Publications by authors named "Kevin A Keay"

39 Publications

Escalating morphine dosage fails to elicit conditioned analgesia in a preclinical chronic neuropathic pain model.

Behav Pharmacol 2021 Sep;32(6):479-486

School of Medical Sciences (Neuroscience) and the Brain and Mind Centre, The University of Sydney, New South Wales, Australia.

Many people with chronic pain escalate their opioid dosage to counteract tolerance effects. A treatment regimen consisting of placebos admixed with opioids has been suggested as a possible therapeutic option that could reduce the harm of long-term opioid use. However, the analgesic efficacy of such a regimen requires further investigation before widespread adoption. We have recently reported that a 4-day pharmacological conditioning procedure, which paired morphine (6 mg/kg) with contextual cues, elicited placebo analgesia in subpopulations of male (35%) and female (25%) rats with sciatic nerve chronic constriction injury (CCI). Here, we investigated how an escalating morphine dosage during conditioning affects the incidence and strength of placebo analgesia. Forty-four male, Sprague-Dawley rats received CCI. Thirty-eight (86%) rats developed strong cold allodynia by day 6 post-surgery, as measured by hind paw withdrawal (HPW) behaviour on a 5°C cold plate (120 s). In this experiment, pharmacological conditioning consisted of an escalating morphine dose over 4 days (8/9/10/12 mg/kg). This dosing regimen produced strong reductions in HPW behaviour and counteracted the effects of morphine tolerance during conditioning. However, none of the rats given the placebo treatment (n = 12) demonstrated reductions in HPW behaviour when morphine was substituted for saline (i.e. placebo analgesia), but instead showed a strong behavioural response (rearing). These results demonstrate that a high, escalating dose of morphine failed to produce conditioned placebo analgesia in rats with CCI. It is possible that admixing placebos with opioids may be similarly ineffective in chronic pain patients when the opioids regimen is high or escalating.
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http://dx.doi.org/10.1097/FBP.0000000000000642DOI Listing
September 2021

Evidence that increased cholecystokinin (CCK) in the periaqueductal gray (PAG) facilitates changes in Resident-Intruder social interactions triggered by peripheral nerve injury.

J Neurochem 2021 Sep 6;158(5):1151-1171. Epub 2021 Aug 6.

School of Medical Sciences and the Brain and Mind Centre, The University of Sydney, New South Wales, Australia.

Individual differences in the effects of a chronic neuropathic injury on social behaviours characterize both the human experience and pre-clinical animal models. The impacts of these changes to the well-being of the individual are often underappreciated. Earlier work from our laboratory using GeneChip® microarrays identified increased cholecystokinin (CCK) gene expression in the periaqueductal gray (PAG) of rats that showed persistent changes in social interactions during a Resident-Intruder encounter following sciatic nerve chronic constriction injury (CCI). In this study, we confirmed these gene regulation patterns using RT-PCR and identified the anatomical location of the CCK-mRNA as well as the translated CCK peptides in the midbrains of rats with a CCI. We found that rats with persistent CCI-induced changes in social behaviours had increased CCK-mRNA in neurons of the ventrolateral PAG and dorsal raphe nuclei, as well as increased CCK-8 peptide expression in terminal boutons located in the lateral and ventrolateral PAG. The functional significance of these changes was explored by microinjecting small volumes of CCK-8 into the PAG of uninjured rats and observing their Resident-Intruder social interactions. Disturbances to social interactions identical to those observed in CCI rats were evoked when injection sites were located in the rostral lateral and ventrolateral PAG. We suggest that CCI-induced changes in CCK expression in these PAG regions contributes to the disruptions to social behaviours experienced by a subset of individuals with neuropathic injury.
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http://dx.doi.org/10.1111/jnc.15476DOI Listing
September 2021

Rapid GFAP and Iba1 expression changes in the female rat brain following spinal cord injury.

Neural Regen Res 2022 Feb;17(2):378-385

Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Science, Faculty of Science, University of Technology Sydney; School of Medical Sciences (Neuroscience), The University of Sydney, Sydney, NSW, Australia.

Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury (SCI) to such comorbidities. Here, we interrogated the expression of astrocyte- and microglial-specific markers glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy; half of the rats received a mild contusion injury at the level of the T10 vertebral body (SCI group), the other half did not (Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus (dorsal and ventral) in rats were collected. GFAP and Iba1 mRNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP mRNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee (UTS ACEC13-0069).
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http://dx.doi.org/10.4103/1673-5374.317982DOI Listing
February 2022

Assessing the Anti-Inflammatory Activity of the Anxiolytic Drug Buspirone Using CRISPR-Cas9 Gene Editing in LPS-Stimulated BV-2 Microglial Cells.

Cells 2021 May 25;10(6). Epub 2021 May 25.

Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.

Buspirone is an anxiolytic drug with robust serotonin receptor 1A (Htr1a) agonist activities. However, evidence has demonstrated that this drug also targets the dopamine D3 receptor (Drd3), where it acts as a potent antagonist. In vivo, Drd3 blockade is neuroprotective and reduces inflammation in models of Parkinson's disease. To test if buspirone also elicited anti-inflammatory activities in vitro, we generated stable Drd3 and Htr1a BV2 microglial cell lines using CRISPR-Cas9 technology and then tested the effects of buspirone after lipopolysaccharide (LPS) challenge. We found that LPS exposure had no effect on cell viability, except in Htr1a cells, where viability was reduced ( < 0.001). Drug treatment reduced viability in Drd3 cells, but not in WT or Htr1a cells. Buspirone counteracted LPS-induced NO release, NOS2, IL-1β and TNF-α gene expression in WT cells, whereas it exerted limited effects in Drd3 or Htr1a microglia. In summary, our findings indicate that buspirone attenuates microglial polarization after LPS challenge. These results also highlight some major effects of Drd3 or Htr1a genetic ablation on microglial biology, raising important questions on the complex role of neurotransmitters in regulating microglia functions.
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http://dx.doi.org/10.3390/cells10061312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229595PMC
May 2021

Nerve injury alters restraint-induced activation of the basolateral amygdala in male rats.

Brain Struct Funct 2021 May 13;226(4):1209-1227. Epub 2021 Feb 13.

Faculty of Medicine and Health, School of Medical Sciences (Neuroscience), The University of Sydney, Sydney, NSW, 2006, Australia.

