ORCID Profile
0000-0003-4930-1536
Current Organisation
Murdoch University
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Publisher: Bentham Science Publishers Ltd.
Date: 09-2021
DOI: 10.2174/1567205018666211022164025
Abstract: Nitric oxide synthase (NOS) is well known for its involvement in the regulation of the nervous, cardiovascular, and immune systems. Neuronal NOS (nNOS) is the most characterized NOS among all the isoforms. It accounts for most of the production of nitric oxide (NO) in the nervous system required for synaptic transmission and neuroplasticity. Previous studies have described the localization of nNOS in specific brain regions of interest. There is substantial evidence in the literature suggesting that nNOS signaling has significant involvement in several disease pathologies. However, the association between brain nNOS expression profiles and disease remains largely unknown. In this review, we attempt to delineate the contribution of nNOS signaling in memory and mood disorders in order to achieve a better understanding of nNOS in disease modulation.
Publisher: Wiley
Date: 22-07-2020
DOI: 10.1111/NYAS.14436
Abstract: Alzheimer's disease (AD) is an age‐related neurodegenerative disorder characterized by the hallmark pathologies of amyloid‐beta plaques and neurofibrillary tangles. Symptoms of this devastating disease include behavioral changes and deterioration of higher cognitive functions. Impairment of neurogenesis has also been shown to occur in AD, which adversely impacts new neuronal cell growth, differentiation, and survival. This impairment possibly results from the cumulative effects of the various pathologies of AD. Preclinical studies have suggested that the administration of melatonin—the pineal hormone primarily responsible for the regulation of the circadian rhythm—targets the effects of AD pathologies and improves cognitive impairment. It is postulated that by mitigating the effect of these pathologies, melatonin can also rescue neurogenesis impairment. This review aims to explore the effect of AD pathologies on neurogenesis, as well as the mechanisms by which melatonin is able to ameliorate AD pathologies to potentially promote neurogenesis.
Publisher: MDPI AG
Date: 21-04-2021
DOI: 10.3390/JCM10091807
Abstract: Increasing evidence, particularly from animal studies, suggests that dopamine and GABA are important modulators of cognitive flexibility. In humans, increasing dopamine synthesis through its precursor tyrosine has been shown to result in performance improvements, but few studies have reported the effects of GABA supplementation in healthy participants. We conducted a double-blind, placebo-controlled, randomized experiment to test the interactive effects of tyrosine and GABA administration on two measures of cognitive flexibility, response inhibition and task switching. A total of 48 healthy volunteers were split into four groups (placebo, tyrosine alone, GABA alone, and tyrosine and GABA combined). They completed cognitive flexibility tasks at baseline and after drug administration. We found that tyrosine alone had no impact on the measures of cognitive flexibility, whereas GABA alone and in combination with tyrosine worsened task switching. Our results provide preliminary evidence that putative increases in GABA and dopamine synthesis do not interact to affect cognitive flexibility performance.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Elsevier BV
Date: 2023
Publisher: Frontiers Media SA
Date: 28-07-2022
DOI: 10.3389/FNAGI.2022.964336
Abstract: Alzheimer’s disease (AD) is the most common form of dementia. Although previous studies have selectively investigated the localization of amyloid-beta (Aβ) deposition in certain brain regions, a comprehensive characterization of the rostro-caudal distribution of Aβ plaques in the brain and their inter-regional correlation remain unexplored. Our results demonstrated remarkable working and spatial memory deficits in 9-month-old 5xFAD mice compared to wildtype mice. High Aβ plaque load was detected in the somatosensory cortex, piriform cortex, thalamus, and dorsal/ventral hippoc us moderate levels of Aβ plaques were observed in the motor cortex, orbital cortex, visual cortex, and retrosplenial dysgranular cortex and low levels of Aβ plaques were located in the amygdala, and the cerebellum but no Aβ plaques were found in the hypothalamus, raphe nuclei, vestibular nucleus, and cuneate nucleus. Interestingly, the deposition of Aβ plaques was positively associated with brain inter-regions including the prefrontal cortex, somatosensory cortex, medial amygdala, thalamus, and the hippoc us. In conclusion, this study provides a comprehensive morphological profile of Aβ deposition in the brain and its inter-regional correlation. This suggests an association between Aβ plaque deposition and specific brain regions in AD pathogenesis.
