ORCID Profile
0000-0001-6150-8893
Current Organisations
The University of Edinburgh
,
University of Adelaide
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Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.BBR.2014.01.036
Abstract: Alterations in immune function of various humoral and cellular factors, including chemokines, secondary to early stress may play a role in the enhanced vulnerability to psychiatric conditions in those with a history of childhood adversity. C57BL/6 (WT) mice and mice deficient for the chemokine receptor type 7 (CCR7(-/-)) were used to determine the effects of maternal separation on a range of behaviours and the biological stress response. Unpredictable maternal separation (MS) was conducted for 3h daily from postnatal day 1 to 14, with subsequent behavioural testing at 10 weeks of age. Corticosterone was quantified in 11-week-old mice. Maternally separated (MS) CCR7(-/-), but not WT mice, displayed reduced interest in social novelty compared to CCR7(-/-) naïve mice. Separated CCR7(-/-) mice also exhibited significantly lower serum corticosterone concentrations compared to non-separated mice. CCR7(-/-) mice spent less time in the centre during an open field test and more time in the closed arm of the elevated zero maze compared to their wild-type (WT) controls suggesting they were more anxious, however, no difference was observed between MS and control mice in either strain or test. Together these findings suggest that CCR7 is involved in mediating social behaviour and stress response following maternal separation, whereas other behaviours such as anxiety appear to be modified by CCR7 independent of maternal separation. The observed altered cell-mediated immune function possibly underlying the behavioural and neuroendocrine differences in CCR7(-/-) mice following maternal separation requires further investigation.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2014
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.BBR.2019.111912
Abstract: Increasingly, it is being recognised that traumatic brain injury (TBI) is not just an acute event but instead results in ongoing neuronal injury that may lead to chronic impairments in multiple cognitive domains. Of these, deficits in executive function are one of the more common changes reported following TBI, and are a major predictor of well-being, social function and quality of life in in iduals with a history of TBI. In order to fully understand the relationship between TBI and executive dysfunction, including brain mechanisms that may account for this, experimental models are clearly needed. However, to date, there have been a lack of preclinical studies systematically comparing the effect of injury severity on executive function, particularly at long-term timepoints post-injury. Furthermore, many previous studies have not used behavioural measures that are sensitive to the full range of executive function impairments that may manifest after injury, particularly in models of diffuse axonal injury (Lv et al.). The current study aimed to investigate the temporal profile, up to 12 months post-injury, of the evolution of executive dysfunction following different severities of injury in an experimental model of DAI. In order to do so, we utilised a rodent touchscreen paradigm to administer the 5 Choice- Continuous Performance Task (5C-CPT), an extension of the 5-choice serial reaction time task (5CSRT). Interestingly, there were no differences in learning, motivation, attention, response time or impulsivity at 1 month, 6 months or 12 months post-injury in any of the TBI groups compared to sham, regardless of the initial severity of the injury. Instead, most of the effects on executive function seen at the 12 month timepoint appeared to be a result of ageing, not injury. As even the 12-month timepoint represents middle age in the rat, future studies will be needed to further probe these effects, in order to determine whether DAI may influence the presentation of executive dysfunction in older age.
Publisher: Frontiers Media SA
Date: 18-03-2020
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.BBR.2019.111917
Abstract: Environmental enrichment (EE) has been shown to modulate behavior and hippoc al gene expression however, the currently available literature does not explain the differential effects that may relate to the duration of EE. To investigate the differential effects of short- and long-term EE on locomotion, anxiety-, depressive- and cognition-like behaviors, and hippoc al gene expression under physiological conditions. We assigned either short-term or long-term intervention with respective controls to healthy C57BL/6 mice (n = 12-16/group). The short-term EE group received EE for four weeks starting at eight months of age, while the long-term EE group received EE for six months starting at three months of age. Differential effects of the duration of EE on various behaviors and hippoc al gene expression at nine months of age were measured using an established behavioral battery and high-throughput RT-qPCR, respectively. Both short-term and long-term EE significantly enhanced locomotion in the home cage and reduced depressive-like behavior in the forced-swim test. Long-term EE, however, reduced locomotion in the open-field test. Additionally, short-term EE reduced the mean body weight and showed anxiolytic effects in the elevated-zero maze (EZM), while these effects were lost after long-term EE. There were no effects of either short-term or long-term EE on the expression of 43 hippoc al genes of interest tested at adjusted p < 0.05. Both short and long-term EE are equally beneficial for baseline locomotor activity and depressive-like behavior. However, long-term EE affects locomotion adversely in a threatening environment and is anxiogenic.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.PARKRELDIS.2014.02.008
Abstract: Dyskinesia or abnormal involuntary movements (AIMs) are a disabling effect of chronic L-DOPA administration and consequent pulsatile stimulation of dopamine receptors. This abnormal activation causes maladaptive changes including upregulation of FosB expression in dynorphin containing striatal cells. Substance P (SP) is co-localized within dynorphin positive cells and is increased within the substantia nigra by L-DOPA (L-3,4-dihydroxyphenylalanine) treatment. Accordingly, we determined if treatment with a SP NK1 receptor antagonist reduced the onset of L-DOPA induced dyskinesia (LID) in the hemi-parkinsonian rodent model. Adult male Sprague-Dawley rats underwent unilateral 6-OHDA (6-hydroxydopamine-hydrobromide) lesions of the medial forebrain bundle. At day 21, daily administration commenced of either L-DOPA (6 mg/kg plus 15 mg/kg of benseraside), L-DOPA with the NK1 antagonist N-acetyl-L-tryptophan (NAT) or equal volume of saline. Animals were tested with the rodent AIM scale assessing axial, contralateral forelimb and orolingual AIMs. Assessment of L-DOPA induced turning was undertaken, and motor function determined using the accelerating rotarod and adjusting step test. Dopaminergic neuronal counts and immunoreactivity for SP and FosB were undertaken. All animals treated with L-DOPA alone developed dyskinesia, whereas combined administration of NAT with L-DOPA significantly reduced onset of AIMs and prevented mild to moderate dyskinesia. In non-dyskinetic NAT treated animals, similar numbers of FosB+ striatal cells were recorded as in saline treated animals. Importantly NAT treatment did not interfere with the anti-parkinsonian effect of L-DOPA. Daily administration of a SP NK1 receptor antagonist may represent a novel treatment regime that reduces the onset of LID whilst conserving motor function.