The amygdala is critical for the production of appropriate responses towards emotional or stressful stimuli. It has a characteristic neuronal activation pattern to acute stressors. Chronic pain and acute stress have each been shown to independently modulate the activity of the amygdala. Few studies have investigated the effect of pain or injury, on amygdala activation to acute stress. This study investigated the effects of a neuropathic injury on the activation response of the amygdala to an acute restraint stress. Chronic constriction injury of the right sciatic nerve (CCI) was used to create neuropathic injury and a single brief 15-min acute restraint was used as an emotional/psychological stressor. All rats received cholera toxin B (CTB) retrograde tracer injections into the medial prefrontal cortex (mPFC) to assess if the amygdala to mPFC pathway was specifically regulated by the combination of neuropathic injury and acute stress. To assess differential patterns of activity in amygdala subregions, cFos expression was used as a marker for "acute", restraint triggered neuronal activation, and FosB/ΔFosB expression was used to reveal prolonged neuronal activation/sensitisation triggered by CCI. Restraint resulted in a characteristic increase in cFos expression in the medial amygdala, which was not altered by CCI. Rats with a CCI showed increased cFos expression in the basolateral amygdala (BLA), in response to an acute restraint stress, but not in neurons projecting to the prefrontal cortex. Further, CCI rats showed an increase in FosB/ΔFosB expression which was exclusive to the BLA. This increase likely reflects sensitisation of the BLA as a consequence of nerve injury which may contribute to heightened sensitivity of BLA neurons to acute emotional/ psychological stressors.
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http://dx.doi.org/10.1007/s00429-021-02235-6DOI Listing
May 2021

Morphine-Conditioned Placebo Analgesia in Female and Male Rats with Chronic Neuropathic Pain: c-Fos Expression in the Rostral Ventromedial Medulla.

Neuroscience 2021 03 5;457:51-73. Epub 2020 Dec 5.

School of Medical Sciences, Discipline of Anatomy & Histology, Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia. Electronic address:

Placebo analgesia has great potential to overcome the inadequacies of current drug therapies to treat conditions of chronic pain. The rostral ventromedial medulla (RVM) has been implicated as a critical relay in the antinociceptive pathway underpinning placebo analgesia in humans. We developed a model of opiate-conditioned placebo analgesia in rats with neuropathic injury to identify medullary nuclei active during placebo analgesia. Using female and male rats the degree of thermal allodynia was first determined following nerve injury, and a pharmacological conditioning procedure, pairing contextual cues with the experience of morphine-induced analgesia, was used to elicit placebo analgesic reactions. This protocol revealed clear subpopulations of placebo reactors (36% of males, 25% of females) and non-reactors in proportions similar to those reported in human studies. We detected injury-specific c-Fos expression in the gracile nucleus and morphine-specific c-Fos expression in the serotonergic midline raphe nuclei and the caudal nuclei of the solitary tract. However, c-Fos expression did not differ between placebo reactors and non-reactors in either serotonergic or non-serotonergic neurons of the RVM. Despite a subpopulation of rats demonstrating placebo reactions, we found no evidence for enhanced activity in the nuclei from which the classical RVM → spinal cord descending analgesic pathways emerge.
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http://dx.doi.org/10.1016/j.neuroscience.2020.11.038DOI Listing
March 2021

Periaqueductal gray inputs to the paraventricular nucleus of the thalamus: Columnar topography and glucocorticoid (in)sensitivity.

Brain Res 2021 01 23;1750:147171. Epub 2020 Oct 23.

School of Medical Sciences (Anatomy & Histology), Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia. Electronic address:

The ability to cope with a novel acute stressor in the context of ongoing chronic stress is of critical adaptive value. The hypothalamic-pituitary-adrenal (HPA) axis contributes to the integrated physiological and behavioural responses to stressors. Under conditions of chronic stress, the posterior portion of the paraventricular thalamic nucleus (pPVT) mediates the 'habituation' of HPA-axis responses, and also facilitates HPA-axis reactivation to novel acute stressors amidst this habituation. Since pPVT neurons are sensitive to the inhibitory effects of circulating glucocorticoids, a glucocorticoid-insensitive neural pathway to the pPVT is likely essential for this reactivation process. The pPVT receives substantial inputs from neurons of the periaqueductal gray (PAG) region, which is organised into longitudinal columns critical for processing acute and/or chronic stressors. We investigated the columnar organisation of PAG → pPVT projections and for the first time determined their glucocorticoid sensitivity. Retrograde tracer injections were made into different rostro-caudal regions of the pPVT, and their PAG columnar inputs compared. Glucocorticoid receptor immunoreactivity (GR-ir) was quantified in these projection neurons. We found that the dorsolateral PAG projected most strongly to rostral pPVT and the ventrolateral PAG most strongly to the caudal pPVT. Despite abundant GR-ir in the PAG, we report a striking absence of GR-ir in PAG → pPVT neurons. Our data suggests that these pathways, which are insensitive to the direct actions of circulating glucocorticoids, likely play an important role in both the habituation of HPA-axis to chronic stressors and its facilitation to acute stressors in chronically stressed rats.
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http://dx.doi.org/10.1016/j.brainres.2020.147171DOI Listing
January 2021

Robust Dopaminergic Differentiation and Enhanced LPS-Induced Neuroinflammatory Response in Serum-Deprived Human SH-SY5Y Cells: Implication for Parkinson's Disease.

J Mol Neurosci 2021 Mar 13;71(3):565-582. Epub 2020 Aug 13.

Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, PO Box 123, Broadway, NSW, 2007, Australia.

