Stereoscopic vision enables the perception of depth. To study the brain mechanisms behind stereoscopic vision using non-invasive brain imaging (‘MRI’), scientists need to reproduce the independent views of the left and right eyes in the brain scanner using ‘dichoptic’ displays. However, high quality dichoptic displays are technically challenging and costly to implement in the MRI scanner. The novel miniature stereoscope system (‘MRI stereoscope’) is an affordable and open-source tool that displays high-quality dichoptic images inside the MRI scanner. The MRI stereoscope takes advantage of commonly used display equipment, the MRI head coil, and a display screen. To validate the MRI stereoscope, binocular disparity stimuli were presented in a 3T MRI scanner while neural activation was recorded using functional MRI in six human participants. The comparison of large binocular disparities compared to disparities close to zero evoked strong responses across dorsal and ventral extra-striate visual cortex. In cont...

Over half of all spinal cord injuries are cervical, which can lead to paralysis and respiratory compromise, causing significant morbidity and mortality. Effective treatments to restore breathing after severe upper cervical injury are lacking; thus, it is imperative to develop therapies to address this. Epidural stimulation has successfully restored motor function after spinal cord injury for stepping, standing, reaching, grasping, and postural control. We hypothesized that closed-loop stimulation triggered via healthy hemidiaphragm EMG activity has the potential to elicit functional neuroplasticity in spinal respiratory pathways after cervical spinal cord injury. To test this, we delivered closed-loop, electrical, epidural stimulation (CLES) at the level of the phrenic motor nucleus (C4) for three days after C2 hemisection (C2HS) in freely behaving rats. A 2x2 Latin Square experimental design incorporated two treatments, C2HS injury and CLES therapy resulting in four groups of adult, female Sprague-Dawley ...

The aging brain undergoes structural changes even in very healthy individuals. Quantifying these changes could help disentangle pathological changes from those associated with the normal human aging process. Using longitudinal MRI data from 227 carefully selected healthy human cohort with age ranging from 50 to 80 years old at baseline scan, we quantified age-related volumetric changes in the brain of healthy human older adults. Longitudinally, the rates of tissue loss in total gray matter (GM) and white matter were 2,497.5 mm3 per year and 2,579.8 mm3 per year, respectively. Across the whole brain, the rates of GM decline varied with regions in the frontal and parietal lobes having faster rates of decline, whereas some regions in the occipital and temporal lobes appeared relatively preserved. In contrast, cross sectional changes were mainly observed in the temporal-occipital regions. Similar longitudinal atrophic changes were also observed in subcortical regions including thalamus, hippocampus, putamen, a...

Striatal adenosine A1 receptor (A1R) activation can inhibit dopamine release. A1Rs on other striatal neurons are activated by an adenosine tone that is limited by equilibrative nucleoside transporter 1 (ENT1) that is enriched on astrocytes and is ethanol-sensitive. We explored whether dopamine release in nucleus accumbens core is under tonic inhibition by A1Rs, and is regulated by astrocytic ENT1 and ethanol. In ex vivo striatal slices from male and female mice, A1R agonists inhibited dopamine release evoked electrically or optogenetically and detected using fast-scan cyclic voltammetry, most strongly for lower stimulation frequencies and pulse numbers, thereby enhancing the activity-dependent contrast of dopamine release. Conversely, A1R antagonists reduced activity-dependent contrast but enhanced evoked dopamine release levels, even for single optogenetic pulses indicating an underlying tonic inhibition. The ENT1 inhibitor NBTI reduced dopamine release and promoted A1R-mediated inhibition, and conversely...

Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in the ATXN3 gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human mutant ATXN3, we identified early and robust transcriptional changes in selectively vulnerable brain regions that implicate oligodendrocytes in disease pathogenesis. We mapped transcriptional changes across early, mid, and late stages of disease in two selectively vulnerable brain regions, the cerebellum and brainstem. The most significant disease-associated module through weighted gene co-expression n...

Amacrine cells (ACs) are the most diverse neuronal cell type in the vertebrate retina. Yet little is known about the contribution of ACs to visual processing and retinal disease. A major challenge in evaluating AC function is genetic accessibility. A classic tool of mouse genetics, Cre-mediated recombination, can provide such access. We have screened existing genetically-modified mouse strains and identified multiple candidates that express Cre-recombinase in subsets of retinal ACs. The Cre-expressing mice were crossed to fluorescent-reporter mice to assay Cre expression. In addition, a Cre-dependent fluorescent reporter plasmid was electroporated into the subretinal space of Cre strains. Herein, we report 3 mouse lines ( Tac1::IRES-cre , Camk2a-cre , and Scx-cre that express Cre recombinase in sub-populations of ACs. In 2 of these lines, recombination occurred in multiple AC types and a small number of other retinal cell types, while recombination in the Camk2a-cre line appears specific to a morphological...

Autonomic parasympathetic preganglionic neurons (PGN) drive contraction of the bladder during micturition but remain quiescent during bladder filling. This quiescence is postulated to be due to recurrent inhibition of PGN by fast-firing adjoining interneurons. Here, we defined four distinct neuronal types within lamina VII of the lumbosacral spinal cord, where PGN are situated, by combining whole cell patch clamp recordings with k-means clustering of a range of electrophysiological parameters. Additional morphological analysis separated these neuronal classes into parasympathetic preganglionic populations (PGN) and a fast firing interneuronal population. Kv3 channels are voltage-gated potassium channels (Kv) that allow fast and precise firing of neurons. We found that blockade of Kv3 channels by tetraethylammonium (TEA) reduced neuronal firing frequency and isolated high-voltage-activated Kv currents in the fast-firing population but had no effect in PGN populations. Furthermore, Kv3 blockade potentiated t...

The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra™), a novel FDA approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behaviour and pronociceptive signalling in dorsal root ganglia (DRG) and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, increased PI3K/Akt-signalling in small-diameter DRG neurons and an increase of CD68+ cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH follo...

Value-based decision-making is often studied in a static context, where participants decide which option to select from those currently available. However, everyday life often involves an additional dimension: deciding when to select to maximise reward. Recent evidence suggests that agents track the latent reward of an option, updating changes in their latent reward estimate, to achieve appropriate selection timing ( latent reward tracking ). However, this strategy can be difficult to distinguish from one in which the optimal selection time is estimated in advance, allowing an agent to wait a pre-determined amount of time before selecting, without needing to monitor an option’s latent reward ( distance-to-goal tracking ). Here we show that these strategies can in principle be dissociated. Human brain activity was recorded using electroencephalography (EEG) while female and male participants performed a novel decision task. Participants were shown an option and decided when to select it, as its latent rewar...

The brain continues to respond selectively to environmental stimuli during sleep. However, the functional role of such responses, and whether they reflect information processing or rather sensory inhibition is not fully understood. Here, we present 17 human sleepers (14 females) with their own name and two unfamiliar first names, spoken by either a familiar voice (FV) or an unfamiliar voice (UFV), while recording polysomnography during a full night’s sleep. We detect K-complexes, sleep spindles, and micro-arousals, and assess event-related, and frequency responses as well as inter-trial phase synchronization to the different stimuli presented during non-rapid eye movement (NREM) sleep. We show that UFVs evoke more K-complexes and micro-arousals than FVs. When both stimuli evoke a K-complex, we observe larger evoked potentials, more precise time-locking of brain responses in the delta band (1-4 Hz), and stronger activity in the high frequency (>16Hz) range, in response to UFVs relative to FVs. Crucially, ...