Publisher: Wiley
Date: 06-2012
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.BRAINRES.2012.02.045
Abstract: The amyloid precursor protein (APP) increases following traumatic brain injury (TBI), although the functional significance of this remains unclear largely because the functions of the subsequent APP metabolites are so different: Aβ is neurotoxic whilst sAPPα is neuroprotective. To investigate this further, APP wildtype and knockout mice were subjected to mild diffuse TBI and their outcomes compared. APP knockout mice displayed significantly worse cognitive and motor deficits, as demonstrated by the Barnes Maze and rotarod respectively, than APP wildtype mice. This was associated with a significant increase in hippoc al and cortical cell loss, as well as axonal injury, in APP knockout mice and an impaired neuroreparative response as indicated by diminished GAP-43 immunoreactivity when compared to APP wildtype mice. This study is the first to demonstrate that endogenous APP is beneficial following mild TBI, suggesting that the upregulation of APP observed following injury is an acute protective response.
Publisher: Cold Spring Harbor Laboratory
Date: 17-06-2021
DOI: 10.1101/2021.06.16.448746
Abstract: Fyn kinase has recently been established as a major upstream regulator of neuroinflammation in PD. This study aimed to determine if inhibition of Fyn kinase could lead to reduced neuroinflammation and improvements in motor and non-motor impairments in an early-stage model of PD. An experimental model of PD was produced using intra-striatal injection (4µl) of the neurotoxin 6-OHDA (5µg/µl). Sprague Dawley rats (n=42) were given either vehicle, 6mg/kg or 12mg/kg of Fyn kinase inhibitor (AZD0530) daily for 32 days via oral gavage and tested on a battery of tasks assessing motor, cognitive and neuropsychiatric outcomes. AZD 0530 administration led to improvement in volitional locomotion and recognition memory, as well as a reduction in depressive-like behaviour. Pathologically, an inflammatory response was observed however, there were no significant differences in markers of neuroinflammation between treatment groups. Taken together, results indicate a potential therapeutic benefit for use of Fyn kinase inhibition to treat non-motor symptoms of PD, although mechanisms remain to be elucidated. Fyn kinase has recently been proposed as a major upstream regulator of microglial activation in Parkinson’s disease (PD). This study was the first to evaluate the effects of Fyn kinase inhibition in a rodent model of PD. Fyn kinase inhibition using the Fyn kinase inhibitor AZD 0530 was capable of improving volitional locomotion and recognition memory and reducing depressive-like behaviour in a rodent model of PD. Interestingly, while increases in microglial activation were observed in this rodent model of PD, AZD 0530 did not significantly reduce this activation. This suggests that the behavioural improvements associated with Fyn kinase inhibition may occur independently of neuroinflammation and may be attributable to other brain mechanisms, including actions on NMDA or 5-HT 6 receptors.
Publisher: Frontiers Media SA
Date: 03-04-2014
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.BBR.2020.112501
Abstract: The known effects of aging on the brain and behavior include impaired cognition, increases in anxiety and depressive-like behaviors, and reduced locomotor activity. Environmental exposures and interventions also influence brain functions during aging. We investigated the effects of normal aging under controlled environmental conditions and in the absence of external interventions on locomotor activity, cognition, anxiety and depressive-like behaviors, immune function and hippoc al gene expression in C57BL/6 mice. Healthy mice at 4, 9, and 14 months of age underwent behavioral testing using an established behavioral battery, followed by cellular and molecular analysis using flow cytometry, immunohistochemistry, and quantitative PCR. We found that 14-month-old mice showed significantly reduced baseline locomotion, increased anxiety, and impaired spatial memory compared to younger counterparts. However, no significant differences were observed for depressive-like behavior in the forced-swim test. Microglia numbers in the dentate gyrus, as well as CD8+ memory T cells increased towards late middle age. Aging processes exerted a significant effect on the expression of 43 genes of interest in the hippoc us. We conclude that aging is associated with specific changes in locomotor activity, cognition, anxiety-like behaviors, neuroimmune responses and hippoc al gene expression.
Publisher: Wiley
Date: 16-12-2023
DOI: 10.1111/IJMR.12323
Abstract: Digital transformation has become a research focus in recent years. Likewise, internal communication (IC) is one of the fastest‐growing specialisations in public relations and communication management. This research explores digital internal communication (DIC) at the nexus between digital transformation and IC. We provide an integrative review of the literature our thematic analysis of selected journal articles and other scholarly texts is guided by the concept of organisations as socio‐technical systems. Furthermore, we create a template using NVivo software to organise the emerging themes and clusters following the logic of communication levels. This template allows us to explain the phenomenon of DIC in a socio‐technical organisational system and discuss how the emerging themes are interrelated, people‐focused, and linked to competency development and trust‐building. As a contribution to theory, we offer a conceptual model which illustrates the dynamics of DIC as an interplay of socio‐technical elements on three communication levels. This conceptual model can be further developed in scholarly discussions on DIC and by organisations reflecting on their IC use in a digital workplace environment.