Parkinson's disease (PD) is a chronic neurodegenerative condition characterized by motor symptoms such as bradykinesia, resting tremor, and rigidity. PD diagnosis is based on medical history, review of signs, symptoms, neurological and physical examinations. Unfortunately, by the time the disease is diagnosed, dopamine (DA) neuronal loss is often extended, thereby resulting in ineffective therapies. Recent evidence suggests that neuroinflammation may be pivotal during PD onset and progression. However, suitable cellular models and biomarkers to detect early signs of neuroinflammation are still missing. In this study, we developed a well-differentiated DAergic neuronal cell line where we triggered a neuroinflammatory response to assess the temporal expression of the tissue- and urokinase plasminogen activators (tPA and uPA) and their endogenous inhibitor (PAI-1) along with that of pro-inflammatory mediators and the neuronal marker nNOS. Human neuroblastoma cells SH-SY5Y were differentiated into DAergic neuronal-like cells using a combination of 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum depletion. Terminally-differentiated neurons were then exposed to lipopolysaccharide (LPS) for short (up to 24 h) or long term (up to 10 days) to mimic acute or chronic inflammation. Results demonstrated that uPA protein expression was stably upregulated during chronic inflammation, whereas the expression of nNOS protein better reflected the cellular response to acute inflammation. Additional studies revealed that the temporal induction of uPA was associated with increased AKT phosphorylation, but did not seem to involve cAMP-responsive element-binding protein (CREB) activation, nor the mitogen-activated protein kinase (MAPK) pathway. In conclusion, our in vitro data suggests that nNOS and uPA may serve as viable candidate biomarkers of acute and chronic neuroinflammation.
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http://dx.doi.org/10.1007/s12031-020-01678-6DOI Listing
March 2021

Dopamine: an immune transmitter.

Neural Regen Res 2020 Dec;15(12):2173-2185

Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Science, Faculty of Science, University of Technology Sydney; Laboratory of Neural Structure and Function (LNSF), School of Medical Sciences, (Anatomy and Histology), Faculty of Medicine and Health, University of Sydney, Sydney, Australia.

The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson's disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson's disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.
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http://dx.doi.org/10.4103/1673-5374.284976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749467PMC
December 2020

Disability-specific genes GRIN1, GRIN2 and CNR1 show injury-dependent protein expression in the lumbar spinal cord of CCI rats.

Neurosci Lett 2020 05 20;728:134982. Epub 2020 Apr 20.

School of Medical Sciences, Discipline of Anatomy & Histology, Faculty of Medicine and Health, University of Sydney, NSW, 2006, Australia. Electronic address:

The sensory changes triggered by peripheral nerve injury result from functional changes in both neurons and glia in the dorsal horn of the spinal cord. Whether the disrupted affective-motivational states often comorbid with injury-evoked changes in sensation are driven directly by these functional changes is a question only recently investigated. Using a combination of GeneChip microarrays and RT-PCR techniques we identified differences in mRNA expression unique to rats with sustained changes to their social behaviour following sciatic nerve chronic constriction injury (CCI). Amongst these changes were the mRNAs encoding several of the NMDA subunits and the CB1 receptor. However, as protein translation is not a necessary consequence of the upregulation or downregulation of genes we decided to evaluate the functional significance of our initial observations using immunohistochemical detection of their translated protein products to determine their location and abundance in the lumbar spinal cord. Spinal cord tissue from rats with ('Affected'), and without ('Unaffected') changes in social behaviour after CCI was compared with tissue from uninjured controls. The expression of NMDA-1 (NR1) subunit, NMDA-2D subunit, Cannabinoid Receptor 1 (CB1), Glucocorticoid Receptor (GR) and Glial Fibrillary Acidic Protein (GFAP) immunoreactivities was quantified for these rats and revealed that nerve injury increased the expression of NMDA-2D, CB1 and GFAP immunoreactivity compared to uninjured controls. However, these changes were not specific to rats whose social behaviours were 'Affected' or 'Unaffected' by the nerve injury. Our data thus suggest that the development and expression of changes in social behaviour seen in a proportion of rats following CCI are unlikely to be directly related to the spinal changes in NMDA-2D, CB1 and GFAP expression induced by the nerve injury.
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http://dx.doi.org/10.1016/j.neulet.2020.134982DOI Listing
May 2020

An International Partnership of 12 Anatomy Departments - Improving Global Health through Internationalization of Medical Education.

Ann Glob Health 2020 03 6;86(1):27. Epub 2020 Mar 6.

Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, US.

Background: At a time of global interconnectedness, the internationalization of medical education has become important. Anatomy as an academic discipline, with its close connections to the basic sciences and to medical education, can easily be connected with global health and internationalization of medical education. Here the authors present an international program based on a partnership between twelve anatomy departments in ten countries, on four continents. Details of a proposed plan for the future direction of the program are also discussed.

Objective: The aim is to improve global healthcare by preparing future global healthcare leaders via early international networking, international collaboration and exchange, intercultural experience, and connecting two seemingly distant academic disciplines - anatomy and global health - via internationalization of medical education.

Methods: Based in the anatomy course, the program involved early international collaboration between preclinical medical and dental students. The program provided a stepwise progression for learning about healthcare and intercultural topics beyond pure anatomy education - starting with virtual small groups of international students, who subsequently presented their work to a larger international audience during group videoconferences. The above progressed to in-person visits for research internships in the basic sciences within industrialized countries.

Findings: Students appreciated the international and intercultural interaction, learned about areas outside the scope of anatomy (e.g., differences in healthcare education and delivery systems, Public and Global Health challenges, health ethics, and cultural enrichment), and valued the exchange travel for basic sciences research internships and cultural experience.

Conclusions: This unique collaboration of international anatomy departments can represent a new role for the medical anatomy course beyond pure anatomy teaching - involving areas of global health and internationalization of medical education - and could mark a new era of international collaboration among anatomists.
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http://dx.doi.org/10.5334/aogh.2665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059426PMC
March 2020

μ-Opioid and dopamine-D2 receptor expression in the nucleus accumbens of male Sprague-Dawley rats whose sucrose consumption, but not preference, decreases after nerve injury.

Behav Brain Res 2020 03 10;381:112416. Epub 2019 Dec 10.

School of Medical Sciences, Discipline of Anatomy & Histology, University of Sydney, NSW, 2006, Australia.

