Publications by authors named "Jess Nithianantharajah"

39 Publications

Longitudinal hippocampal volumetric changes in mice following brain infarction.

Sci Rep 2021 May 13;11(1):10269. Epub 2021 May 13.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.

Hippocampal atrophy is increasingly described in many neurodegenerative syndromes in humans, including stroke and vascular cognitive impairment. However, the progression of brain volume changes after stroke in rodent models is poorly characterized. We aimed to monitor hippocampal atrophy occurring in mice up to 48-weeks post-stroke. Male C57BL/6J mice were subjected to an intraluminal filament-induced middle cerebral artery occlusion (MCAO). At baseline, 3-days, and 1-, 4-, 12-, 24-, 36- and 48-weeks post-surgery, we measured sensorimotor behavior and hippocampal volumes from T-weighted MRI scans. Hippocampal volume-both ipsilateral and contralateral-increased over the life-span of sham-operated mice. In MCAO-subjected mice, different trajectories of ipsilateral hippocampal volume change were observed dependent on whether the hippocampus contained direct infarction, with a decrease in directly infarcted tissue and an increase in non-infarcted tissue. To further investigate these volume changes, neuronal and glial cell densities were assessed in histological brain sections from the subset of MCAO mice lacking hippocampal infarction. Our findings demonstrate previously uncharacterized changes in hippocampal volume and potentially brain parenchymal cell density up to 48-weeks in both sham- and MCAO-operated mice.
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http://dx.doi.org/10.1038/s41598-021-88284-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119705PMC
May 2021

Focal Ischemic Injury to the Early Neonatal Rat Brain Models Cognitive and Motor Deficits with Associated Histopathological Outcomes Relevant to Human Neonatal Brain Injury.

Int J Mol Sci 2021 Apr 29;22(9). Epub 2021 Apr 29.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne 3010, Australia.

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.
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http://dx.doi.org/10.3390/ijms22094740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124303PMC
April 2021

Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2.

Genes Brain Behav 2021 Jan 29;20(1):e12723. Epub 2020 Dec 29.

Synome Ltd, Babraham Research Campus, Cambridge, UK.

The postsynaptic terminal of vertebrate excitatory synapses contains a highly conserved multiprotein complex that comprises neurotransmitter receptors, cell-adhesion molecules, scaffold proteins and enzymes, which are essential for brain signalling and plasticity underlying behaviour. Increasingly, mutations in genes that encode postsynaptic proteins belonging to the PSD-95 protein complex, continue to be identified in neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability and epilepsy. These disorders are highly heterogeneous, sharing genetic aetiology and comorbid cognitive and behavioural symptoms. Here, by using genetically engineered mice and innovative touchscreen-based cognitive testing, we sought to investigate whether loss-of-function mutations in genes encoding key interactors of the PSD-95 protein complex display shared phenotypes in associative learning, updating of learned associations and reaction times. Our genetic dissection of mice with loss-of-function mutations in Syngap1, Nlgn3, Dlgap1, Dlgap2 and Shank2 showed that distinct components of the PSD-95 protein complex differentially regulate learning, cognitive flexibility and reaction times in cognitive processing. These data provide insights for understanding how human mutations in these genes lead to the manifestation of diverse and complex phenotypes in NDDs.
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http://dx.doi.org/10.1111/gbb.12723DOI Listing
January 2021

Translation-Focused Approaches to GPCR Drug Discovery for Cognitive Impairments Associated with Schizophrenia.

ACS Pharmacol Transl Sci 2020 Dec 28;3(6):1042-1062. Epub 2020 Oct 28.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

There are no effective therapeutics for cognitive impairments associated with schizophrenia (CIAS), which includes deficits in executive functions (working memory and cognitive flexibility) and episodic memory. Compounds that have entered clinical trials are inadequate in terms of efficacy and/or tolerability, highlighting a clear translational bottleneck and a need for a cohesive preclinical drug development strategy. In this review we propose hippocampal-prefrontal-cortical (HPC-PFC) circuitry underlying CIAS-relevant cognitive processes across mammalian species as a target source to guide the translation-focused discovery and development of novel, procognitive agents. We highlight several G protein-coupled receptors (GPCRs) enriched within HPC-PFC circuitry as therapeutic targets of interest, including noncanonical approaches (biased agonism and allosteric modulation) to conventional clinical targets, such as dopamine and muscarinic acetylcholine receptors, along with prospective novel targets, including the orphan receptors GPR52 and GPR139. We also describe the translational limitations of popular preclinical cognition tests and suggest touchscreen-based assays that probe cognitive functions reliant on HPC-PFC circuitry and reflect tests used in the clinic, as tests of greater translational relevance. Combining pharmacological and behavioral testing strategies based in HPC-PFC circuit function creates a cohesive, translation-focused approach to preclinical drug development that may improve the translational bottleneck currently hindering the development of treatments for CIAS.
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http://dx.doi.org/10.1021/acsptsci.0c00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737210PMC
December 2020