Publisher: Elsevier BV
Date: 2020
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BBI.2017.04.006
Abstract: A history of repeated concussion has been linked to the later development of neurodegeneration, which is associated with the accumulation of hyperphosphorylated tau and the development of behavioral deficits. However, the role that exogenous factors, such as immune activation, may play in the development of neurodegeneration following repeated mild traumatic brain injury (rmTBI) has not yet been explored. To investigate, male Sprague-Dawley rats were administered three mTBIs 5days apart using the diffuse impact-acceleration model to generate ∼100G. Sham animals underwent surgery only. At 1 or 5days following the last injury rats were given the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline. TLR4 activation had differential effects following rmTBI depending on the timing of activation. When given at 1day post-injury, LPS acutely activated microglia, but decreased production of pro-inflammatory cytokines like IL-6. This was associated with a reduction in neuronal injury, both acutely, with a restoration of levels of myelin basic protein (MBP), and chronically, preventing a loss of both MBP and PSD-95. Furthermore, these animals did not develop behavioral deficits with no changes in locomotion, anxiety, depressive-like behavior or cognition at 3months post-injury. Conversely, when LPS was given at 5days post-injury, it was associated acutely with an increase in pro-inflammatory cytokine production, with an exacerbation of neuronal damage and increased levels of aggregated and phosphorylated tau. At 3months post-injury, there was a slight exacerbation of functional deficits, particularly in cognition and depressive-like behavior. This highlights the complexity of the immune response following rmTBI and the need to understand how a history of rmTBI interacts with environmental factors to influence the potential to develop later neurodegeneration.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.BBR.2019.02.045
Abstract: Traumatic brain injury (TBI) is a common risk factor for later neurodegeneration, which can manifest as dementia. Despite this, little is known about the time-course of development of functional deficits, particularly cognitive and neuropsychiatric impairments, and whether these differ depending on the nature of the initiating insult. Therefore, this study investigated long term functional impairment at 12 months post-injury following diffuse TBI of different severities. Male Sprague-Dawley rats (420-480 g 10-12 weeks) were either given a sham surgery (n = 14) or subjected to Marmarou's impact acceleration model of diffuse TBI for a single mild TBI (n = 12), repetitive mild TBI (3 mild diffuse injuries at 5 day intervals) (n = 14) or moderate to severe TBI (n = 14). At 12 months after injury, they were tested on a functional battery encompassing motor, neuropsychiatric (anxiety and depressive-like) and cognitive function. Our results showed that moderate to severe TBI animals exhibited significant impairments in cognitive flexibility (p = 0.009) on the Barnes maze when compared to age-matched sham animals. Neither repetitive mild TBI nor single mild TBI animals showed significant functional impairments when compared to shams. Thus, this study provides the first insight into chronic functional impairments associated with different severities of diffuse TBI, with moderate to severe TBI being a higher risk factor for impaired cognitive function at 12 months post-injury. Taken together, this may have implications for risk of dementia development following different severities of injury.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.BBI.2016.09.027
Abstract: A history of traumatic brain injury (TBI) is linked to an increased risk for the later development of dementia. This encompasses a variety of neurodegenerative diseases including Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE), with AD linked to history of moderate-severe TBI and CTE to a history of repeated concussion. Of note, both AD and CTE are characterized by the abnormal accumulation of hyperphosphorylated tau aggregates, which are thought to play an important role in the development of neurodegeneration. Hyperphosphorylation of tau leads to destabilization of microtubules, interrupting axonal transport, whilst tau aggregates are associated with synaptic dysfunction. The exact mechanisms via which TBI may promote the later tauopathy and its role in the later development of dementia are yet to be fully determined. Following TBI, it is proposed that axonal injury may provide the initial perturbation of tau, by promoting its dissociation from microtubules, facilitating its phosphorylation and aggregation. Altered tau dynamics may then be exacerbated by the chronic persistent inflammatory response that has been shown to persist for decades following the initial impact. Importantly, immune activation has been shown to play a role in accelerating disease progression in other tauopathies, with pro-inflammatory cytokines, like IL-1β, shown to activate kinases that promote tau hyperphosphorylation. Thus, targeting the inflammatory response in the sub-acute phase following TBI may represent a promising target to halt the alterations in tau dynamics that may precede overt neurodegeneration and later development of dementia.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2015
Publisher: Frontiers Media SA
Date: 04-2102
DOI: 10.3389/FNBEH.2021.659679
Abstract: In adult pre-clinical models, traumatic brain injury (TBI) has been shown to prime microglia, exaggerating the central inflammatory response to an acute immune challenge, worsening depressive-like behavior, and enhancing cognitive deficits. Whether this phenomenon exists following mTBI during adolescence has yet to be explored, with age at injury potentially altering the inflammatory response. Furthermore, to date, studies have predominantly examined hippoc al-dependent learning domains, although pre-frontal cortex-driven functions, including attention, motivation, and impulsivity, are significantly affected by both adolescent TBI and acute inflammatory stimuli. As such, the current study examined the effects of a single acute peripheral dose of LPS (0.33 mg/kg) given in adulthood following mTBI in mid-adolescence in male Sprague–Dawley rats on performance in the 5-choice serial reaction time task (5-CSRTT). Only previously injured animals given LPS showed an increase in omissions and reward collection latency on the 5-CSRTT, with no effect noted in sham animals given LPS. This is suggestive of impaired motivation and a prolonged central inflammatory response to LPS administration in these animals. Indeed, morphological analysis of myeloid cells within the pre-frontal cortex, via IBA1 immunohistochemistry, found that injured animals administered LPS had an increase in complexity in IBA1+ve cells, an effect that was seen to a lesser extent in sham animals. These findings suggest that there may be ongoing alterations in the effects of acute inflammatory stimuli that are driven, in part by increased reactivity of microglial cells.
