ORCID Profile
0000-0001-7621-0045
Current Organisation
University of Newcastle Australia
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Thermodynamics and Statistical Physics | Chemical Thermodynamics and Energetics | Physical Chemistry (Incl. Structural)
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Physical Sciences | Climate Change Models |
Publisher: American Chemical Society (ACS)
Date: 30-01-2020
Publisher: Cold Spring Harbor Laboratory
Date: 24-12-2020
DOI: 10.1101/2020.12.23.424233
Abstract: Parvalbumin-expressing interneurons (PVINs) in the spinal dorsal horn are found primarily in laminae II inner and III. Inhibitory PVINs (iPVINs) play an important in segregating innocuous tactile input from pain-processing circuits, achieved through presynaptic inhibition of myelinated low-threshold mechanoreceptors and postsynaptic inhibition of distinct spinal circuits. By comparison, relatively little is known of the role of excitatory PVINs (ePVINs) in sensory processing. Here we use neuroanatomical and optogenetic approaches to show that ePVINs comprise a larger proportion of the PVIN population than previously reported, and that both ePVIN and iPVIN populations form synaptic connections amongst (and between) themselves. We find that these cells contribute to neuronal networks that influence activity within several functionally distinct circuits, and that aberrant activity of ePVINs under pathological conditions contributes to the development of mechanical hypersensitivity.
Publisher: eLife Sciences Publications, Ltd
Date: 12-11-2019
DOI: 10.7554/ELIFE.49190
Abstract: Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and lification of pain and identify these interneurons as a future analgesic target.
Publisher: Frontiers Media SA
Date: 17-04-2020
Abstract: The superficial dorsal horn (SDH, LI-II) of the spinal cord receives and processes multimodal sensory information from skin, muscle, joints, and viscera then relay it to the brain. Neurons within the SDH fall into two broad categories, projection neurons and interneurons. The later can be further sub ided into excitatory and inhibitory types. Traditionally, interneurons within the SDH have been ided into overlapping groups according to their neurochemical, morphological and electrophysiological properties. Recent clustering analyses, based on molecular transcript profiles of cells and nuclei, have predicted many more functional groups of interneurons than expected using traditional approaches. In this study, we used electrophysiological and morphological data obtained from genetically-identified excitatory (vGLUT2) and inhibitory (vGAT) interneurons in transgenic mice to cluster cells into groups sharing common characteristics and subsequently determined how many clusters can be assigned by combinations of these properties. Consistent with previous reports, we show differences exist between excitatory and inhibitory interneurons in terms of their excitability, nature of the ongoing excitatory drive, action potential (AP) properties, sub-threshold current kinetics, and morphology. The resulting clusters based on statistical and unbiased assortment of these data fell well short of the numbers of molecularly predicted clusters. There was no clear characteristic that in isolation defined a population, rather multiple variables were needed to predict cluster membership. Importantly though, our analysis highlighted the appropriateness of using transgenic lines as tools to functionally sub ide both excitatory and inhibitory interneuron populations.
Publisher: Frontiers Media SA
Date: 05-05-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-07-2021
DOI: 10.1097/J.PAIN.0000000000002422
Abstract: Parvalbumin-expressing interneurons (PVINs) in the spinal dorsal horn are found primarily in laminae II inner and III. Inhibitory PVINs play an important role in segregating innocuous tactile input from pain-processing circuits through presynaptic inhibition of myelinated low-threshold mechanoreceptors and postsynaptic inhibition of distinct spinal circuits. By comparison, relatively little is known of the role of excitatory PVINs (ePVINs) in sensory processing. Here, we use neuroanatomical and optogenetic approaches to show that ePVINs comprise a larger proportion of the PVIN population than previously reported and that both ePVIN and inhibitory PVIN populations form synaptic connections among (and between) themselves. We find that these cells contribute to neuronal networks that influence activity within several functionally distinct circuits and that aberrant activity of ePVINs under pathological conditions is well placed to contribute to the development of mechanical hypersensitivity.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2023
DOI: 10.1038/S41598-023-38605-9
Abstract: Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1–3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.
