Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice.

Delta oscillations (0.5-4 Hz) are a robust feature of basal ganglia pathophysiology in patients with Parkinson's disease (PD) in relationship to tremor, but their relationship to other parkinsonian symptoms has not been investigated. While delta oscillations have been observed in mouse models of PD, they have only been investigated in anesthetized animals, suggesting that the oscillations may be an anesthesia artifact and limiting the ability to relate them to motor symptoms. Here, we establish a novel approach to detect spike oscillations embedded in noise to provide the first study of delta oscillations in awake, dopamine-depleted mice. We find that approximately half of neurons in the substantia nigra pars reticulata (SNr) exhibit delta oscillations in dopamine depletion and that these oscillations are a strong indicator of dopamine loss and akinesia, outperforming measures such as changes in firing rate, irregularity, bursting, and synchrony. These oscillations are typically weakened, but not ablated, during movement. We further establish that these oscillations are caused by the loss of D2-receptor activation and do not originate from motor cortex, contrary to previous findings in anesthetized animals. Instead, SNr oscillations precede those in M1 at a 100- to 300-ms lag, and these neurons' relationship to M1 oscillations can be used as the basis for a novel classification of SNr into two subpopulations. These results give insight into how dopamine loss leads to motor dysfunction and suggest a reappraisal of delta oscillations as a marker of akinetic symptoms in PD.NEW & NOTEWORTHY This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson's disease (PD) treatment.

State transitions in the substantia nigra reticulata predict the onset of motor deficits in models of progressive dopamine depletion in mice.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose cardinal motor symptoms are attributed to dysfunction of basal ganglia circuits under conditions of low dopamine. Despite well-established physiological criteria to define basal ganglia dysfunction, correlations between individual parameters and motor symptoms are often weak, challenging their predictive validity and causal contributions to behavior. One limitation is that basal ganglia pathophysiology is studied only at end-stages of depletion, leaving an impoverished understanding of when deficits emerge and how they evolve over the course of depletion. In this study, we use toxin- and neurodegeneration-induced mouse models of dopamine depletion to establish the physiological trajectory by which the substantia nigra reticulata (SNr) transitions from the healthy to the diseased state. We find that physiological progression in the SNr proceeds in discrete state transitions that are highly stereotyped across models and correlate well with the prodromal and symptomatic stages of behavior.

Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice.

The identification of distinct cell types in the basal ganglia has been critical to our understanding of basal ganglia function and the treatment of neurological disorders. The external globus pallidus (GPe) is a key contributor to motor suppressing pathways in the basal ganglia, yet its neuronal heterogeneity has remained an untapped resource for therapeutic interventions. Here we demonstrate that optogenetic interventions that dissociate the activity of two neuronal populations in the GPe, elevating the activity of parvalbumin (PV)-expressing GPe neurons over that of Lim homeobox 6 (Lhx6)-expressing GPe neurons, restores movement in dopamine-depleted mice and attenuates pathological activity of basal ganglia output neurons for hours beyond stimulation. These results establish the utility of cell-specific interventions in the GPe to target functionally distinct pathways, with the potential to induce long-lasting recovery of movement despite the continued absence of dopamine.

A silicon neural probe fabricated using DRIE on bonded thin silicon.

A silicon neural probe fabricated using a deep reactive ion etching based process on 250 µm thin silicon wafers was developed. The fabricated probes replicate the design of soft parylene-C based probes embedded in dissolvable needles and can therefore also be used to test the encapsulation properties of parylene-C in-vivo without introducing additional effects introduced by the dissolvable gel. The process also demonstrates the possibility of performing conventional photolithography on substrates bonded to a handle wafer using a backgrinding liquid wax (BGL7080) as an adhesive. This technique would allow integration of Si wafer thinning into the fabrication of neural probes, potentially allowing a range of neural probes of different thicknesses to be fabricated. Fabricated probes were characterized using electrochemical impedance spectroscopy (EIS) yielding a measured impedance value of ~80 kΩ at 1 kHz for 15 µm by 115 µm platinum electrodes, indicating that extracellular neural recordings are possible. The neural probes were inserted into the substantia nigra of a mouse that showed successful recording of neural activity. Probes fabricated using this technique can thus be potentially used in the study of Parkinson's disease.

Mapping neural circuits with CLARITY.

The use of whole-brain imaging has shed new light on the organization of the dopamine system.

Controversies in Neuroscience: A Literature-Based Course for First Year Undergraduates that Improves Scientific Confidence While Teaching Concepts.

Controversies in Neuroscience is a half-semester elective for first year science students at Carnegie Mellon University with an emphasis on discussing primary literature to highlight current research topics and to introduce students to neuroscience. In order to evaluate the effectiveness of teaching first-year students using a literature-only approach, we took advantage of an opportunity to teach the same topics to a traditional textbook-based upper division course as to the first year seminar. Students in both courses took surveys at the beginning and end of the course, and self-reported confidence levels as well as exam scores were compared. At the conclusion of both courses, students reported increased level of comfort with scientific terminology and methodology. In addition, students enrolled in the first-year seminar performed at least as well or better than students involved in the upper division course on exam material. These results suggest that first year students are capable of making great strides in learning and understanding scientific principles strictly through exposure to primary literature, even with little or no access to a standard textbook. Furthermore, introducing students to primary literature-based courses early on in their undergraduate career can increase enthusiasm for learning science and improve confidence with neuroscience concepts and methodology. We therefore conclude that it is valuable to provide students opportunities to critically evaluate scientific literature early in their undergraduate careers.