Publisher: Springer Science and Business Media LLC
Date: 11-10-2016
Publisher: Springer Science and Business Media LLC
Date: 28-08-2019
DOI: 10.3758/S13415-019-00743-X
Abstract: Physical exercise (PE) and environmental enrichment (EE) have consistently been shown to modulate behavior and neurobiological mechanisms. The current literature lacks evidence to confirm the relationship between PE and EE, if any, and whether short-term treatment with PE, EE, or PE+EE could be considered to correct age-related behavioral deficits. Three-, 8-, and 13-month-old C57BL/6 mice were assigned to either PE, EE, or PE+EE treatment groups (n = 12-16/group) for 4 weeks before behavioral testing and were compared to controls. Differential effects of the treatments on various behaviors and hippoc al gene expression were measured using an established behavioral battery and high-throughput qPCR respectively. Short-term EE enhanced locomotor activity at 9 and 14 months of age, whereas the combination of PE and EE reduced locomotor activity in the home cage at 14 months. Short-term EE also was found to reverse the age-related increase in anxiety at 9 months and spatial memory deficits at 14 months of age. Conversely, short-term PE induced spatial learning impairment and depressive-like behavior at four months but showed no effects in 9- and 14-month-old mice. PE and PE+EE, but not EE, modified the expression of several hippoc al genes at 9 months of age compared with control mice. In conclusion, short-term EE may help to alleviate age-related cognitive decline and increase in anxiety, without altering hippoc al gene expression. On the contrary, PE is detrimental at a young age for both affective-like behaviors and spatial learning and memory but showed no effects at middle and late middle age despite hippoc al gene expression alterations.
Publisher: Public Library of Science (PLoS)
Date: 09-08-2016
Publisher: Informa UK Limited
Date: 03-2012
DOI: 10.1586/ECI.11.99
Publisher: Springer Science and Business Media LLC
Date: 23-04-2021
DOI: 10.1038/S41598-021-88237-0
Abstract: Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.
Publisher: Frontiers Media SA
Date: 07-10-2014
Publisher: Aging and Disease
Date: 2016
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.BBR.2020.113067
Abstract: Adolescents are more likely than adults to develop chronic symptoms, such as impulsivity and difficulty concentrating, following a mild traumatic brain injury (mTBI) which may relate to disruption of pre-frontal cortex (PFC development). During adolescence the PFC is undergoing extensive remodelling, driving maturation of executive functions incorporating attention, motivation and impulse control. In part maturation of the PFC is driven by outgrowth of dopaminergic neurons to the PFC under the guidance of specific axonal targeting cues, including netrin-1. How a mTBI in adolescence may alter the expression of these axonal targeting cues, and the influence on PFC development is not yet known. As such the effects of mTBI in mid-adolescence on executive functioning in adulthood (12 weeks) were examined via the 5-choice serial reaction task in both male and female Sprague Dawley rats. Animals at p35 (n = 12-16 per group) were injured via weight drop (100 g from 0.75 m) and injury confirmed by a significant increase in righting reflex. Interestingly, while a mid-adolescence mTBI in females led to significantly higher omissions and decreased accuracy when task difficulty was high (stimulus duration 1 s), males had significantly increased premature response rate when the intertrial interval was varied. Examination of levels of TH, as a reflection of dopaminergic innervation, found no difference in either gender post-TBI in the PFC, but a significant increase in the limbic system (nucleus accumbens) in males, but not females, chronically post-TBI, suggesting an imbalance between the regions. The increase in TH was accompanied by a chronic reduction in netrin-1 within the nucleus accumbens in males only. Taken together, these results indicate that mTBI in adolescence leads to sex specific effects in different domains of PFC function in adulthood, which may relate to subtle alterations in the developmental trajectory of the mesocortical limbic pathway in males only.
Publisher: Wiley
Date: 28-08-2014
DOI: 10.1111/JNC.12391
Abstract: We have previously shown that following traumatic brain injury (TBI) the presence of the amyloid precursor protein (APP) may be neuroprotective. APP knockout mice have increased neuronal death and worse cognitive and motor outcomes following TBI, which is rescued by treatment with exogenous sAPPα (the secreted ectodomain of APP generated by α-secretase cleavage). Two neuroprotective regions were identified in sAPPα, the N and C-terminal domains D1 and D6a/E2 respectively. As both D1 and D6a/E2 contain heparin binding activity it was hypothesized that this is responsible for the neuroprotective activity. In this study, we focused on the heparin binding site, encompassed by residues 96-110 in D1, which has previously been shown to have neurotrophic properties. We found that treatment with APP96-110 rescued motor and cognitive deficits in APP-/- mice following focal TBI. APP96-110 also provided neuroprotection in Sprague-Dawley rats following diffuse TBI. Treatment with APP96-110 significantly improved functional outcome as well as preserve histological cellular morphology in APP-/- mice following focal controlled cortical impact injury. Furthermore, following administration of APP96-110 in rats after diffuse impact acceleration TBI, motor and cognitive outcomes were significantly improved and axonal injury reduced. These data define the heparin binding site in the D1 domain of sAPPα, represented by the sequence APP96-110, as the neuroprotective site to confer neuroprotection following TBI. The product of α-secretase cleavage of the amyloid precursor protein, sAPPα is neuroprotective following traumatic brain injury (TBI). Of interest was whether this neuroprotective activity could be further delineated to a heparin binding region within sAPPα, corresponding to the region APP96-110 (see diagram demonstrating the domain structure of sAPPα). Indeed treatment with APP96-110 improved functional outcome following TBI, an effect that was not seen with a mutated version of the peptide that had reduced heparin binding affinity.