Publisher: Frontiers Media SA
Date: 25-04-2014
Publisher: Aging and Disease
Date: 2023
Publisher: Cold Spring Harbor Laboratory
Date: 17-03-2014
Abstract: Behavioral flexibility is vital for survival in an environment of changing contingencies. The nucleus accumbens may play an important role in behavioral flexibility, representing learned stimulus–reward associations in neural activity during response selection and learning from results. To investigate the role of nucleus accumbens neural activity in behavioral flexibility, we used light-activated halorhodopsin to inhibit nucleus accumbens shell neurons during specific time segments of a bar-pressing task requiring a win–stay/lose–shift strategy. We found that optogenetic inhibition during action selection in the time segment preceding a lever press had no effect on performance. However, inhibition occurring in the time segment during feedback of results—whether rewards or nonrewards—reduced the errors that occurred after a change in contingency. Our results demonstrate critical time segments during which nucleus accumbens shell neurons integrate feedback into subsequent responses. Inhibiting nucleus accumbens shell neurons in these time segments, during reinforced performance or after a change in contingencies, increases lose–shift behavior. We propose that the activity of nucleus shell accumbens shell neurons in these time segments plays a key role in integrating knowledge of results into subsequent behavior, as well as in modulating lose–shift behavior when contingencies change.
Publisher: MDPI AG
Date: 12-10-2020
DOI: 10.3390/JCM9103260
Abstract: Major depression contributes significantly to the global disability burden. Since the first clinical study of deep brain stimulation (DBS), over 446 patients with depression have now undergone this neuromodulation therapy, and 29 animal studies have investigated the efficacy of subgenual cingulate DBS for depression. In this review, we aim to provide a comprehensive overview of the progress of DBS of the subcallosal cingulate in humans and the medial prefrontal cortex, its rodent homolog. For preclinical animal studies, we discuss the various antidepressant-like behaviors induced by medial prefrontal cortex DBS and examine the possible mechanisms including neuroplasticity-dependent/independent cellular and molecular changes. Interestingly, the response rate of subcallosal cingulate Deep brain stimulation marks a milestone in the treatment of depression. DBS achieved response and remission rates of 64–76% and 37–63%, respectively, from clinical studies monitoring patients from 6–24 months. Although some studies showed its stimulation efficacy was limited, it still holds great promise as a therapy for patients with treatment-resistant depression. Overall, further research is still needed, including more credible clinical research, preclinical mechanistic studies, precise selection of patients, and customized electrical stimulation paradigms.
Publisher: Elsevier BV
Date: 2020
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.NUTRES.2017.10.011
Abstract: Behavioral flexibility (BF) performance is influenced by both psychological and physiological factors. Recent evidence suggests that impulsivity and blood glucose can affect executive function, of which BF is a subdomain. Here, we hypothesized that impulsivity, fasting blood glucose (FBG), glucose changes (ie, glucoregulation) from postprandial blood glucose (PBG) following the intake of a 15-g glucose beverage could account for variability in BF performance. The Stroop Color-Word Test and the Wisconsin Card Sorting Test (WCST) were used as measures of BF, and the Barratt Impulsiveness Scale (BIS-11) to quantify participants' impulsivity. In Study 1, neither impulsivity nor FBG could predict performance on the Stroop or the WCST. In Study 2, we tested whether blood glucose levels following the intake of a sugary drink, and absolute changes in glucose levels following the intake of the glucose beverage could better predict BF. Results showed that impulsivity and the difference in blood glucose between time 1 (postprandial) and time 2, but not blood glucose levels at time 2 per se could account for variation in performance on the WCST but not on the Stroop task. More specifically, lower impulsivity scores on the BIS-11, and smaller differences in blood glucose levels from time 1 to time 2 predicted a decrease in the number of total and perseverative errors on the WCST. Our results show that measures of impulsivity and glucoregulation can be used to predict BF. Importantly our data extend the work on glucose and cognition to a clinically relevant domain of cognition.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.YFRNE.2022.100986
Abstract: Melatonin and novel melatonin-based therapies such as melatonin-containing hybrid molecules, melatonin analogues, and melatonin derivatives have been investigated as potential therapeutics against Alzheimer's disease (AD) pathogenesis. In this review, we examine the developmental trends of melatonin therapies for AD from 1997 to 2021. We then highlight the neuroprotective mechanisms of melatonin therapy derived from preclinical studies. These mechanisms include the alleviation of amyloid-related burden, neurofibrillary tangle accumulation, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, and impaired neuroplasticity and neurotransmission. We further illustrate the beneficial effects of melatonin on behavior in animal models of AD. Next, we discuss the clinical effects of melatonin on sleep, cognition, behavior, psychiatric symptoms, electroencephalography findings, and molecular biomarkers in patients with mild cognitive impairment and AD. We then explore the effectiveness of novel melatonin-based therapies. Lastly, we discuss the limitations of current melatonin therapies for AD and suggest two emerging research themes for future study.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2019
