Biology subjects

Viney, T. J.

Publications and source records attributed to Viney, T. J..

6 recordsLinked to original sources

bioRxiv2025

Granularity of thalamic head direction cells

Head direction signaling is fundamental for spatial orientation and navigation. The anterodorsal nucleus of the thalamus (ADn) contains a high density of head direction (HD) cells that process sensorimotor inputs for subsequent synaptic integration in postsynaptic cortical areas. We tested the hypothesis that individual HD cells show differences in their firing patterns and connectivity by recording and juxtacellularly labeling single HD cells in subregions of the ADn in awake mice during passive rotation. We identified HD cells that exhibited different response profiles to light, sound, and movement. We also identified a mediolateral gradient of calretinin-expressing (CR+) ADn cells, with CR+ HD cells having narrower tuning widths, lower maximal firing rates, and different intrinsic properties compared to CR-cells. Axons of labeled HD cells could be followed to the retrosplenial cortex, with collaterals innervating the thalamic reticular nucleus (type I cells); others additionally innervated the dorsomedial striatum (type II cells). Most medial CR+ cells preferentially projected to ventral retrohippocampal regions. Surprisingly, we also identified a subpopulation of medial CR+ cells with twisted dendrites and descending axons that avoided the thalamic reticular nucleus, termed tortuosa HD cells (type III cells). We conclude that HD cells of the mouse ADn comprise distinct cell types, providing parallel head-direction-modulated sensorimotor messages to synaptic target neurons within the head direction network.

neuroscience↗

bioRxiv2025

Novel in situ seeding immunodetection assay uncovers neuronal-driven alpha-synuclein seeding in Parkinson's disease

Aggregates of alpha-synuclein (-syn) and tau propagate through template-induced misfolding in the brains of Parkinsons (PD) and Alzheimers disease (AD) patients. Prion-like seeding is crucial in disease initiation and progression and represents a major target for drug-modifying therapies. The detection of aggregated -syn and tau seeding activity with seeding amplification assays (SAAs) have remarkable diagnostic and research potential. However, current SAAs rely on bulk tissue homogenates or fluids, losing critical spatial and cellular resolution. Here, we report our novel in situ seeding immunodetection (isSID) assay that enables the visualization of -syn and tau seeding activities with unprecedented morphological detail in intact biological samples. Using the isSID assay, we confirm seeding activity in the pathological aggregates of PD and AD, among others, while uncovering neuron-driven -syn seeding events that precede the onset of clinical symptoms in PD. Our findings provide new fundamental insights into the pathogenesis underlying neurodegeneration and establish an invaluable tool for studying protein aggregation dynamics, with potential applications in biomarker discovery, diagnostics and drug testing.

neuroscience↗

bioRxiv2024

Pathological tau alters head direction signaling and induces spatial disorientation

Spatial disorientation, an early symptom of dementia, is emerging as an early and reliable cognitive biomarker predicting future memory problems associated with Alzheimers disease, but the underlying neural mechanisms have yet to be fully defined. The anterodorsal thalamic nucleus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimers disease and ageing. The ADn contains a high density of head direction (HD) cells, which contribute to spatial navigation and orientation. Hence, their disruption may contribute to spatial disorientation. To test this, we virally expressed human mutant tau (htau) in the ADn of adult mice. HD-tau mice were defined by phosphorylated and oligomeric forms of htau in ADn somata and in axon terminals in postsynaptic target regions. Compared to controls, HD-tau mice exhibited increased looping behavior during spatial learning, and made a greater number of head turns during memory recall, indicative of spatial disorientation. Using in vivo extracellular recordings, we identified htau-expressing ADn cells and found a lower proportion of HD cells in the ADn from HD-tau mice, along with reduced directionality and altered burst firing. These findings provide evidence that expression of pathological human tau can alter HD signaling, leading to impairments in spatial orientation.

neuroscience↗

bioRxiv2024

Synaptic targets and cellular sources of CB1 cannabinoid receptor and vesicular glutamate transporter-3 expressing nerve terminals in relation to GABAergic neurons in the human cerebral cortex

Cannabinoid receptor 1 (CB1) regulates synaptic transmission through presynaptic receptors in nerve terminals, and its physiological roles are of clinical relevance. The cellular sources and synaptic targets of CB1-expressing terminals in the human cerebral cortex are undefined. We demonstrate a variable laminar pattern of CB1-immunorective axons and electron microscopically show that CB1-positive GABAergic terminals make type-2 synapses innervating dendritic shafts (69%), dendritic spines (20%) and somata (11%) in neocortical layers 2-3. Of the CB1-immunopositive GABAergic terminals, 25% were vesicular-glutamate-transporter-3 (VGLUT3)-immunoreactive, suggesting GABAergic/glutamatergic co-transmission on dendritic shafts. In vitro recorded and labelled VGLUT3 or CB1-positive GABAergic interneurons expressed cholecystokinin, vasoactive-intestinal-polypeptide and calretinin, had diverse firing, axons and dendrites, and included rosehip, neurogliaform and basket cells, but not double bouquet or axo-axonic cells. CB1-positive interneurons innervated pyramidal cells and GABAergic interneurons. Most glutamatergic synaptic terminals formed type-1 synapses and some were positive for CB1 receptor concentrated in the presynaptic active zone, unlike in GABAergic terminals. From the sampled VGLUT3-positive terminals, 60% formed type-1 synapses with dendritic spines (80%) or shafts (20%) and 52% were also positive for VGLUT1, suggesting intracortical origin. Some VGLUT3-positive terminals were immunopositive for vesicular-monoamine-transporter-2, suggesting 5-HT/glutamate co-transmission. Overall, the results show that CB1 regulates GABA release mainly to dendritic shafts of both pyramidal cells and interneurons, and predict CB1-regulated co-release of GABA and glutamate from single cortical interneurons. We also demonstrate the co-existence of multiple vesicular glutamate transporters in a select population of terminals probably originating from cortical neurons and innervating dendritic spines in the human cerebral cortex.

neuroscience↗

bioRxiv2023

Pathway-specific progression of Tau pathology in the human thalamus

The Papez circuit comprises several interconnected brain areas important for spatial navigation and orientation. An early symptom of dementia is disorientation, suggesting that brain regions responsible for providing a sense of direction are adversely affected. We examined post-mortem human tissue from cases with no cognitive impairment, mild cognitive impairment, and Alzheimers disease. A key part of the Papez circuit, the anterodorsal thalamic nucleus (ADn), contained a high density of misfolded pathological Tau (pTau) at all disease stages, including in control cases. Moreover, pTau preferentially accumulated in calretinin-expressing neurons. At the subcellular level, we detected pTau filaments in ADn cell bodies, dendrites, and in specialized presynaptic terminals. Large vesicular-glutamate-transporter-2-containing terminals from the lateral mammillary nucleus, rather than corticothalamic terminals, preferentially contained pTau, suggesting that Tau crosses specific synapses within the Papez circuit. As the ADn contains a high density of head direction cells, pTau may degrade the processing of orientation signals, explaining why people become disorientated years-to-decades before memory deficits emerge.

neuroscience↗

bioRxiv2021

Consequences of human Tau aggregation in the hippocampal formation of ageing mice in vivo

Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing prosubicular pyramidal cells but the firing population retains its coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely-moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms maintain cortical neuronal coordination, counteracting the widespread pTau aggregation, loss of high-firing cells, and neurodegeneration.

neuroscience↗