MicroRNA-210 Regulates Dendritic Morphology and Behavioural Flexibility in Mice.

Mol Neurobiol 2021 Apr 9;58(4):1330-1344. Epub 2020 Nov 9.

Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.

MicroRNAs are known to be critical regulators of neuronal plasticity. The highly conserved, hypoxia-regulated microRNA-210 (miR-210) has been shown to be associated with long-term memory in invertebrates and dysregulated in neurodevelopmental and neurodegenerative disease models. However, the role of miR-210 in mammalian neuronal function and cognitive behaviour remains unexplored. Here we generated Nestin-cre-driven miR-210 neuronal knockout mice to characterise miR-210 regulation and function using in vitro and in vivo methods. We identified miR-210 localisation throughout neuronal somas and dendritic processes and increased levels of mature miR-210 in response to neural activity in vitro. Loss of miR-210 in neurons resulted in higher oxidative phosphorylation and ROS production following hypoxia and increased dendritic arbour density in hippocampal cultures. Additionally, miR-210 knockout mice displayed altered behavioural flexibility in rodent touchscreen tests, particularly during early reversal learning suggesting processes underlying updating of information and feedback were impacted. Our findings support a conserved, activity-dependent role for miR-210 in neuroplasticity and cognitive function.
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http://dx.doi.org/10.1007/s12035-020-02197-6DOI Listing
April 2021

Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19.

Aust N Z J Psychiatry 2020 Oct 1:4867420961472. Epub 2020 Oct 1.

Department of Neurology & Neurosciences, The Central Clinical School, Alfred Hospital, Monash University, Melbourne, VIC, Australia.

Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood-brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.
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http://dx.doi.org/10.1177/0004867420961472DOI Listing
October 2020

A molecular insight into the dissociable regulation of associative learning and motivation by the synaptic protein neuroligin-1.

BMC Biol 2020 09 14;18(1):118. Epub 2020 Sep 14.

Florey Institute of Neuroscience and Mental Health, Florey Department of Neuroscience, Melbourne Brain Centre, University of Melbourne, 30 Royal Parade, Parkville, Victoria, 3052, Australia.

Background: In a changing environment, a challenge for the brain is to flexibly guide adaptive behavior towards survival. Complex behavior and the underlying neural computations emerge from the structural components of the brain across many levels: circuits, cells, and ultimately the signaling complex of proteins at synapses. In line with this logic, dynamic modification of synaptic strength or synaptic plasticity is widely considered the cellular level implementation for adaptive behavior such as learning and memory. Predominantly expressed at excitatory synapses, the postsynaptic cell-adhesion molecule neuroligin-1 (Nlgn1) forms trans-synaptic complexes with presynaptic neurexins. Extensive evidence supports that Nlgn1 is essential for NMDA receptor transmission and long-term potentiation (LTP), both of which are putative synaptic mechanisms underlying learning and memory. Here, employing a comprehensive battery of touchscreen-based cognitive assays, we asked whether impaired NMDA receptor transmission and LTP in mice lacking Nlgn1 does in fact disrupt decision-making. To this end, we addressed two key decision problems: (i) the ability to learn and exploit the associative structure of the environment and (ii) balancing the trade-off between potential rewards and costs, or positive and negative utilities of available actions.

Results: We found that the capacity to acquire complex associative structures and adjust learned associations was intact. However, loss of Nlgn1 alters motivation leading to a reduced willingness to overcome effort cost for reward and an increased willingness to exert effort to escape an aversive situation. We suggest Nlgn1 may be important for balancing the weighting on positive and negative utilities in reward-cost trade-off.