DOI: 10.1038/S41598-019-52610-X
Abstract: Animal studies have demonstrated that catecholamines regulate several aspects of fear conditioning. In humans, however, pharmacological manipulations of the catecholaminergic system have been scarce, and their primary focus has been to interfering with catecholaminergic activity after fear acquisition or expression had taken place, using L-Dopa, primarily, as catecholaminergic precursor. Here, we sought to determine if putative increases in presynaptic dopamine and norepinephrine by tyrosine administered before conditioning could affect fear expression. Electrodermal activity (EDA) of 46 healthy participants (24 placebo, 22 tyrosine) was measured in an instructed fear task. Results showed that tyrosine abolished fear expression compared to placebo. Importantly, tyrosine did not affect EDA responses to the aversive stimulus (UCS) or alter participants’ mood. Therefore, the effect of tyrosine on fear expression cannot be attributed to these factors. Taken together, these findings provide evidence that the catecholaminergic system influences fear expression in humans.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 21-03-2022
DOI: 10.1111/NYAS.14767
Abstract: Government restrictions to the movement of people due to the COVID‐19 pandemic have had a wide range of effects on scientific activity. Here, we show that during the pandemic there has been a reduction in the number of registered non‐COVID‐19 clinical trials. Furthermore, using the Oxford COVID‐19 Government Response Tracker Stringency Index (SI) as an indicator of COVID‐19–related workplace adjustment (e.g., restrictions on gatherings, workplace closures, and stay‐at‐home orders), we demonstrate that this drop in clinical trial registration has been greater in countries with a higher SI. This could have significant consequences for the discovery of treatments that are required to reduce the global burden of disease.
Publisher: Bentham Science Publishers Ltd.
Date: 09-2021
DOI: 10.2174/1567205018666211208142036
Abstract: Neuroscience has long sought to develop methods that can “edit” or even “erase” memories, with the aim to provide treatments for memory-related neurological and psychiatric diseases such as anxiety and addiction. Current efforts are heavily focused on modifying cognitive behavioral therapy protocols or pharmacological treatments, but the efficacy and safety of these methods have been called into question by several studies. Advances in modern technology and the rapid emergence of techniques that can directly stimulate/alter neuronal activity, such as neuromodulation, have great potential in achieving the goal of memory modification for treating dementia such as Alzheimer’s disease. However, more research and validation studies are required before these memory editing technologies can be applied clinically. In this mini-review, we compare and highlight the advantages and disadvantages of cognitive behavioral therapy, pharmacological methods, and neuromodulation techniques. We believe that neuromodulation techniques will play a key role in overcoming the challenges of translating memory-manipulating techniques to clinical applications.
Publisher: SAGE Publications
Date: 2020
Abstract: The serotonergic precursor tryptophan and the dopaminergic precursor tyrosine have been shown to be important modulators of mood, behaviour and cognition. Specifically, research on the function of tryptophan has characterised this molecule as particularly relevant in the context of pathological disorders such as depression. Moreover, a large body of evidence has now been accumulated to suggest that tryptophan may also be involved in executive function and reward processing. Despite some clear differentiation with tryptophan, the data reviewed in this paper illustrates that tyrosine shares similar functions with tryptophan in the regulation of executive function and reward, and that these processes in turn, rather than acting in isolation, causally influence each other.
Publisher: MDPI AG
Date: 03-2023
Abstract: A promising direction in the research on Alzheimer’s Disease (AD) is the identification of biomarkers that better inform the disease progression of AD. However, the performance of amyloid-based biomarkers in predicting cognitive performance has been shown to be suboptimal. We hypothesise that neuronal loss could better inform cognitive impairment. We have utilised the 5xFAD transgenic mouse model that displays AD pathology at an early phase, already fully manifested after 6 months. We have evaluated the relationships between cognitive impairment, amyloid deposition, and neuronal loss in the hippoc us in both male and female mice. We observed the onset of disease characterized by the emergence of cognitive impairment in 6-month-old 5xFAD mice coinciding with the emergence of neuronal loss in the subiculum, but not amyloid pathology. We also showed that female mice exhibited significantly increased amyloid deposition in the hippoc us and entorhinal cortex, highlighting sex-related differences in the amyloid pathology of this model. Therefore, parameters based on neuronal loss might more accurately reflect disease onset and progression compared to amyloid-based biomarkers in AD patients. Moreover, sex-related differences should be considered in studies involving 5xFAD mouse models.
