GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model

Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. 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 are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions

A Hippocampus-Accumbens Tripartite Neuronal Motif Guides Appetitive Memory in Space

Retrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Hippocampal pyramidal cells (PYRs) of the mammalian brain provide mnemonic representations of space. Yet the substrates by which these hippocampal representations support memory-guided behavior remain unknown. Here, we uncover a direct connection from dorsal CA1 (dCA1) hippocampus to nucleus accumbens (NAc) that enables the behavioral manifestation of place-reward memories. By monitoring neuronal ensembles in mouse dCA1→NAc pathway, combined with cell-type selective optogenetic manipulations of input-defined postsynaptic neurons, we show that dCA1 PYRs drive NAc medium spiny neurons and orchestrate their spiking activity using feedforward inhibition mediated by dCA1-connected parvalbumin-expressing fast-spiking interneurons. This tripartite cross-circuit motif supports spatial appetitive memory and associated NAc assemblies, being independent of dorsal subiculum and dispensable for both spatial novelty detection and reward seeking. Our findings demonstrate that the dCA1→NAc pathway instantiates a limbic-motor interface for neuronal representations of space to promote effective appetitive behavior

Distinct developmental origins manifest in the specialized encoding of movement by adult neurons of the external globus pallidus

SummaryTranscriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets

Cortical and thalamic innervation of the striatum

The basal ganglia are a collection of sub-cortical nuclei involved in the execution of a range of motor and cognitive behaviours. The striatum is the input nucleus of the basal ganglia, receiving major excitatory innervation from the cerebral cortex and intralaminar thalamic nuclei. The main target of these two pathways are the principal striatal neurons, the medium-sized spiny neurons (MSNs), which are subdivided based on their axonal targets and the expression of molecular markers. Direct pathway neurons project to the output nuclei of the basal ganglia and express the D dopamine receptor subtype, whereas indirect pathway MSNs project to the output nuclei via the globus pallidus, and express the D receptor. The striatum also contains interneurons that are essential in processing information within striatum; the cholinergic interneuron is of particular interest due to its role in reward-related behaviour. The aim of this study was to examine the cortical and thalamic innervation of subtypes of striatal neurons.To examine whether the cortical or thalamic afferents selectively innervate direct or indirect pathway neurons, transgenic mice expressing GFP under either the D or D receptor promoter were used. Striatal sections from these mice were immunostained to reveal the GFP and selective markers of the cortical and thalamic afferents, VGluT1 and VGluT2, respectively. A quantitative electron microscopic examination of synaptic connectivity was carried out. The results indicate that there is no selectivity of either the cortical or thalamic pathway for D or D expressing MSNs. Thus both direct and indirect pathway MSNs are involved in the processing of both cortical and thalamic information.The cortical and thalamic innervation to cholinergic interneurons was also examined. Stimulation of cortex and thalamus in vivo in anaesthetised rats resulted in short-latency excitatory responses in identified cholinergic interneurons, indicative of monosynaptic connections. After recording, cholinergic interneurons were filled with neurobiotin. The synaptic innervation from cortex and thalamus was then examined in two individual, electrophysiologically characterised, and neurochemically identified cholinergic interneurons. One neuron received input from both cortex and thalamus, whereas the other neuron received input from the thalamus only. These results provide anatomical and physiological data illustrating how the excitatory inputs to striatum innervate cholinergic interneurons.</p

Cortical and thalamic innervation of striatum

The basal ganglia are a collection of sub-cortical nuclei involved in the execution of a range of motor and cognitive behaviours. The striatum is the input nucleus of the basal ganglia, receiving major excitatory innervation from the cerebral cortex and intralaminar thalamic nuclei. The main target of these two pathways are the principal striatal neurons, the medium-sized spiny neurons (MSNs), which are subdivided based on their axonal targets and the expression of molecular markers. Direct pathway neurons project to the output nuclei of the basal ganglia and express the D, dopamine receptor subtype, whereas indirect pathway MSNs project to the output nuclei via the globus pallidus, and express the D2 receptor. The striatum also contains interneurons that are essential in processing information within striatum; the cholinergic interneuron is of particular interest due to its role in reward-related behaviour. The aim of this study was to examine the cortical and thalamic innervation of subtypes of striatal neurons. To examine whether the cortical or thalamic afferents selectively innervate direct or indirect pathway neurons, transgenic mice expressing GFP under either the D, or D2 receptor promoter were used. Striatal sections from these mice were immunostained to reveal the GFP and selective markers of the cortical and thalamic afferents, VGluTI and VGluT2, respectively. A quantitative electron microscopic examination ofsynaptic connectivity was carried out. The results indicate that there is no selectivity of either the cortical or thalamic pathway for D, or D2 expressing MSNs. Thus both direct and indirect pathway MSNs are involved in the processing of both cortical and thalamic information The cortical and thalamic innervation to cholinergic interneurons was also examined. Stimulation of cortex and thalamus in vivo in anaesthetised rats resulted in short-latency excitatory responses in identified cholinergic interneurons, indicative of monosynaptic connections. After recording, cholinergic interneurons were filled with neurobiotin. The synaptic innervation from cortex and thalamus was then examined in two individual, electrophysiologically characterised, and neurochemically identified cholinergic interneurons. One neuron received input from both cortex and thalamus, whereas the other neuron received input from the thalamus only. These results provide anatomical and physiological data illustrating how the excitatory inputs to striatum innervate cholinergic interneurons.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Cortical and thalamic innervation of the striatum