Publisher: Elsevier BV
Date: 11-0011
DOI: 10.1016/J.BBR.2018.06.036
Abstract: Altered TNF levels are associated with cognitive impairment in depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). Exercise improves cognition-like behaviours, reduces the expression of tumour necrosis factor alpha (TNF), and increases expression of the soluble TNF receptors soluble TNFR1 (sTNFR1) and sTNFR2. We suggest TNF and its receptors are involved in cognitive function and dysfunction, and investigate whether exercise mediates its effects on cognitive function via TNF and its receptors. We utilised C57BL/6, TNF Recognition memory improved with exercise in WT mice, was impaired in TNFR1 TNF receptor signalling via the TNFR1 and TNFR2 appears to mediate the effects of exercise on cognitive-like behaviours. The potential for exercise to regulate human TNF and TNF signalling and cognitive dysfunction needs investigation under inflammatory conditions including depression and neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.BBR.2018.04.009
Abstract: TBI is a significant risk factor for the development of dementia, with the interaction between structural damage from TBI and neuroinflammation potentially driving this relationship. This study investigated the early chronic post-TBI neuroinflammatory response and its relationship to both neurodegenerative pathology and functional impairment up to 3 months post-injury. Sprague-Dawley rats underwent either sham surgery or the Marmarou model of diffuse moderate-severe TBI. At 1-month and 3-months post-injury, a functional battery encompassing motor function, depressive-like behaviour, anxiety and cognition was performed. Western blot and immunohistochemical analysis assessed a range of inflammatory, neurodegenerative and oxidative stress markers. At both 1 and 3-months post injury, depressive-like behaviour was significantly increased in TBI animals, with TBI animals also exhibiting impaired cognitive flexibility at 3 months, although learning and memory remained intact. This was accompanied by a significant decrease in markers of synaptic integrity and astrocytic and microglia number within the pre-frontal cortex at 1-month post-injury, although this resolved by 3-months post-injury. In contrast, minimal pathology was evident within the hippoc us at 1 month, with only a decrease in neurofilament-light seen at 3 months post-injury. Thus, following a moderate-severe diffuse injury, the pre-frontal cortex is most vulnerable to early neuro-structural changes. While these changes are resolved at 3 months post-injury, future studies should investigate whether they re-emerge or progress to other areas, such as the hippoc us, at later time points, which could predispose in iduals to the development of dementia.
Publisher: Wiley
Date: 12-05-2016
DOI: 10.1111/BPH.13155
Publisher: Emerald
Date: 27-09-2023
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BRAINRES.2010.12.077
Abstract: The amyloid precursor protein (APP) is known to increase following traumatic brain injury (TBI). This increase in levels of APP may be deleterious to outcome due to the production of neurotoxic Aβ. Conversely, this upregulation may be beneficial as cleavage of APP via the alternative non-amyloidogenic pathway produces the soluble α form of APP (sAPPα), which is known to have many neuroprotective and neurotrophic functions. Indeed it has previously been shown that treatment with sAPPα following a diffuse injury in rats improves outcome. However, the exact location within the sAPPα molecule which contains this neuroprotective activity has yet to be determined. The sAPPα peptide can consist of up to 6 domains, with the main isoform in the brain missing the 4th and 5th. Of the remaining domains, the D1 and D6a domains seem the most likely as they have been shown to have beneficial actions in vitro. This present study examined the effects of in vivo posttraumatic administration via an intracerebroventricular injection of the D1, D2 and D6a domains of sAPPα on outcome following moderate-impact acceleration TBI in rats. While treatment with either the D1 or D6a domains was found to significantly improve motor and cognitive outcome, as assessed on the rotarod and Y maze, treatment with the D2 domain had no effect. Furthermore axonal injury was reduced in D1 and D6a domain treated animals, but not those that received the D2 domain. As the D1 and D6a domains contain a heparin binding region while the D2 domain does not, this suggests that sAPPα mediates its neuroprotective response through its ability to bind to heparin sulfate proteoglycans.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.NEULET.2012.03.017
Abstract: Treatment with sAPPα, the product of non-amyloidogenic processing of the amyloid precursor protein (APP) has been shown to be protective following diffuse traumatic brain injury (TBI), by improving motor outcome and reducing axonal injury. However the effects of treatment with sAPPα following a focal TBI have yet to be determined. To investigate this, mice were subjected to a controlled cortical impact injury and treated with either sAPPα or its vehicle at 30 min post-injury. Following treatment with sAPPα the mice showed a significant improvement in motor and cognitive function early following injury, as determined on the ledged beam and Barnes Maze, respectively, relating to a more rapid rate of recovery. However the effect of treatment with sAPPα was not as dramatic as that seen previously following a diffuse injury. Nonetheless, these improvements in functional outcome were acompanied by a small but significant improvement in the amount of cortical and hippoc al at 7 days post-injury, and provide further support for the efficacy of sAPPα as a potential neuroprotective agent following TBI.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2021
DOI: 10.1007/S10571-020-00862-X
Abstract: Physical exercise (PE) and environmental enrichment (EE) can modulate immunity. However, the differential effects of short-term PE, EE, and PE + EE on neuroimmune mechanisms during normal aging has not been elucidated. Hence, a cohort of 3-, 8-, and 13-month-old immunologically unchallenged C57BL/6 wild-type mice were randomly assigned to either Control, PE, EE, or PE + EE groups and provided with either no treatment, a running wheel, a variety of plastic and wooden objects alone or in combination with a running wheel for seven weeks, respectively. Immunohistochemistry and 8-color flow cytometry were used to determine the numbers of dentate gyrus glial cells, and the proportions of CD4 + and CD8 + T cell numbers and their subsets from cervical lymph nodes, respectively. An increase in the number of IBA1 + microglia in the dentate gyrus at 5 and 10 months was observed after EE, while PE and PE + EE increased it only at 10 months. No change in astroglia number in comparison to controls were observed in any of the treatment groups. Also, all treatments induced significant differences in the proportion of specific T cell subsets, i.e., CD4 + and CD8 + T naïve (T N ), central memory (T CM ), and effector memory (T EM ) cells. Our results suggest that in the short-term, EE is a stronger modulator of microglial and peripheral T cell subset numbers than PE and PE + EE, and the combination of short-term PE and EE has no additive effects.
