Highlights d Striosomes powerfully inhibit SNc dopamine neurons through GABA-BRs on SNr dendrite d Dopamine neurons show rebound activity after inhibition from the striatum, but not GPe d Striosomal inputs are synaptically optimized to produce rebound d Striosomes selectively inhibit ventral, rebound-ready dopamine neurons

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.

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 highprobability 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.

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

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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.

Letter to the EditorGait disorder is a particularly disabling and treatment refractory symptom of Parkinson's disease (PD), contributing to higher fall risk [1] and restrictions of daily activities [2]. Although Parkinsonian gait can improve with deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) [3], gait is not considered to be adequately treated [4].Two "closed-loop" DBS alternatives have been proposed: adaptive DBS (aDBS), where stimulation varies with local field potential (LFP) power (e.g. beta-band 13e30 Hz) [5], and responsive DBS (rDBS), where stimulation is entrained to a specific phase of the pathological movement (e.g. tremor) [6]. Two studies have evaluated aDBS effect on gait [7,8], and none has evaluated rDBS effect on gait.Beta-band power is modulated with the gait cycle [9]. We hypothesize that rDBS timed to gait events might allow, or even enhance, this normal, physiological beta modulation, improving gait. We developed and tested a rDBS system delivering short duration pulse trains at specific gait phases in real-time. To assess the accuracy of stimulation delivery, gait phases were aligned with stimulation artifacts collected from a surface EMG electrode on the neck. To measure efficacy of this rDBS system, we assessed spatial and temporal gait metrics.Sixteen PD individuals with bilateral DBS leads (13 STN, 3 GPi) and Medtronic SC, PC, or RC implantable neural stimulators (INSs) were enrolled. All gave informed consent according to a University of Minnesota Institutional Review Board approved protocol. Data from four participants (all STN) were excluded due to technical difficulties (stimulation not delivered at the target gait phase). Detailed participant demographics are in Table S1.Participants walked on an instrumented treadmill (C-Mill, Motek Medical, Netherlands) for one-minute trials. Each trial was under one of five conditions: off-stimulation, continuous stimulation, stimulation triggered on ipsilateral heel-strike (IHS), on contralateral heel-strike (CHS), or on contralateral toe-off (CTO).

Substania nigra (SNc) dopaminergic neurons show a pause-rebound firing pattern in response to aversive events. Because these neurons integrate information from predominately inhibitory brain areas, it is important to determine which inputs functionally inhibit the dopamine neurons and whether this pause-rebound firing pattern can be produced by a solely inhibitory input. Here, we functionally map geneticallydefined inhibitory projections from the dorsal striatum (striosome and matrix) and globus pallidus (GPe; parvalbumin and Lhx6) onto SNc neurons. We find that GPe and striosomal inputs both pause firing in SNc neurons, but rebound firing only occurs after inhibition from striosomes. Indeed, we find that striosomes are synaptically optimized to produce rebound and preferentially inhibit a subpopulation of ventral, intrinsically rebound-ready SNc dopaminergic neurons on their reticulata dendrites. Therefore, we describe a self-contained dendrite-specific striatonigral circuit that can produce pauserebound firing in the absence of excitatory input.