Conclusions: Our findings update canonical views of this key synaptic molecule in behavior and suggest Nlgn1 may be essential for regulating distinct cognitive processes underlying action selection. Our data demonstrate that learning and motivational computations can be dissociated within the same animal model, from a detailed behavioral dissection. Further, these results highlight the complexities in mapping synaptic mechanisms to their behavioral consequences, and the future challenge to elucidate how complex behavior emerges through different levels of neural hardware.
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http://dx.doi.org/10.1186/s12915-020-00848-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646379PMC
September 2020

Acute NMDA receptor antagonism impairs working memory performance but not attention in rats-Implications for the NMDAr hypofunction theory of schizophrenia.

Behav Neurosci 2020 Aug;134(4):323-331

Department of Medicine (Royal Melbourne Hospital), University of Melbourne.

Cognitive deficits in schizophrenia, which include impairments in working memory and attention, represent some of the most disabling symptoms of this complex psychiatric condition, and lack effective treatments. NMDA receptor (NMDAr) hypofunction is a strong candidate mechanism underlying schizophrenia pathophysiology, and has been modeled preclinically using acute administration of NMDAr antagonists to rodents to investigate biological mechanisms underpinning cognitive dysfunction. However, whether and how NMDAr hypofunction specifically influences all affected cognitive domains is unclear. Here we studied the effects of the NMDAr antagonist MK-801 (dizocilpine) on tasks of attention and working memory in rats using automated touchscreen chambers. Adult male Wistar rats were trained to perform the trial-unique nonmatching to location (TUNL) task of spatial working memory, or the 5-choice serial reaction time task (5CSRTT) of attention. Once trained, rats received injection of vehicle (saline) or low-dose MK-801 (0.06 mg/kg sc) 10 min prior to commencing test sessions. MK-801 significantly impaired working memory, as evidenced by reduced performance accuracy on the TUNL task (p < .0001), compared with vehicle. However, we found no significant effects on attentional processing or perseveration on the 5CSRTT. Additional measures indicated that MK-801 impaired behavioral flexibility in the TUNL task, and decreased response inhibition in both tasks. Using the automated touchscreen system to measure different cognitive functions under the same testing environment, we demonstrate that spatial working memory, response inhibition, and behavioral flexibility are more vulnerable to NMDAr hypofunction than attentional processing. This may have implications for the NMDAr hypofunction hypothesis of schizophrenia. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000402DOI Listing
August 2020

In the Loop: Extrastriatal Regulation of Spiny Projection Neurons by GPR52.

ACS Chem Neurosci 2020 07 7;11(14):2066-2076. Epub 2020 Jul 7.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.

GPR52 is a Gα-coupled orphan receptor identified as a putative target for the treatment of schizophrenia. The unique expression and signaling profile of GPR52 in key areas of dopamine and glutamate dysregulation suggests its activation may resolve both cortical and striatal dysfunction in the disorder. GPR52 mRNA is enriched in the striatum, almost exclusively on dopamine D-expressing medium spiny neurons (MSNs), and to a lesser extent in the cortex, predominantly on D-expressing pyramidal neurons. Synthetic, small molecule GPR52 agonists are effective in preclinical models of psychosis; however, the relative contribution of cortical and striatal GPR52 is unknown. Here we show that the GPR52 agonist, 3-BTBZ, inhibits phencyclidine-induced hyperlocomotor activity to a greater degree than amphetamine-induced motor effects, suggesting a mechanism beyond functional antagonism of striatal dopamine D receptor signaling. Using DARPP-32 phosphorylation and electrophysiological recordings in either striatopallidal or striatonigral MSNs, we were surprised to find no significant effect of 3-BTBZ in striatopallidal MSNs, but GPR52-mediated effects in striatonigral MSNs, where its mRNA is absent. 3-BTBZ increases phosphorylation of T75 on DARPP-32 in striatonigral MSNs, an effect that was dependent on cortical inputs. A similar role for GPR52 in regulating extrastriatal glutamatergic drive onto striatonigral MSNs was also evident in recordings of spontaneous excitatory postsynaptic currents and was shown to be dependent on the metabotropic glutamate (mGlu) receptor subtype 1. Our results demonstrate that GPR52-mediated regulation of striatal function depends heavily on extrastriatal inputs, which may further support its utility as a novel target for the treatment of schizophrenia.
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http://dx.doi.org/10.1021/acschemneuro.0c00197DOI Listing
July 2020

MK-801 impairs working memory on the Trial-Unique Nonmatch-to-Location test in mice, but this is not exclusively mediated by NMDA receptors on PV+ interneurons or forebrain pyramidal cells.