Publisher: Informa Healthcare
Date: 25-04-2012
DOI: 10.1517/13543784.2012.683113
Abstract: Subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality, even for patients who receive early neurointerventionist management. Early mechanisms of secondary brain injury precede the delayed vasospasm phase and contribute to the poor outcome. These mechanisms and their intervention are discussed, including high intracranial pressure (ICP), low cerebral perfusion pressure (CPP), acute vasospasm, disturbed cerebral autoregulation, cerebral edema, oxidative stress, seizures, microvascular damage and hyperglycemia. Erythropoietin, statins and magnesium have been particularly promising in experimental studies. Multiple mechanisms, including delayed vasospasm, may contribute to cerebral ischemia and poor outcome following SAH. Treatments that simultaneously target multiple secondary injury pathways show significant potential as therapeutic agents, particularly those that attenuate vasospasm in addition to having other neuroprotective properties.
Publisher: Elsevier
Date: 2018
Publisher: Oxford University Press (OUP)
Date: 08-2013
DOI: 10.1002/STEM.1426
Abstract: Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to lify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between in idual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously.
Publisher: Future Medicine Ltd
Date: 06-2017
Abstract: Repeated head impacts have been suggested to be associated with the development of the neurodegenerative disorder, chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau within the brain, with accompanying cognitive and behavioral deficits. How a history of repeated head impacts can lead to the later development of CTE is not yet known, and as such appropriate animal models are required. Over the last decade a number of rodent models of repeated mild traumatic brain injury have been developed that are broadly based on traditional traumatic brain injury models, in controlled cortical impact, fluid percussion and weight drop models, with adaptations to allow for better modeling of the mechanical forces associated with concussion.
Publisher: Frontiers Media SA
Date: 21-11-2014
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.BRAINRESBULL.2019.02.014
Abstract: Regular exercise can reduce depression-, anxiety-, and impaired cognitive-like behaviours, and upregulate hippoc al genes associated with neuroplasticity. However, the effects of ceasing exercise on depression-, anxiety-, and cognitive-like behaviours, and hippoc al gene expression remain unknown. 12-week-old C57BL/6 mice (n = 12-16/group) were randomised to six months of exercise (exercise (EXC)), four months of exercise then two months of no exercise (exercise-cessation (EC)), or no-exercise control (CONT) until aged nine months. Depression-, anxiety-, and cognitive-like behaviours were tested with the forced swim test, open field and elevated zero maze, Y-maze, and Barnes maze. The expression of 75 hippoc al genes were investigated by high-throughput quantitative polymerase chain reaction (qPCR). Exercise cessation increased depression- and anxiety-like behaviours, and impaired spatial learning and cognitive flexibility compared to CONT and EXC mice. 10/75 hippoc al genes were differentially expressed in EC mice, including increased expression of neurogenesis associated genes (Ntrk1), and reduced expression of immune (Il10, Gfap) and monoamine related genes (Htr1a) compared to CONT mice. Altered expression of nine genes including increased Slc6a4 and reduced Sirt1 expression were shown in EC mice compared to EXC mice. Exercise cessation increased depression- and anxiety-like behaviours and impaired some cognition-like behaviours with altered neurogenic, monoaminergic, and immune hippoc al gene expression consistent with the pathogenesis of depression and related anxiety described by the neurogenic, monoaminergic, and immune hypotheses of depression. Mice and humans share mammalian physiology, so these findings could be relevant to humans. These results require replication and possibly translation into high-quality pilot clinical trials.
Publisher: Public Library of Science (PLoS)
Date: 10-01-2018
Publisher: University of Adelaide Press
Date: 06-2011
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JAD.2018.02.058
Abstract: Regular exercise in adults improves depressive symptoms (DS) and major depressive disorder (MDD), however the clinical effects of ceasing exercise are largely unknown. Seven databases were searched from inception to December 2017. Eligibility criteria included English language studies investigating the effects of ceasing exercise on DS or MDD in regularly active adults with or without prior DS or MDD. Blood based markers related to exercise cessation (EC) were assessed, if recorded. Studies investigating exercise follow-up periods were excluded. No studies investigated EC in MDD. Six studies including two RCTS and three studies investigating neurogenic and immune biological markers associated with DS met inclusion criteria (152 healthy adults, females n = 50/32.89%). Compared to baseline, EC increased DS after three days, one week, and two weeks. Female participants had significantly more DS than male participants. Following EC, no changes in brain derived neurotrophic factor (BDNF) or tumour necrosis factor alpha (TNF) were evident, however C-reactive protein (CRP) at week one and interleukin 6 (IL6) at week two were reduced. Quality concerns including risks of attrition and reporting bias limit our confidence in these results. Ceasing regular exercise increases DS in healthy adults, with greater DS in females than males. Contrary to the cytokine/inflammatory hypothesis of depression, DS were associated with reduced CRP and IL6 and without increased TNF. High quality trials are needed to extend this field of research in both healthy and MDD populations.
Publisher: Springer New York
Date: 2012
Publisher: MDPI AG
Date: 31-10-2023
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.BRAINRES.2018.05.032
Abstract: Depression can involve disrupted pro-inflammatory TNF signaling via the TNF receptors TNFR1 and TNFR2, or the soluble TNF receptors sTNFR1 and sTNFR2. However, exercise might attenuate pro-inflammatory signaling in depression and related anxiety. We hypothesized that six months voluntary wheel running exercise would improve depression-like and anxiety-like behaviours in WT and TNFR1 We investigated the effects of six months voluntary wheel running exercise on open field (OF) and elevated zero maze (EZM) anxiety-like behaviours, and forced swim test (FST) depression-like behaviours in control and exercise WT, TNF Exercise reduced of anxiety-like behaviours in TNFR2 Exercise associated TNFR1 and TNFR2 signaling in concert in WT exercise mice mediated reductions in aspects of anxiety-like behaviours. These findings are consistent with the current view that imbalances in TNF signaling are involved in disrupted affect. Additional studies are needed to further explore the roles of exercise related TNFR1 and TNFR2 signaling in anxiety-like and depression-like behaviours.