Functional-anatomical changes in reward related brain circuits are described in chronic pain patients who report anhedonia or depressed mood. In pre-clinical rodent models of neuropathic pain there are varying reports of the effects of nerve injury on the motivation to consume sucrose, although hedonic responses to sucrose appear unchanged. These observations are derived from brief periods of exposure to sucrose. When sucrose is available ad libitum over a period of 21 days, there are marked individual differences in consumption. The motivation for, and hedonic experience of, drinking sucrose is mediated in part by dopamine-D2 and μ-opioid receptors in the nucleus accumbens (NAc). This study investigated the effects of chronic constriction injury (CCI) on ad libitum sucrose consumption in male Sprague Dawley rats and the expression of accumbal dopamine D2 and μ-opioid receptors. Nerve injury reduced sucrose drinking predominantly in rats with the highest pre-injury consumption levels. Despite these reductions in consumption, sucrose preferences were stable. In the NAc of rats whose sucrose consumption was affected by CCI, immunohistochemical analyses revealed bilateral reductions of dopamine D2-receptor expression in the core and shell; and a lateralised reduction of μ-opioid receptor expression in the core and dorsomedial shell of the right NAc. These alterations in receptor expression are located in regions which have been identified as hedonic hot and coldspots along an affective-motivational keyboard which directs behaviours either towards, or away from salient stimuli. These changes likely underlie the reduction in sucrose consumption observed in a subgroup of rats following nerve injury.
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http://dx.doi.org/10.1016/j.bbr.2019.112416DOI Listing
March 2020

Altered monoamine levels in the dorsal striatum of the rat are associated with alterations in behavioural selection and motivation following peripheral nerve injury and acute stress.

Eur J Neurosci 2019 09 10;50(5):2786-2800. Epub 2019 Aug 10.

Discipline of Anatomy & Histology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia.

Chronic neuropathic pain and psychological stress interact to compromise goal-directed control over behaviour following mild psychological stress. The dorsomedial (DMS) and dorsolateral (DLS) striatum in the rat are crucial for the expression of goal-directed and habitual behaviours, respectively. This study investigated whether changes in monoamine levels in the DMS and DLS following nerve injury and psychological stress reflect these behavioural differences. Neuropathic pain was induced by a chronic constriction injury (CCI) of the sciatic nerve in Sprague-Dawley rats. Acute stress was induced using a 15-min restraint. Behavioural flexibility was assessed using the outcome devaluation paradigm. Noradrenaline, serotonin, dopamine and associated metabolites were measured bilaterally from the DLS and DMS. In uninjured rats, restraint increased dopaminergic markers in the left and serotonergic markers in the right of both the DMS and DLS, indicating a possible left hemisphere-mediated dominance. CCI led to a slightly different lateralised effect, with a larger effect in the DMS than in the DLS. Individual differences in behavioural flexibility following CCI negatively correlated with dopaminergic markers in the right DLS, but positively correlated with these markers in the left DMS. A combination of CCI and restraint reduced behavioural flexibility, which was associated with the loss of the left/DMS dominance. These data suggest that behavioural flexibility following psychological stress or pain is associated with a left hemisphere dominance within the dorsal striatum. The loss of behavioural flexibility following the combined stressors is then associated with a transition from left to right, and DMS to DLS dominance.
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http://dx.doi.org/10.1111/ejn.14518DOI Listing
September 2019

Peripheral nerve injury attenuates stress-induced Fos-family expression in the Locus Coeruleus of male Sprague-Dawley rats.

Brain Res 2019 09 10;1719:253-262. Epub 2019 Jun 10.

School of Medical Sciences, Discipline of Anatomy & Histology, Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia. Electronic address:

The ability to cope with acute stressors is impaired in people with chronic neuropathic injuries. The regulation of stress coping responses depends critically on several parallel interconnected neural circuits, one of which originates in the Locus Coeruleus. In rats, chronic constriction injury (CCI) and acute stress each modulate noradrenergic activity of the Locus Coeruleus (LC) although with different temporal patterns. This study investigated the effects of CCI on the neuronal activity of the LC to acute restraint stress using the immunohistochemical detection of Fos-family protein expression. Male Sprague-Dawley rats underwent CCI surgery and 11 days later were restrained for 15 min. The number and location of single-labelled neurons (c-Fos, FosB/ΔFosB and tyrosine hydroxylase (TH) immunoreactive) neurons and double labelled neurons (c-Fos, or FosB/ΔFosB with TH) were quantified for the LC and surrounding regions. Comparisons were made with rats that underwent sham surgery or anaesthesia (20 min). Restraint triggered a struggling response in all rats. CCI attenuated restraint-induced Fos expression in LC neurons. A significant proportion (30-50%) of these LC Fos positive neurons did not contain TH. These data suggest that nerve injury might impair the ordinary cellular response of the LC to an acute stress. The association of stress-related disorders in people with neuropathic injuries suggests that the observations made in this study may reflect a part of the mechanism underlying these clinical comorbidities.
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http://dx.doi.org/10.1016/j.brainres.2019.06.007DOI Listing
September 2019

PACAP and VIP expression in the periaqueductal grey of the rat following sciatic nerve constriction injury.

Neuropeptides 2019 Apr 15;74:60-69. Epub 2018 Dec 15.

School of Medical Sciences (Anatomy and Histology), The University of Sydney, Sydney, NSW 2006, Australia.

Nerve injuries often result in neuropathic pain with co-morbid changes in social behaviours, motivation, sleep-wake cycles and neuroendocrine function. In an animal model of neuropathic injury (CCI) similar co-morbid changes are evoked in a subpopulation (~30%) of injured rats. In addition to anatomical evidence of altered neuronal and glial function, the periaqueductal grey (PAG) of these rats shows evidence of cell death. These changes in the PAG may play a role in the disruption of the normal emotional coping responses triggered by nerve injury. Cell death can occur via a number of mechanisms, including the disruption of neuroprotective mechanisms. Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two endogenous neuropeptides whose activities are tightly regulated by two receptors subtypes, namely the PAC1 and VPAC receptors. These peptides and their receptors exert robust neuroprotective roles. In these studies, we hypothesized that rats expressing disabilities following CCI showed altered expression of PACAP and VIP in the PAG. Rats were categorized as having either Pain alone, Transient or Persistent disability, based on changes in social behaviours pre- and post-CCI. Social interaction behavioural tested (BT), sham-injured and naïve untested rats were also included. For measurements of mRNA and protein expression we utilised micro-dissected PAGs blocks taken from each group. At the mRNA level, VIP was downregulated and PAC1 was upregulated in BT animals, whilst VPAC1 mRNA was specifically increased in the Pain alone group. Interestingly, protein levels of both PACAP and VIP were remarkably increased in the Persistent Disability group. Taken together, sciatic nerve CCI that triggers neuropathic pain and persistent disability results in abnormally increased VIP and PACAP expression in the PAG. Our data also suggest that these effects are likely to be governed by post-transcriptional mechanisms.
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http://dx.doi.org/10.1016/j.npep.2018.12.002DOI Listing
April 2019

Prolonged ad libitum access to low-concentration sucrose changes the neurochemistry of the nucleus accumbens in male Sprague-Dawley rats.

