Biology subjects

Doig, N. M.

Publications and source records attributed to Doig, N. M..

4 recordsLinked to original sources

bioRxiv2025

Selective innervation of subpopulations of striatal neurons by distinct sets of neurons of the external globus pallidus

The striatum, the primary input nucleus of the basal ganglia, contains diverse populations of projection neurons and interneurons, each with distinct roles in motor processing. The external globus pallidus contains distinct populations of inhibitory neurons that are highly interconnected with other regions of the basal ganglia. How pallidal neurons innervate different populations of striatal neurons is critical for our understanding of their role in motor processing. Here we use monosynaptic viral tracing in transgenic mice to quantitively define the organization of pallidostriatal connectivity. We show that FoxP2-expressing arkypallidal neurons provide the greatest input to the striatum, primarily targeting indirect pathway spiny projection neurons and cholinergic interneurons. In contrast, prototypic pallidal neurons, defined by Nkx2-1 expression, preferentially innervate parvalbumin- and somatostatin-expressing interneurons. These data reveal a structured and selective organization of pallidostriatal projections, suggesting that distinct classes of pallidal neurons modulate striatal circuits through complementary pathways. Mapping these connections is key to understanding how basal ganglia networks coordinate motor control.

neuroscience↗

bioRxiv2024

Rapid modulation of striatal cholinergic interneurons and dopamine release by satellite astrocytes

Astrocytes are increasingly thought to have underestimated and important roles in modulating neuronal circuits. Astrocytes in striatum can regulate dopamine transmission by governing the extracellular tone of axonal neuromodulators, including GABA and adenosine. However, here we reveal that striatal astrocytes occupy a cell type-specific anatomical and functional relationship with cholinergic interneurons (ChIs), through which they rapidly excite ChIs and govern dopamine release via nicotinic acetylcholine receptors on subsecond timescales. We identify that ChI somata are in unexpectedly close proximity to astrocyte somata, in mouse and human, forming a "soma-to-soma" satellite-like configuration not typically observed for other striatal neurons. Transient depolarization of astrocytes in mouse striatum reversibly regulated ChI excitability by decreasing extracellular calcium. These findings reveal a privileged satellite astrocyte-interneuron interaction for striatal ChIs operating on subsecond timescales via regulation of extracellular calcium dynamics to shape downstream striatal circuit activity and dopamine signaling.

neuroscience↗

bioRxiv2020

A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

neuroscience↗

bioRxiv2019

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

Striatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions. HighlightsO_LIGABA transporters set the level of GABA inhibition of DA output in dorsal striatum C_LIO_LIAstrocytes facilitate DA release levels by limiting tonic GABA inhibition C_LIO_LITonic inhibition of DA release is augmented in a mouse model of early parkinsonism C_LIO_LIDA and GABA co-release are reduced in a mouse model of early parkinsonism C_LI

neuroscience↗