how the relationships between gait metrics and walking speed vary between overground and treadmill walking in people with PD and healthy controls. METHODS: We compared 29 healthy controls to 27 people with PD in the OFF-medication state. Subjects first walked overground on an instrumented gait walkway, then on an instrumented treadmill at 85%, 100% and 115% of their overground walking speed. Average stride length and cadence were computed for each subject in both overground and treadmill walking. RESULTS: Stride length and cadence both differed between overground and treadmill walking. Regressions of stride length and cadence on gait speed showed a log-log relationship for both overground and treadmill gait in both PD and control groups. The difference between the PD and control groups during overground gait was maintained for treadmill gait, not only when treadmill speed matched overground speed, but also with ± 15% variation in treadmill speed from that value. SIGNIFICANCE: These results show that the impact of PD on stride length and cadence and their relationship to gait speed is preserved in treadmill as compared to overground walking. We conclude that a treadmill protocol is suitable for laboratory use in studies of PD gait therapeutics.

Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in parkinsonian mice.

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson's disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of movement-related STN activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.

Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release.

Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic axons and directly inhibited release, but also likely acts by reducing excitation from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insights into the actions of benzodiazepines within the striatum.

Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons.

Substantia nigra (SNc) dopaminergic neurons respond to aversive stimuli with inhibitory pauses in firing followed by transient rebound activation. We tested integration of inhibitory synaptic inputs onto SNc neurons from genetically defined populations in dorsal striatum (striosome and matrix) and external globus pallidus (GPe; parvalbumin- and Lhx6-positive), and examined their contribution to pause-rebound firing. Activation of striosome projections, which target "dendron bouquets" in the pars reticulata (SNr), consistently quiets firing and relief from striosome inhibition triggers rebound activity. Striosomal inhibitory postsynaptic currents (IPSCs) display a prominent GABA-B receptor-mediated component that strengthens the impact of SNr dendrite synapses on somatic excitability and enables rebounding. By contrast, GPe projections activate GABA-A receptors on the soma and proximal dendrites but do not result in rebounding. Lastly, optical mapping shows that dorsal striatum selectively inhibits the ventral population of SNc neurons, which are intrinsically capable of rebounding. Therefore, we define a distinct striatonigral circuit for generating dopamine rebound.

Implicitly-learned spatial attention is unimpaired in patients with Parkinson's disease.

Extensive research has examined how current goals influence spatial attention. Yet the allocation of spatial attention is also guided by previous experience, which may induce consistent spatial preferences when a visual search target is frequently found in one region of space. Here, we examined the role of the dopaminergic system in acquiring and maintaining location probability learning. We tested Parkinson's patients and age-matched controls in a difficult visual search task in two sessions. In Session 1, unbeknownst to the participants, the target appeared most often in one quadrant in an early, training phase of the experiment. The target was randomly located in a later, testing phase. Both Parkinson's patients and controls acquired an attentional preference toward the high-probability quadrant during training that persisted in the testing phase. Learning yielded a large reduction in response time (345 ms) in Parkinson's patients, and this effect was highly significant. In Session 2, administered several days later, the target's high-probability quadrant changed. Both groups acquired a new preference for Session 2's high-probability quadrant, demonstrating reversal learning. These findings contrast with previously observed deficits in PD in acquiring probabilistic learning and contextual cueing. This result suggests that not all habit-like behaviors depend on the basal ganglia and the dopaminergic system. Instead, preservation of location probability learning may compensate for other types of attentional deficits in PD.

Aging affects the balance between goal-guided and habitual spatial attention.

Visual clutter imposes significant challenges to older adults in everyday tasks and often calls on selective processing of relevant information. Previous research has shown that both visual search habits and task goals influence older adults' allocation of spatial attention, but has not examined the relative impact of these two sources of attention when they compete. To examine how aging affects the balance between goal-driven and habitual attention, and to inform our understanding of different attentional subsystems, we tested young and older adults in an adapted visual search task involving a display laid flat on a desk. To induce habitual attention, unbeknownst to participants, the target was more often placed in one quadrant than in the others. All participants rapidly acquired habitual attention toward the high-probability quadrant. We then informed participants where the high-probability quadrant was and instructed them to search that screen location first-but pitted their habit-based, viewer-centered search against this instruction by requiring participants to change their physical position relative to the desk. Both groups prioritized search in the instructed location, but this effect was stronger in young adults than in older adults. In contrast, age did not influence viewer-centered search habits: the two groups showed similar attentional preference for the visual field where the target was most often found before. Aging disrupted goal-guided but not habitual attention. Product, work, and home design for people of all ages--but especially for older individuals--should take into account the strong viewer-centered nature of habitual attention.

Habitual attention in older and young adults.

Age-related decline is pervasive in tasks that require explicit learning and memory, but such reduced function is not universally observed in tasks involving incidental learning. It is unknown if habitual attention, involving incidental probabilistic learning, is preserved in older adults. Previous research on habitual attention investigated contextual cuing in young and older adults, yet contextual cuing relies not only on spatial attention but also on context processing. Here we isolated habitual attention from context processing in young and older adults. Using a challenging visual search task in which the probability of finding targets was greater in 1 of 4 visual quadrants in all contexts, we examined the acquisition, persistence, and spatial-reference frame of habitual attention. Although older adults showed slower visual search times and steeper search slopes (more time per additional item in the search display), like young adults they rapidly acquired a strong, persistent search habit toward the high-probability quadrant. In addition, habitual attention was strongly viewer-centered in both young and older adults. The demonstration of preserved viewer-centered habitual attention in older adults suggests that it may be used to counter declines in controlled attention. This, in turn, suggests the importance, for older adults, of maintaining habit-related spatial arrangements. (PsycINFO Database Record