Publisher: Frontiers Media SA
Date: 28-06-2019
Publisher: Springer Science and Business Media LLC
Date: 23-06-2021
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.JAD.2019.09.031
Abstract: The catecholaminergic precursor to dopamine, tyrosine, is an important modulator of cognitive performance. A number of studies have demonstrated that the beneficial effects of tyrosine on cognitive performance are most pronounced when in iduals are exposed to stressful situations, such as hypothermia. However, little is known about whether manipulation of stress using non-aversive stimuli, such as cognitive demand, can also bring about similar improvements. We conducted a randomized, double-blind, placebo-controlled experiment to test the effects of tyrosine administration and cognitive load (low or high) on cognitive flexibility, a measure known to be influenced by catecholaminergic function. A total of 70 healthy volunteers completed a baseline cognitive flexibility test (Wisconsin Card Sorting Test: WCST). Participants were given a dose of either tyrosine (2.0 g) or placebo (cellulose) and subject to either low cognitive load (simple reaction time task) or high cognitive load (digit memory span task), immediately followed by a WCST for a second time. Contrary to expectations, we found that instead of ameliorating performance under the high cognitive load condition, tyrosine worsened cognitive flexibility. Physiological marker of stress was not measured. Our results suggest that aversive stressors and cognitive demand modulate the effects of tyrosine on cognitive performance in a differential manner.
Publisher: MDPI AG
Date: 23-05-2023
Abstract: High-frequency stimulation (HFS) is a promising therapy for patients with depression. However, the mechanisms underlying the HFS-induced antidepressant-like effects on susceptibility and resilience to depressive-like behaviors remain obscure. Given that dopaminergic neurotransmission has been found to be disrupted in depression, we investigated the dopamine(DA)-dependent mechanism of the antidepressant-like effects of HFS of the prelimbic cortex (HFS PrL). We performed HFS PrL in a rat model of mild chronic unpredictable stress (CUS) together with 6-hydroxydopamine lesioning in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA). Animals were assessed for anxiety, anhedonia, and behavioral despair. We also examined levels of corticosterone, hippoc al neurotransmitters, neuroplasticity-related proteins, and morphological changes in dopaminergic neurons. We found 54.3% of CUS animals exhibited decreased sucrose consumption and were designated as CUS-susceptible, while the others were designated CUS-resilient. HFS PrL in both the CUS-susceptible and CUS-resilient animals significantly increased hedonia, reduced anxiety, decreased forced swim immobility, enhanced hippoc al DA and serotonin levels, and reduced corticosterone levels when compared with the respective sham groups. The hedonic-like effects were abolished in both DRN- and VTA-lesioned groups, suggesting the effects of HFS PrL are DA-dependent. Interestingly, VTA-lesioned sham animals had increased anxiety and forced swim immobility, which was reversed by HFS PrL. The VTA-lesioned HFS PrL animals also had elevated DA levels, and reduced p-p38 MAPK and NF-κB levels when compared to VTA-lesioned sham animals. These findings suggest that HFS PrL in stressed animals leads to profound antidepressant-like responses possibly through both DA-dependent and -independent mechanisms.
Publisher: Public Library of Science (PLoS)
Date: 03-03-2016
Publisher: Elsevier BV
Date: 12-2023
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
DOI: 10.1038/NATURE24303
Abstract: Gravitational waves were discovered with the detection of binary black-hole mergers and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova. The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate. Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short γ-ray burst. The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 ± 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 ± 0.1 times light speed. The power source is constrained to have a power-law slope of -1.2 ± 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90-140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2018
DOI: 10.1038/S41467-018-04784-7
Abstract: Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. In contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioral roles for different dopamine neuron projections in fear extinction learning.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Wiley
Date: 25-06-2022
DOI: 10.1111/NYAS.14850
Abstract: Dementia is a major burden on global health for which there are no effective treatments. The use of noninvasive visual stimulation to ameliorate cognitive deficits is a novel concept that may be applicable for treating dementia. In this study, we investigated the effects of transcorneal electrical stimulation (TES) on memory enhancement using two mouse models, in aged mice and in the 5XFAD model of Alzheimer's disease. After 3 weeks of TES treatment, mice were subjected to Y-maze and Morris water maze tests to assess hippoc al-dependent learning and memory. Immunostaining of the hippoc us of 5XFAD mice was also performed to examine the effects of TES on amyloid plaque pathology. The results showed that TES improved the performance of both aged and 5XFAD mice in memory tests. TES also reduced hippoc al plaque deposition in male, but not female, 5XFAD mice. Moreover, TES significantly reversed the downregulated level of postsynaptic protein 95 in the hippoc us of male 5XFAD mice, suggesting the effects of TES involve a postsynaptic mechanism. Overall, these findings support further investigation of TES as a potential treatment for cognitive dysfunction and mechanistic studies of TES effects in other dementia models.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2020
Publisher: Elsevier BV
Date: 03-2019
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Japan
Location: Cyprus
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Luca Aquili.