The basal ganglia are a collection of sub-cortical nuclei involved in the execution of a range of motor and cognitive behaviours. The striatum is the input nucleus of the basal ganglia, receiving major excitatory innervation from the cerebral cortex and intralaminar thalamic nuclei. The main target of these two pathways are the principal striatal neurons, the medium-sized spiny neurons (MSNs), which are subdivided based on their axonal targets and the expression of molecular markers. Direct pathway neurons project to the output nuclei of the basal ganglia and express the D dopamine receptor subtype, whereas indirect pathway MSNs project to the output nuclei via the globus pallidus, and express the D receptor. The striatum also contains interneurons that are essential in processing information within striatum; the cholinergic interneuron is of particular interest due to its role in reward-related behaviour. The aim of this study was to examine the cortical and thalamic innervation of subtypes of striatal neurons.To examine whether the cortical or thalamic afferents selectively innervate direct or indirect pathway neurons, transgenic mice expressing GFP under either the D or D receptor promoter were used. Striatal sections from these mice were immunostained to reveal the GFP and selective markers of the cortical and thalamic afferents, VGluT1 and VGluT2, respectively. A quantitative electron microscopic examination of synaptic connectivity was carried out. The results indicate that there is no selectivity of either the cortical or thalamic pathway for D or D expressing MSNs. Thus both direct and indirect pathway MSNs are involved in the processing of both cortical and thalamic information.The cortical and thalamic innervation to cholinergic interneurons was also examined. Stimulation of cortex and thalamus in vivo in anaesthetised rats resulted in short-latency excitatory responses in identified cholinergic interneurons, indicative of monosynaptic connections. After recording, cholinergic interneurons were filled with neurobiotin. The synaptic innervation from cortex and thalamus was then examined in two individual, electrophysiologically characterised, and neurochemically identified cholinergic interneurons. One neuron received input from both cortex and thalamus, whereas the other neuron received input from the thalamus only. These results provide anatomical and physiological data illustrating how the excitatory inputs to striatum innervate cholinergic interneurons.This thesis is not currently available via ORA

Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility.

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here&nbsp;we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC

Paranode Abnormalities and Oxidative Stress in Optic Nerve Vulnerable to Secondary Degeneration: Modulation by 670 nm Light Treatment

Secondary degeneration of nerve tissue adjacent to a traumatic injury results in further loss of neurons, glia and function, via mechanisms that may involve oxidative stress. However, changes in indicators of oxidative stress have not yet been demonstrated in oligodendrocytes vulnerable to secondary degeneration in vivo. We show increases in the oxidative stress indicator carboxymethyl lysine at days 1 and 3 after injury in oligodendrocytes vulnerable to secondary degeneration. Dihydroethidium staining for superoxide is reduced, indicating endogenous control of this particular reactive species after injury. Concurrently, node of Ranvier/paranode complexes are altered, with significant lengthening of the paranodal gap and paranode as well as paranode disorganisation. Therapeutic administration of 670 nm light is thought to improve oxidative metabolism via mechanisms that may include increased activity of cytochrome c oxidase. Here, we show that light at 670 nm, delivered for 30 minutes per day, results in in vivo increases in cytochrome c oxidase activity co-localised with oligodendrocytes. Short term (1 day) 670 nm light treatment is associated with reductions in reactive species at the injury site. In optic nerve vulnerable to secondary degeneration superoxide in oligodendrocytes is reduced relative to handling controls, and is associated with reduced paranode abnormalities. Long term (3 month) administration of 670 nm light preserves retinal ganglion cells vulnerable to secondary degeneration and maintains visual function, as assessed by the optokinetic nystagmus visual reflex. Light at a wavelength of 670 nm may serve as a therapeutic intervention for treatment of secondary degeneration following neurotrauma. © 2013 Szymanski et al

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

International audienceInappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA