Biology subjects

Norman, S.

Publications and source records attributed to Norman, S..

6 recordsLinked to original sources

bioRxiv2025

Non-invasive in vivo bidirectional magnetogenetic modulation of pain circuits.

Primary nociceptors in the dorsal root ganglion (DRG) receive sensory information from discrete parts of the body and are responsible for initiating signaling events that in supraspinal regions will be interpreted as physiological or pathological pain. Genetic, pharmacologic and electric neuromodulation of nociceptor activity in freely moving non-transgenic animals has been shown to be challenging due to many factors including the immunogenicity of non-mammalian proteins, procedure invasiveness and poor temporal precision. Here, we introduce a magnetogenetic strategy that enables remote bidirectional regulation of nociceptor activity. Magnetogenetics utilizes a source of direct magnetic field (DMF) to control neuronal activity in cells that express an anti-ferritin nanobody-TRPV1 receptor fusion protein (Nb-Ft-TRPV1). In our study, AAV2retro-mediated delivery of an excitatory Nb-Ft-TRPV1 construct into the sciatic nerve of wild-type mice resulted in stable long-term transgene expression accompanied by significant reduction of mechanical withdrawal thresholds during DMF exposure, place aversion of the DMF zone and activity changes in the anterior cingulate (ACC) nucleus. Conversely, delivery of an inhibitory variant of the Nb-Ft-TRPV1 construct, engineered to gate chloride ions in response to DMF, led to reversed behavioral manifestations of mechanical allodynia and showed place preference for the DMF zone, suggestive of functional pain relief. Changes in DRG activity were confirmed by post-mortem levels, immediately following DMF exposure, of the activity-induced gene cfos, which increased with the excitatory construct in normal mice and decreased with the inhibitory construct in pain models Our study demonstrates that magnetogenetic channels can achieve long-term expression in the periphery without losing functionality, providing a stable gene therapy system for non-invasive, magnetic field regulation of pain-related neurons for research and potential clinical applications.

neuroscience↗

bioRxiv2023

Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy

Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. AAV-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine 2a receptor-cre driver mice resulted in motor freezing when placed in an MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in-vivo using clinically available devices. TeaserA novel magnetogenetics toolbox to regulate neural circuits in-vivo.

neuroscience↗

bioRxiv2021

Computational neural network provides naturalistic solution for recovery of finger dexterity after stroke

Finger dexterity is a fundamental movement skill of humans and the ability to individuate fingers imparts high motor flexibility. Disruption of dexterity due to brain injury reduces quality of life. Thus, understanding the neurological mechanisms responsible for recovery is critical to effective neurorehabilitation. Two neuronal pathways have been proposed to play crucial roles in finger individuation: the corticospinal tract, originating from primary motor cortex and premotor areas, and the subcortical reticulospinal tract, originating from the reticular formation in the brainstem. Finger individuation in patients with lesions to these pathways may recover. However, it remains an open question how the cortical-reticular network reorganizes and contributes to this recovery following a stroke. We hypothesized that interactive connections between cortical and subcortical neurons reflect dynamics appropriate for generating outgoing commands for finger movement. To test this hypothesis, we developed an Artificial Neural Network (ANN) representing a premotor planning input layer, a cortical layer including excitatory and inhibitory neurons and, a reticular layer that control motoneurons eliciting unilateral flexion of two fingers. The ANN was trained to reproduce "normal" activity of finger individuation and strength. Analysis of the trained ANN revealed that the natural dynamical solution was a near-linear relationship between the force of the instructed and uninstructed finger, resembling individuation patterns in humans. A simulated stroke lesion was then applied to the ANN and the resulting finger dexterity was assessed at multiple stages post stroke. Analysis revealed: (1) increased unintended force produced by uninstructed fingers (i.e., enslaving) and (2) weakening of the force in the instructed finger immediately after stroke, (3) improved finger control during recovery that typically occurs early after stroke, and (4) association of this behavior with increased neural plasticity of the residual neurons, as reflected by strengthening of connectivity weights between premotor and focal cortical excitatory and inhibitory neurons, but reduction in connectivity in shared cortical neurons. Interestingly, the network solution predicted that the reticulospinal pathway also contributed to the improved behavior. Lastly, the ANN also predicts the effect of cortical lesion size on finger individuation. Our model provides a framework by which to understand a number of experimental findings. The model solution suggests that a key mechanism of finger individuation is establishment of an interactive relationship between cortical and subcortical regions, appropriate to produce desired finger movement.

neuroscience↗

bioRxiv2020

Neural correlates of cognitive motor signals in primary somatosensory cortex.