Publisher: Wiley
Date: 17-05-2012
DOI: 10.1111/J.1471-4159.2012.07761.X
Abstract: The amyloid precursor protein (APP) is thought to be neuroprotective following traumatic brain injury (TBI), although definitive evidence at moderate to severe levels of injury is lacking. In the current study, we investigated histological and functional outcomes in APP-/- mice compared with APP+/+ mice following a moderate focal injury, and whether administration of sAPPα restored the outcomes in knockout animals back to the wildtype state. Following moderate controlled cortical impact injury, APP-/- mice demonstrated greater impairment in motor and cognitive outcome as determined by the ledged beam and Barnes Maze tests respectively (p < 0.05). This corresponded with the degree of neuronal damage, with APP-/- mice having significantly greater lesion volume (25.0 ± 1.6 vs. 20.3 ± 1.6%, p < 0.01) and hippoc al damage, with less remaining CA neurons (839 ± 245 vs. 1353 ± 142 and 1401 ± 263). This was also associated with an impaired neuroreparative response, with decreased GAP-43 immunoreactivity within the cortex around the lesion edge compared with APP+/+ mice. The deficits observed in the APP-/- mice related to a lack of sAPPα, as treatment with exogenously added sAPPα post-injury improved APP-/- mice histological and functional outcome to the point that they were no longer significantly different to APP+/+ mice (p < 0.05). This study shows that endogenous APP is potentially protective at moderate levels of TBI, and that this neuroprotective activity is related to the presence of sAPPα. Importantly, it indicates that the mechanism of action of exogenously added sAPPα is independent of the presence of endogenous APP.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.BBR.2017.08.035
Abstract: A small but significant proportion of mild traumatic brain injury (mTBI) sufferers will report persistent symptoms, including depression, anxiety and cognitive deficits, in the months, or even years, following the initial event. This is known as post-concussion syndrome and its pathogenesis is not yet known. This study sought to investigate the role of a peripheral inflammatory insult in the development of ongoing behavioral symptoms following a mTBI. To investigate, male Sprague-Dawley rats were administered a single mTBI using the diffuse impact-acceleration model to generate ∼100G of force. Sham animals underwent surgery only. At 5days following surgery, rats were given either the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline via an intraperitoneal injection. mTBI animals showed an exaggerated response to LPS, with an increase in the expression of pro-inflammatory cytokines within the hippoc us at 24h post-dose, an effect not seen in sham animals. This was associated with the development of persistent behavioral deficits in the mTBI:LPS animals at 3 months post-injury. These behavioral deficits consisted of increased time spent immobile on the forced swim-test, indicative of depressive like behavior, impaired cognitive performance on the Barnes Maze and decreased anxiety on the Elevated Plus Maze. In contrast, animals administered mTBI alone had no deficits. This study provides evidence that a peripheral inflammatory stimulus can facilitate ongoing symptoms following a mTBI. As such this provides a basis for further exploration of exogenous factors which promote immune system activation as potential targets for intervention to allow the resolution of symptoms following a mTBI.
Publisher: Mary Ann Liebert Inc
Date: 03-2017
Abstract: Traumatic brain injury (TBI) is the leading cause of disability and death worldwide, affecting as many as 54,000,000-60,000,000 people annually. TBI is associated with significant impairments in brain function, impacting cognitive, emotional, behavioral, and physical functioning. Although much previous research has focused on the impairment immediately following injury, TBI may have much longer-lasting consequences, including neuropsychiatric disorders and cognitive impairment. TBI, even mild brain injury, has also been recognized as a significant risk factor for the later development of dementia and Alzheimer's disease. Although the link between TBI and dementia is currently unknown, several proposed mechanisms have been put forward, including alterations in glucose metabolism, excitotoxicity, calcium influx, mitochondrial dysfunction, oxidative stress, and neuroinflammation. A treatment for the devastating long-term consequences of TBI is desperately needed. Unfortunately, however, no such treatment is currently available, making this a major area of unmet medical need. Increasing the level of neurotrophic factor expression in key brain areas may be one potential therapeutic strategy. Of the neurotrophic factors, granulocyte-colony stimulating factor (G-CSF) may be particularly effective for preventing the emergence of long-term complications of TBI, including dementia, because of its ability to reduce apoptosis, stimulate neurogenesis, and increase neuroplasticity.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.PBB.2015.05.021
Abstract: The atypical antipsychotic drug, quetiapine, has recently been suggested to not only show efficacy in schizophrenia, bipolar, major depressive and general anxiety disorders, but to also have a possible anti-inflammatory effect, which could be important in the treatment of the inflammatory aspects of psychiatric diseases. Male C57BL/6 mice were given either quetiapine (i.p. 10mg/kg), its main active metabolite norquetiapine (i.p. 10mg/kg), or saline as a vehicle control, once a day for 14days. On the 14th day, this dose was followed by a single dose of either LPS (i.p. 1mg/kg) or saline. 24h post LPS short-term recognition memory and anhedonia behaviour were measured using the Y-maze and saccharin preference test respectively. Immediately following behavioural testing, mice were culled before serum, prefrontal cortex and hippoc al analysis of cytokine levels was conducted. It was found that LPS challenge led to increased serum and brain cytokine levels as well as anhedonia, with no significant effect on recognition memory. Quetiapine and norquetiapine both increased levels of the anti-inflammatory cytokine IL-10 and decreased levels of the pro-inflammatory cytokine IFN-γ in serum 4h post LPS. Within the brain, a similar pattern was seen in gene expression in the hippoc us at 4h for Il-10 and Ifn-γ, however norquetiapine led to an increase in Il-1β expression in the PFC at 4h, while both drugs attenuated the increased Il-10 in different regions of the brain at 24h. These effects in the serum and brain, however, had no effect on the observed LPS induced changes in behaviour. Both quetiapine and its metabolite norquetiapine appear to have a partial anti-inflammatory effect on IL-10 and IFN-γ following acute LPS challenge in serum and brain, however these effects did not translate into behavioural changes.