Publisher: Frontiers Media SA
Date: 21-12-2020
DOI: 10.3389/FPHYS.2020.560802
Abstract: The pain experience depends on the relay of nociceptive signals from the spinal cord dorsal horn to higher brain centers. This function is ultimately achieved by the output of a small population of highly specialized neurons called projection neurons (PNs). Like output neurons in other central nervous system (CNS) regions, PNs are invested with a substantial axon collateral system that ramifies extensively within local circuits. These axon collaterals are widely distributed within and between spinal cord segments. Anatomical data on PN axon collaterals have existed since the time of Cajal, however, their function in spinal pain signaling remains unclear and is absent from current models of spinal pain processing. Despite these omissions, some insight on the potential role of PN axon collaterals can be drawn from axon collateral systems of principal or output neurons in other CNS regions, such as the hippoc us, amygdala, olfactory cortex, and ventral horn of the spinal cord. The connectivity and actions of axon collaterals in these systems have been well-defined and used to confirm crucial roles in memory, fear, olfaction, and movement control, respectively. We review this information here and propose a framework for characterizing PN axon collateral function in the dorsal horn. We highlight that experimental approaches traditionally used to delineate axon collateral function in other CNS regions are not easily applied to PNs because of their scarcity relative to spinal interneurons (INs), and the lack of cellular organization in the dorsal horn. Finally, we emphasize how the rapid development of techniques such as viral expression of optogenetic or chemogenetic probes can overcome these challenges and allow characterization of PN axon collateral function. Obtaining detailed information of this type is a necessary first step for incorporation of PN collateral system function into models of spinal sensory processing.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2023
DOI: 10.1101/2023.06.01.543241
Abstract: Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.
Publisher: MyJove Corporation
Date: 09-02-2022
DOI: 10.3791/62920
Abstract: The roles and connectivity of specific types of neurons within the spinal cord dorsal horn (DH) are being delineated at a rapid rate to provide an increasingly detailed view of the circuits underpinning spinal pain processing. However, the effects of these connections for broader network activity in the DH remain less well understood because most studies focus on the activity of single neurons and small microcircuits. Alternatively, the use of microelectrode arrays (MEAs), which can monitor electrical activity across many cells, provides high spatial and temporal resolution of neural activity. Here, the use of MEAs with mouse spinal cord slices to study DH activity induced by chemically stimulating DH circuits with 4-aminopyridine (4-AP) is described. The resulting rhythmic activity is restricted to the superficial DH, stable over time, blocked by tetrodotoxin, and can be investigated in different slice orientations. Together, this preparation provides a platform to investigate DH circuit activity in tissue from naïve animals, animal models of chronic pain, and mice with genetically altered nociceptive function. Furthermore, MEA recordings in 4-AP-stimulated spinal cord slices can be used as a rapid screening tool to assess the capacity of novel antinociceptive compounds to disrupt activity in the spinal cord DH.
Publisher: Cold Spring Harbor Laboratory
Date: 18-06-2019
DOI: 10.1101/673533
Abstract: The passage of nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate neurons that contain the calcium-binding protein calretinin (CR). We show that CR + interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relays signals to lamina I projection neurons. In vivo photoactivation of CR + interneurons resulted in a significant nocifensive behavior that was morphine sensitive and cause a conditioned place aversion. Furthermore, halorhodopsin-mediated inhibition of CR + interneurons elevated sensory thresholds. These results suggest that neuronal circuits in the superficial dorsal horn that involve excitatory CR + neurons are important for the generation and lification of pain, and identify these interneurons as a future analgesic target.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-02-2021
DOI: 10.1097/J.PAIN.0000000000002194
Abstract: Projection neurons in the spinal dorsal horn relay sensory information to higher brain centres. The activation of these populations is shaped by afferent input from the periphery, descending input from the brain, and input from local interneuron circuits. Much of our recent understanding of dorsal horn circuitry comes from studies in transgenic mice however, information on projection neurons is still based largely on studies in monkey, cat, and rat. We used viral labelling to identify and record from mouse parabrachial nucleus (PBN) projecting neurons located in the dorsal horn of spinal cord slices. Overall, mouse lamina I spinoparabrachial projection neurons (SPBNs) exhibit many electrophysiological and morphological features that overlap with rat. Unbiased cluster analysis distinguished 4 distinct subpopulations of lamina I SPBNs, based on their electrophysiological properties that may underlie different sensory signalling features in each group. We also provide novel information on SPBNs in the deeper lamina (III-V), which have not been previously studied by patch cl analysis. These neurons exhibited higher action potential discharge frequencies and received weaker excitatory synaptic input than lamina I SPBNs, suggesting this deeper population produces different sensory codes destined for the PBN. Mouse SPBNs from both regions (laminae I and III-V) were often seen to give off local axon collaterals, and we provide neuroanatomical evidence they contribute to excitatory input to dorsal horn circuits. These data provide novel information to implicate excitatory input from parabrachial projection neuron in dorsal horn circuit activity during processing of nociceptive information, as well as defining deep dorsal horn projection neurons that provide an alternative route by which sensory information can reach the PBN.
Start Date: 02-2019
End Date: 12-2024
Amount: $420,000.00
Funder: Australian Research Council
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