Physiol Behav 2019 03 13;201:95-103. Epub 2018 Dec 13.

School of Medical Sciences, Discipline of Anatomy & Histology, University of Sydney, NSW, Australia, 2006.

Overconsumption of sugars contributes to poor health outcomes. Sugars are often added to commercial foods and beverages in low concentrations and these hidden sugars are consumed unnoticed, continuously. These hidden sugars are suggested to increase the motivation for foodstuffs with higher sugar contents, due to their rewarding properties. This process has been attributed in part, to the activity of both dopaminergic and opioidergic systems in the nucleus accumbens. We asked the question whether prolonged continuous consumption of a low concentration sucrose solution was sufficient to trigger alterations in both dopaminergic and opioidergic systems in the nucleus accumbens of male Sprague-Dawley rats. Rats were given access to either, 1% sucrose and water ad libitum for 3 weeks, or water alone, we then assayed the nucleus accumbens for mRNA and protein expression levels of D1 and D2 dopamine receptors which mediate appetitive motivation and wanting behaviors and for μ-opioid receptors which mediate liking of rewarding stimuli. Our data revealed that rats express a strong preference for 1% sucrose, and showed increased μ-opioid receptor mRNA expression bilaterally in the nucleus accumbens; increased D1 receptor mRNA expression in the left nucleus accumbens; and increased D2 receptor mRNA expression and decreased D2 receptor protein expression in the right nucleus accumbens. We also noted clear individual differences in the volumes of sucrose ingested over this period, however these differences did not correlate with the changes in neurochemistry. Our data show that prolonged ad libitum access to low concentration sucrose alters brain circuits critical for coding reward which may contribute to an enhanced drive for sweet foods and beverages.
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http://dx.doi.org/10.1016/j.physbeh.2018.12.016DOI Listing
March 2019

Hippocampal volume, social interactions, and the expression of the normal repertoire of resident-intruder behavior.

Brain Behav 2017 09 7;7(9):e00775. Epub 2017 Aug 7.

School of Medical Sciences (Anatomy & Histology) The University of Sydney Sydney NSW Australia.

Introduction: Reduced hippocampal volumes are reported in individuals with disrupted emotional coping behaviors in both human clinical conditions and in experimental animal models of these populations. In a number of experimental animal models, it has been shown that social interactions can promote resilience and buffer the negative neural consequences of stimuli that disrupt effective coping.

Methods: Hippocampal and dentate gyrus volumes were calculated in 54 male Sprague Dawley rats; (1) single housed ( = 12), (2) single housed and exposed to daily 6-min social interactions testing in a resident-intruder paradigm ( = 11); (3) group housed ( = 12); (4) single housed and sham injured ( = 12); (5) single housed, sham injured, and social interactions tested ( = 7).

Results: We present data which shows that even a brief daily exposure to a conspecific in resident-intruder social interactions test is sufficient to prevent the reduction in hippocampal volume triggered by single housing.

Conclusion: When considered with previously published data, these findings suggest that the expression of the full repertoire of social, nonsocial, dominance, and submissive behaviors in response to the physical presence of an in the home cage plays a significant role in this maintenance of hippocampal volume.
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http://dx.doi.org/10.1002/brb3.775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607542PMC
September 2017

Resolving the contributions of anaesthesia, surgery, and nerve injury on brain derived neurotrophic factor expression in the medial prefrontal cortex of male rats in the CCI model of neuropathic pain.

J Neurosci Res 2017 12 13;95(12):2376-2390. Epub 2017 Jun 13.

Discipline of Biomedical Sciences, School of Medical Sciences, The University of Sydney, New South Wales, 2006, Australia.

The medial prefrontal cortex (mPFC) is critical for selecting and shaping complex behavioral responses. In rodent models of neuropathic pain there is evidence for both structural and functional changes in the mPFC. Brain derived neurotrophic factor (BDNF) plays a critical role in the normal functioning of the mPFC. It has been suggested that the disruption of complex behaviors and mood seen in some neuropathic pain patients is mediated in part by alterations of BDNF in this cortical region. In Sprague-Dawley rats, mPFC levels of BDNF and TrkB mRNA and protein, were quantified and compared to controls (n = 24) 6 days after either: (a) halothane (1.5%) anaesthesia (n = 12), (b) sham surgery under halothane (n = 12), (c) sciatic nerve chronic constriction injury under halothane (n = 48). The social behaviors of the rats were quantified daily during the experimental period. Halothane anaesthesia increased BDNF and TrkB mRNA bilaterally. These increases were reversed in rats that underwent sham surgical and nerve injury procedures. Further, halothane anaesthesia, surgical procedures, and nerve injury each decreased BDNF protein levels. These results reveal a marked and distinct BDNF expression profile in the mPFC of rats that have undergone each stage of the procedure to produce neuropathic pain by chronic constriction injury of the sciatic nerve. The highly sensitive nature of neurotrophic signalling to general anaesthesia in the mature neuronal circuit of the adult rat brain highlights the importance of careful evaluation and interpretation of data evaluating the effects of experimental procedures on neural substrates.
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http://dx.doi.org/10.1002/jnr.24095DOI Listing
December 2017

Imaging Acute and Chronic Pain in the Human Brainstem and Spinal Cord.

Neuroscientist 2018 02 27;24(1):84-96. Epub 2017 Apr 27.

1 Department of Anatomy and Histology, University of Sydney, Sydney, New South Wales, Australia.

While acute pain serves as a protective mechanism designed to warn an individual of potential or actual damaging stimuli, chronic pain provides no benefit and is now considered a disease in its own right. Since the advent of human brain imaging techniques, many investigations that have explored the central representation of acute and chronic pain have focused on changes in higher order brain regions. In contrast, far fewer have explored brainstem and spinal cord function, mainly due to significant technical difficulties. In this review, we present some of the recent human brain imaging studies that have specifically explored brainstem and spinal cord function during acute noxious stimuli and in individuals with chronic pain. We focus particularly on investigations that explore changes in areas that receive nociceptor afferents and compare humans and experimental animal data in an attempt to describe both microscopic and macroscopic changes associated with acute and chronic pain.
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http://dx.doi.org/10.1177/1073858417703911DOI Listing
February 2018

Recruitment of dorsal midbrain catecholaminergic pathways in the recovery from nerve injury evoked disabilities.