Classical systems neuroscience positions primary sensory areas as early feed-forward processing stations for refining incoming sensory information. This view may oversimplify their role given extensive bi-directional connectivity with multimodal cortical and subcortical regions. Here we show that single units in human primary somatosensory cortex encode imagined reaches centered on imagined limb positions in a cognitive motor task. This result suggests a broader role of primary somatosensory cortex in cortical function than previously demonstrated.

neuroscience↗

bioRxiv2019

Chromosomal length reference assembly for Diaphorina citri using single-molecule sequencing and Hi-C proximity ligation with manually curated genes in developmental, structural and immune pathways

BackgroundDiaphorina citri is a vector of "Candidatus Liberibacter asiaticus" (CLas), the gram-negative bacterial pathogen associated with citrus greening disease. Control measures rely on pesticides with negative impacts on the environment, natural ecosystems and human and animal health. In contrast, gene-targeting methods have the potential to specifically target the vector species and/or reduce pathogen transmission. ResultsTo improve the genomic resources needed for targeted pest control, we assembled a D. citri genome based on PacBio long reads followed by proximity ligation-based scaffolding. The 474 Mb genome has 13 chromosomal-length scaffolds. 1,036 genes were manually curated as part of a community annotation project, composed primarily of undergraduate students. We also computationally identified a total of 1,015 putative transcription factors (TFs) and were able to infer motifs for 337 TFs (33 %). In addition, we produced a genome-independent transcriptome and genomes for D. citri endosymbionts. ConclusionsManual annotation provided more accurate gene models for use by researchers and also provided an excellent training opportunity for students from multiple institutions. All resources are available on CitrusGreening.org and NCBI. The chromosomal-length D. citri genome assembly serves as a blueprint for the development of collaborative genomics projects for other medically and agriculturally significant insect vectors.

genomics↗

bioRxiv2019

Full Emergence timing and voltinism of phantom midges, Chaoborus spp., in the UK

After introduction of overwintered fourth instar larvae (2027 in total), emergence timing of adult Chaoborus spp. (Diptera: Chaoboridae) was investigated in four outdoor freshwater microcosms in the UK in 2017. Adults started emerging on 13 April and emergence reached a peak on 2 May. The majority of emergence was completed by 3 June. Emergence rates for each microcosm ranged from 51.4% to 66.2% with a mean of 60.9%. The great majority of emerged adults were C. obscuripes (99.68%). Males appeared to emerge slightly earlier than females. The results indicated that for overwintered C. obscuripes larvae, the adults emerged en masse in spring (rather than emerging gradually over the course of spring and summer). In a separate experiment at the same location, the number of Chaoborus spp. life-cycles occurring per year was determined using six replicate groups of microcosms, each group containing four microcosms. Each microcosm contained 200 L of water and was enclosed within a pop-up frame covered with insect-proof mesh (1 mm2 aperture). The first microcosm in each group was seeded with egg rafts (first generation) of Chaoborus spp. Following adult emergence, as soon as the first egg rafts were laid in each microcosm these were removed and transferred to the second microcosm in that group, and so on. The larvae sampled from the second and subsequent generations in the microcosms were all C. crystallinus. C. crystallinus produced up to four discrete generations within the experimental period, and life-cycle times from egg-to-egg ranged from 14 days (replicate group 5, first generation) to 56 days (replicate 3, second generation). These two experiments, indicated that i) adult C. obscuripes arising from overwintered larvae emerged en masse in the spring, and ii) up to four generations of C. crystallinus occurred; i.e. C. crystallinus exhibited a multi-voltine life history under the temperate conditions of this UK study.

ecology↗