Publisher: Mary Ann Liebert Inc
Date: 03-2020
Publisher: Humana Press
Date: 2011
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.BBR.2015.04.040
Abstract: Tumor necrosis factor alpha (TNF-α) is a vital component of the immune system and CNS. We previously showed that 3-month-old TNF-α and TNF-α receptor knockout mice had impaired cognition, whilst at 12-months-old mice had better cognition. To extend these findings on possible age-dependent TNF-α effects in the brain, we investigated the behaviour of 6-month-old TNF-α knockout mice and their neurobiological correlates. 6-month-old TNF(-/-), TNF-R1(-/-) and TNF-R2(-/-) mice were compared to age-matched WT mice and tested for various behaviours. ELISA hippoc al levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) and qPCR mRNA levels of Tnfa, Tnfr1, Tnfr2, Il10 and Il1β were measured. TNF-R1(-/-) and TNF(-/-) mice were found to have lesser exploratory behaviour than WT mice, while TNF-R1(-/-) mice displayed better memory than WT and TNF-R2(-/-) mice. Both TNF(-/-) and TNF-R2(-/-) mice exhibited significantly lower immobility on the depression test than WT mice. Additionally, TNF(-/-) mice expressed significantly lower levels of BDNF than WT mice in the hippoc us while TNF-R1(-/-) mice displayed significantly lower BDNF levels compared to both WT and TNF-R2(-/-) mice. TNF-R2(-/-) mice also displayed significantly higher levels of NGF compared to TNF-R1(-/-) mice. These results illustrate that TNF-α and its receptors mediate several behavioural phenotypes. Finally, BDNF and NGF levels appear to be regulated by TNF-α and its receptors even under immunologically unchallenged conditions.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.BBR.2017.09.022
Abstract: Preclinical studies have demonstrated exercise improves various types of behaviours such as anxiety-like, depression-like, and cognition-like behaviours. However, these findings were largely conducted in studies utilising short-term exercise protocols, and the effects of lifetime exercise on these behaviours remain unknown. This study investigates the behavioural effects of lifetime exercise in normal healthy ageing C57BL/6 mice over the adult lifespan. 12 week-old C57BL/6 mice were randomly assigned to voluntary wheel running or non-exercise (control) groups. Exercise commenced at aged 3 months and behaviours were assessed in young adult (Y), early middle age (M), and old (O) mice (n=11-17/group). The open field and elevated zero maze examined anxiety-like behaviours, depression-like behaviours were quantified with the forced swim test, and the Y maze and Barnes maze investigated cognition-like behaviours. The effects of lifetime exercise were not simply an extension of the effects of chronic exercise on anxiety-like, depression-like, and cognition-like behaviours. Exercise tended to reduce overt anxiety-like behaviours with ageing, and improved recognition memory and spatial learning in M mice as was expected. However, exercise also increased anxiety behaviours including greater freezing behaviour that extended spatial learning latencies in Y female mice in particular, while reduced distances travelled contributed to longer spatial memory and cognitive flexibility latencies in Y and O mice. Lifetime exercise may increase neurogenesis-associated anxiety. This could be an evolutionary conserved adaptation that nevertheless has adverse impacts on cognition-like function, with particularly pronounced effects in Y female mice with intact sex hormones. These issues require careful investigation in future rodent studies.
Publisher: Springer Nature Singapore
Date: 2022
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.BBR.2021.113269
Abstract: We recently reported that tumor necrosis factor (TNF) signaling via the TNFR1 and TNFR2 receptors mediates the effects of long-term exercise on locomotion, cognition and anxiety, but not depressive-like behavior. We now investigated whether the TNF signaling via its receptors also mediates the effects of short-term exercise on cognition, anxiety and depressive-like behaviors. Thirteen-month-old C57BL/6 (WT), TNF There was no interaction between genotype and exercise in any of the tests but the main effect of genotype, and not exercise, were found to be significant in the open field (OF), forced-swim test (FST) and Barnes maze (BM). In the OF, the control and exercise TNFR2 While TNF signaling via the TNF receptors mediates cognition, anxiety and depressive-like behaviors independently, it does not mediate the effects of short-term exercise on these behaviors in middle-aged mice.
Publisher: American Chemical Society (ACS)
Date: 12-04-2016
Publisher: Mary Ann Liebert Inc
Date: 15-11-2020
Abstract: Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, with patients often suffering from consequences such as cognitive deficits, social abnormalities, anxiety, depression, pain, and motor dysfunction. Given that these impairments often have a significant impact on the patient's quality of life, a key aim of therapeutic intervention in TBI is to mitigate these effects. Translational strategies to develop such interventions have heavily featured animal models of TBI. To assess the efficacy of interventions in these models, a range of behavioral outcomes are utilized. However, in light of the past translational failures that have plagued the TBI field, the clinical relevance of these preclinical behavioral tests is now being scrutinized. This article will summarize the behavioral consequences of TBI in humans describe common methods available for testing cognition, social function, motor ability, pain, as well as depression- and anxiety-like behaviors in animal models of TBI provide an overview of the results from TBI animal model studies that have utilized these methods and discuss these pre-clinical behavior methods and findings in terms of their relevance to the clinical TBI setting. We conclude that there is translational value in these methods and their related findings, but also suggest strategies and future research to improve the clinical relevance of behavior testing in animal models of TBI.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
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