Mol Pain 2015 Aug 18;11:50. Epub 2015 Aug 18.

School of Medical Sciences, Discipline of Anatomy and Histology, The University of Sydney, Sydney, NSW, 2006, Australia.

Background: The periaqueductal gray region (PAG) is one of several brain areas identified to be vulnerable to structural and functional change following peripheral nerve injury. Sciatic nerve constriction injury (CCI) triggers neuropathic pain and three distinct profiles of changes in complex behaviours, which include altered social and sleep-wake behaviours as well as changes in endocrine function. The PAG encompasses subgroups of the A10 dopaminergic and A6 noradrenergic cell groups; the origins of significant ascending projections to hypothalamic and forebrain regions, which regulate sleep, complex behaviours and endocrine function. We used RT-PCR, western blots and immunohistochemistry for tyrosine hydroxylase to determine whether (1) tyrosine hydroxylase increased in the A10/A6 cells and/or; (2) de novo synthesis of tyrosine hydroxylase, in a 'TH-naïve' population of ventral PAG neurons characterized rats with distinct patterns of behavioural and endocrine change co-morbid with CCI evoked-pain.

Results: Evidence for increased tyrosine hydroxylase transcription and translation in the constitutive A10/A6 cells was found in the midbrain of rats that showed an initial 2-3 day post-CCI, behavioural and endocrine change, which recovered by days 5-6 post-CCI. Furthermore these rats showed significant increases in the density of TH-IR fibres in the vPAG.

Conclusions: Our data provide evidence for: (1) potential increases in dopamine and noradrenaline synthesis in vPAG cells; and (2) increased catecholaminergic drive on vPAG neurons in rats in which transient changes in social behavior are seen following CCI. The data suggests a role for dopaminergic and noradrenergic outputs, and catecholaminergic inputs of the vPAG in the expression of one of the profiles of behavioural and endocrine change triggered by nerve injury.
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http://dx.doi.org/10.1186/s12990-015-0049-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538917PMC
August 2015

Evidence for a distinct neuro-immune signature in rats that develop behavioural disability after nerve injury.

J Neuroinflammation 2015 May 20;12:96. Epub 2015 May 20.

Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Room E511, Anderson Stuart Building F13, Sydney, NSW, 2006, Australia.

Background: Chronic neuropathic pain is a neuro-immune disorder, characterised by allodynia, hyperalgesia and spontaneous pain, as well as debilitating affective-motivational disturbances (e.g., reduced social interactions, sleep-wake cycle disruption, anhedonia, and depression). The role of the immune system in altered sensation following nerve injury is well documented. However, its role in the development of affective-motivational disturbances remains largely unknown. Here, we aimed to characterise changes in the immune response at peripheral and spinal sites in a rat model of neuropathic pain and disability.

Methods: Sixty-two rats underwent sciatic nerve chronic constriction injury (CCI) and were characterised as either Pain and disability, Pain and transient disability or Pain alone on the basis of sensory threshold testing and changes in post-CCI dominance behaviour in resident-intruder interactions. Nerve ultrastructure was assessed and the number of T lymphocytes and macrophages were quantified at the site of injury on day six post-CCI. ATF3 expression was quantified in the dorsal root ganglia (DRG). Using a multiplex assay, eight cytokines were quantified in the sciatic nerve, DRG and spinal cord.

Results: All CCI rats displayed equal levels of mechanical allodynia, structural nerve damage, and reorganisation. All CCI rats had significant infiltration of macrophages and T lymphocytes to both the injury site and the DRG. Pain and disability rats had significantly greater numbers of T lymphocytes. CCI increased IL-6 and MCP-1 in the sciatic nerve. Examination of disability subgroups revealed increases in IL-6 and MCP-1 were restricted to Pain and disability rats. Conversely, CCI led to a decrease in IL-17, which was restricted to Pain and transient disability and Pain alone rats. CCI significantly increased IL-6 and MCP-1 in the DRG, with IL-6 restricted to Pain and disability rats. CCI rats had increased IL-1β, IL-6 and MCP-1 in the spinal cord. Amongst subgroups, only Pain and disability rats had increased IL-1β.

Conclusions: This study has defined individual differences in the immune response at peripheral and spinal sites following CCI in rats. These changes correlated with the degree of disability. Our data suggest that individual immune signatures play a significant role in the different behavioural trajectories following nerve injury, and in some cases may lead to persistent affective-motivational disturbances.
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http://dx.doi.org/10.1186/s12974-015-0318-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506439PMC
May 2015

Injury-Dependent and Disability-Specific Lumbar Spinal Gene Regulation following Sciatic Nerve Injury in the Rat.

PLoS One 2015 23;10(4):e0124755. Epub 2015 Apr 23.

School of Medical Sciences (Anatomy & Histology), The University of Sydney, Sydney, NSW, Australia.

Allodynia, hyperalgesia and spontaneous pain are cardinal sensory signs of neuropathic pain. Clinically, many neuropathic pain patients experience affective-motivational state changes, including reduced familial and social interactions, decreased motivation, anhedonia and depression which are severely debilitating. In earlier studies we have shown that sciatic nerve chronic constriction injury (CCI) disrupts social interactions, sleep-wake-cycle and endocrine function in one third of rats, a subgroup reliably identified six days after injury. CCI consistently produces allodynia and hyperalgesia, the intensity of which was unrelated either to the altered social interactions, sleep-wake-cycle or endocrine changes. This decoupling of the sensory consequences of nerve injury from the affective-motivational changes is reported in both animal experiments and human clinical data. The sensory changes triggered by CCI are mediated primarily by functional changes in the lumbar dorsal horn, however, whether lumbar spinal changes may drive different affective-motivational states has never been considered. In these studies, we used microarrays to identify the unique transcriptomes of rats with altered social behaviours following sciatic CCI to determine whether specific patterns of lumbar spinal adaptations characterised this subgroup. Rats underwent CCI and on the basis of reductions in dominance behaviour in resident-intruder social interactions were categorised as having Pain & Disability, Pain & Transient Disability or Pain alone. We examined the lumbar spinal transcriptomes two and six days after CCI. Fifty-four 'disability-specific' genes were identified. Sixty-five percent were unique to Pain & Disability rats, two-thirds of which were associated with neurotransmission, inflammation and/or cellular stress. In contrast, 40% of genes differentially regulated in rats without disabilities were involved with more general homeostatic processes (cellular structure, transcription or translation). We suggest that these patterns of gene expression lead to either the expression of disability, or to resilience and recovery, by modifying local spinal circuitry at the origin of ascending supraspinal pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124755PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408097PMC
January 2016

Different patterns of morphological changes in the hippocampus and dentate gyrus accompany the differential expression of disability following nerve injury.

J Anat 2014 Dec 1;225(6):591-603. Epub 2014 Oct 1.

School of Medical Sciences (Anatomy & Histology), University of Sydney, Sydney, NSW, Australia.

Physical and psychological trauma which results in mood disorders and the disruption of complex behaviours is associated with reductions in hippocampal volume. Clinical evaluation of neuropathic pain reveals mood and behavioural change in a significant number of patients. A rat model of neuropathic injury results in complex behavioural changes in a subpopulation (~30%) of injured rats; these changes are co-morbid with a range of other 'disabilities'. The specific objective of this study was to determine in rats the morphology of the hippocampus and dentate gyrus in individuals with and without complex behavioural disruptions following a constriction injury of the sciatic nerve, and to determine whether rats that develop disabilities following nerve injury have a reduced hippocampal volume compared with injured rats with no disabilities. The social behaviours of nerve-injured rats were evaluated before and after nerve injury. The morphology of the hippocampus of rats with and without behavioural disruptions was compared in serial histological sections. Single-housing and repeated social-interaction testing had no effect on the morphology of either the hippocampus or the dentate gyrus. Rats with transient or ongoing disability identified by behavioural disruption following sciatic nerve injury, show bilateral reductions in hippocampal volume, and lateralised reduction in the dentate gyrus (left side). Disabled rats display a combination of behavioural and physiological changes, which resemble many of the criteria used clinically to diagnose mood disorders. They also show reductions in the volume of the hippocampus similar to people with clinically diagnosed mood disorders. The sciatic nerve injury model reveals a similarity to the human neuropathic pain presentation presenting an anatomically specific focus for the investigation of the neural mechanisms underpinning the co-morbidity of chronic pain and mood disorder.
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http://dx.doi.org/10.1111/joa.12238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262345PMC
December 2014

The hemodynamic response to blood loss in the conscious rat: contributions of cardiac vagal and cardiac spinal signals.

Shock 2014 Apr;41(4):282-91

*School of Medical Sciences (Anatomy & Histology), The University of Sydney, Sydney, New South Wales, Australia; and †Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada.

The hemodynamic response to progressive blood loss passes through three distinct phases: an initial normotensive compensatory phase, a secondary hypotensive decompensatory phase, and a posthemorrhage recompensatory phase. The role of cardiac vagal and cardiac spinal signals in triggering the different phases of the response to hemorrhage was evaluated in the unanesthetized, freely moving rat by observing the effects on the response to 30% blood loss of prior cardiac vagal deafferentation (bilateral vagal rhizotomy) or prior cardiac spinal deafferentation (bilateral stellate ganglionectomy). In comparison to control animals, it was found that (i) cardiac spinal deafferentation significantly delayed the onset of the decompensatory phase, and (ii) cardiac vagal deafferentation slightly potentiated the decompensatory phase and impaired the recompensatory phase. These results indicate that it is cardiac spinal signals, rather than cardiac vagal signals, which in the conscious rat contribute to the triggering and progression of the decompensatory response to blood loss.
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http://dx.doi.org/10.1097/SHK.0000000000000106DOI Listing
April 2014

Differential regulation of glucocorticoid receptor expression in distinct columns of periaqueductal grey in rats with behavioural disability following nerve injury.

Cell Mol Neurobiol 2013 Oct 12;33(7):953-63. Epub 2013 Jul 12.

School of Medical Sciences (Anatomy and Histology), The University of Sydney, Room S502, Anderson Stuart Building, Sydney, NSW, 2006, Australia.

Neuropathic pain is diagnosed primarily by sensory dysfunction, which includes both spontaneous, and stimulus-evoked pain. Clinical evaluation highlights the disabilities which characterise this condition for most patients. Chronic constriction injury of the sciatic nerve (CCI) evokes sensory dysfunction characteristic of neuropathic pain. Approximately, 30 % of CCI rats show disabilities similar to those identified in clinical evaluation of neuropathic pain patients, these include: altered social behaviours; sleep disturbances; and endocrine dysfunction. The periaqueductal grey (PAG) is a nodal point in the brain circuits which regulate these functions, and undergoes a distinct set of neural and glial adaptations following CCI, in rats with disabilities. CCI increases corticosterone, which through its actions at the glucocorticoid receptor (GR), can trigger cellular adaptation. GR expression in PAG was quantified using qRT-PCR, Western blotting and immunohistochemical analyses and nerve-injured rats, with and without disabilities, were compared. Our data showed that the PAG of disabled rats has significantly increased expression of GR mRNA and protein. Further, this increased protein expression reflects contrasting patterns of change in GR expression in PAG subregions. The dorsolateral PAG had significant increases in the number of GR-immunoreactive (GR-IR) cells and the caudal lateral and ventrolateral PAG each had significant reductions in the number of GR-IR cells. These regional increases and decreases correlated with the degree of disability, as indicated by the degree of change in social behaviours. Our results suggest a role for altered PAG, GR-corticosterone interactions and their resultant cellular consequences in the expression of disabilities in a subpopulation of nerve-injured rats.
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http://dx.doi.org/10.1007/s10571-013-9962-3DOI Listing
October 2013

Evidence for cellular injury in the midbrain of rats following chronic constriction injury of the sciatic nerve.

J Chem Neuroanat 2011 Apr 1;41(3):158-69. Epub 2011 Feb 1.

School of Medical Sciences (Anatomy and Histology), The University of Sydney, NSW 2006, Australia.

Complex behavioural disabilities, as well as pain, characterise neuropathic pain conditions for which clinical treatment is sought. In rats, chronic constriction injury (CCI) of the sciatic nerve evokes, allodynia and hyperalgesia as well as three distinct patterns of disability, characterised by changes in social and sleep-wake behaviours: (i) Pain & Disability; (ii) Pain & Transient Disability and (iii) Pain alone. Importantly, the degree of allodynia and hyperalgesia is identical for each of these groups. Social-interactions and sleep-wake behaviours are regulated by neural networks, which converge on the periaqueductal grey (PAG). Rats with Pain & Disability show astrocyte activation restricted to the lateral and ventrolateral PAG. Reactive astrocytes are a hallmark of cell death (apoptosis and necrosis). Quantitative real-time RT-PCR for the mRNAs encoding Bax, Bcl-2, heat shock protein 60 (HSP60), mitogen activated kinase kinase (MEK2) and iNOS was performed on the dorsal midbrains of individual, disability characterised rats, extending our earlier Gene-Chip data, showing a select up-regulation of Bax and MEK2 mRNA, and a down-regulation of HSP60 mRNA, in Pain & Disability rats. The anatomical location of TUNEL and cleaved-caspase-3 immunoreactive profiles in the midbrain was also identified. Rats with Pain & Disability showed: (i) pro-apoptotic ratios of Bax:Bcl-2 mRNAs; (ii) decreased HSP60 mRNA; (iii) increased iNOS and MEK2 mRNAs; (iv) TUNEL-positive profiles in the lateral and ventrolateral PAG; and (v) caspase-3 immunoreactive neurons in the mesencephalic nucleus of the trigeminal nerve. Cell death in these specific midbrain regions may underlie the disabilities characterising this subgroup of nerve-injured rats.
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http://dx.doi.org/10.1016/j.jchemneu.2011.01.004DOI Listing
April 2011

Dopaminergic cells in the periaqueductal grey matter of MPTP-treated monkeys and mice; patterns of survival and effect of deep brain stimulation and lesion of the subthalamic nucleus.

Parkinsonism Relat Disord 2010 Jun 12;16(5):338-44. Epub 2010 Mar 12.

Discipline of Anatomy & Histology F13, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.

In this anatomical study, we have examined the number of tyrosine hydroxylase (TH) cells in the periaqueductal grey matter (PAG) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and mice; further, we explored whether kainic acid lesion or deep brain stimulation (DBS) of the subthalamic nucleus (STN) in MPTP-treated monkeys has any impact on the number of TH(+) cells in the PAG. For monkeys, there were four groups: Normal, MPTP, STN-lesioned (+MPTP) and STN-DBS (+MPTP). For mice, BALB/c albino mice were divided into three groups, Saline, MPTP_50 (50 mg/kg), MPTP_100 (100 mg/kg). Animals were perfused transcardially with aldehyde fixative 6-12 days after their last MPTP injection. Brains were processed for immunochemistry and the number of cells was estimated using the optical fractionator method. Our results revealed significant reductions (25-30%) in TH(+) cell number in the PAG of MPTP-treated monkeys and mice compared to controls. These reductions were not as substantial as those recorded in the SNc in the same animals (40-60%). Further, in monkeys, there were significantly more TH(+) cells in the PAG of STN-lesioned and STN-DBS groups compared to the MPTP group. In fact, the number of TH(+) cells in the STN alteration cases were similar to the Normal group. In summary, our results indicated that MPTP is toxic to TH(+) cells in the PAG of monkeys and mice and that in monkeys, lesion or DBS of the STN offers neuroprotection against this toxicity.
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http://dx.doi.org/10.1016/j.parkreldis.2010.02.008DOI Listing
June 2010

SMART: Sensitivity models for animals in response to training.

Vet J 2009 Jul 17;181(1):72-3. Epub 2009 Apr 17.

Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia.

Trained responses are said to be under stimulus control when they appear reliably and exclusively on cue. The SMART system is a conceptual, three-dimensional graphic that uses four quadrants to chart a horse's responsiveness to various cues from two reins and the trainer's legs and seat. The current plots have been designed for ridden horses. The models assume that the trainer's cues are bilaterally equivalent, unless the intention is to signal a turn or a lateral movement. The extent to which 'go' signals manifest as straight, forward locomotion reflect the bilateral balance of the horse's reactions to the trainer. The Z-axis shows the probability of a favourable response for the specific strength of stimulus from the trainer relative to competing stimuli from other sources. Where Z is 0 for a particular value of X and Y, the horse shows no desired response to the trainer. The X-axis shows left versus right movement; the Y-axis shows 'stop' versus 'go'.
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http://dx.doi.org/10.1016/j.tvjl.2009.03.014DOI Listing
July 2009

Contusive spinal cord injury evokes localized changes in NADPH-d activity but extensive changes in Fos-like immunoreactivity in the rat.

J Anat 2007 Sep 20;211(3):352-70. Epub 2007 Jun 20.

School of Medical Sciences (Anatomy & Histology), University of Sydney, Australia.

The histological detection of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), a marker for nitric oxide-producing cells, was used to evaluate ongoing changes in the neural biochemistry of the rat spinal cord 1 week following contusive spinal cord injury (SCI). In addition, the immunohistochemical detection of the immediate-early gene c-fos was used to identify basal patterns of neural activity at this time. The numbers and laminar locations of NADPH-d- and c-fos-positive cells were examined in spinal segments adjacent to the site of injury (T12-S3) as well as those distant from the injury (C3-C5) in both SCI and un-injured rats. Our data show that contusive SCI results in a significant reduction in NADPH-d labelling in the superficial dorsal horn, and a significant increase in NADPH-d expression in small bipolar neurons and large motoneurons in the ventral horn at the site of the injury. In spinal segments distant to the injury site (C3-C5), NADPH-d activity did not differ from that of uninjured controls. Furthermore, significant reductions in the levels of c-fos expression were observed in SCI rats, in spinal segments both at and distant to the site of injury for all spinal laminae. The only exception was a dramatic increase observed in the sacral parasympathetic nucleus. These data suggest that increased NADPH-d expression is related to conditions specific to the site of injury, whereas the changes in c-fos expression probably indicate more global changes in neuronal activity following SCI.
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http://dx.doi.org/10.1111/j.1469-7580.2007.00765.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375816PMC
September 2007
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