Neuropharmacology 2020 07 21;171:108103. Epub 2020 Apr 21.

Department of Neuroscience, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, Victoria, 3004, Australia; Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria, 3052, Australia. Electronic address:

NMDA receptors (NMDAr) are widely expressed throughout the brain on many cell types, and loss of function of these receptors (ie: NMDAr hypofunction) is a candidate mechanism explaining working memory impairment in schizophrenia. However, the cellular source driving the working memory deficits caused by NMDAr hypofunction has not been explored. The aim of this study was to assess the contribution of NMDAr on pyramidal cells and parvalbumin (PV+) interneurons to impairments in working memory induced by NMDAr hypofunction. We excised GluN1 - the gene encoding the obligatory subunit of the NMDAr - from PV + interneurons or CaMKIIα+ pyramidal cells using Cre-lox technology. Adult male PV GluN1 KO (n = 10) and CaMKIIα GluN1 KO mice (n = 9) and WT controls (n = 10 and n = 13) were trained to perform the Trial-Unique Nonmatching-to-Location (TUNL) task of working memory. Once trained, mice received the NMDAr antagonist MK-801 (0.1 and 0.3 mg/kg ip), and working memory assessed. Neither task acquisition nor working memory differed between the two transgenic lines and WT littermates. MK-801 dose-dependently decreased working memory accuracy in all strains (p < 0.001). PV GluN1 KO mice were sensitised to the impairing effects of MK-801 (p = 0.04), whereas CaMKIIα GluN1 KO mice showed equivalent working memory deficits as WT. Developmental NMDAr hypofunction at either PV+ interneurons or forebrain pyramidal cells is not sufficient to impair working memory, and neither of these cell types exclusively mediates working memory impairment caused by NMDAr antagonism. Reduced NMDAr signalling at PV+ interneurons could predispose circuits to NMDAr hypofunction magnifying deficits in working memory.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108103DOI Listing
July 2020

Altered Caecal Neuroimmune Interactions in the Neuroligin-3 Mouse Model of Autism.

Front Cell Neurosci 2020 9;14:85. Epub 2020 Apr 9.

School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.

The intrinsic nervous system of the gut interacts with the gut-associated lymphoid tissue (GALT) bidirectional neuroimmune interactions. The caecum is an understudied region of the gastrointestinal (GI) tract that houses a large supply of microbes and is involved in generating immune responses. The caecal patch is a lymphoid aggregate located within the caecum that regulates microbial content and immune responses. People with Autism Spectrum Disorder (ASD; autism) experience serious GI dysfunction, including inflammatory disorders, more frequently than the general population. Autism is a highly prevalent neurodevelopmental disorder defined by the presence of repetitive behavior or restricted interests, language impairment, and social deficits. Mutations in genes encoding synaptic adhesion proteins such as the R451C missense mutation in neuroligin-3 (NL3) are associated with autism and impair synaptic transmission. We previously reported that NL3 mice, a well-established model of autism, have altered enteric neurons and GI dysfunction; however, whether the autism-associated R451C mutation alters the caecal enteric nervous system and immune function is unknown. We assessed for gross anatomical changes in the caecum and quantified the proportions of caecal submucosal and myenteric neurons in wild-type and NL3 mice using immunofluorescence. In the caecal patch, we assessed total cellular density as well as the density and morphology of Iba-1 labeled macrophages to identify whether the R451C mutation affects neuro-immune interactions. NL3 mice have significantly reduced caecal weight compared to wild-type mice, irrespective of background strain. Caecal weight is also reduced in mice lacking Neuroligin-3. NL3 caecal ganglia contain more neurons overall and increased numbers of Nitric Oxide (NO) producing neurons (labeled by Nitric Oxide Synthase; NOS) per ganglion in both the submucosal and myenteric plexus. Overall caecal patch cell density was unchanged however NL3 mice have an increased density of Iba-1 labeled enteric macrophages. Macrophages in NL3 were smaller and more spherical in morphology. Here, we identify changes in both the nervous system and immune system caused by an autism-associated mutation in Nlgn3 encoding the postsynaptic cell adhesion protein, Neuroligin-3. These findings provide further insights into the potential modulation of neural and immune pathways.
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http://dx.doi.org/10.3389/fncel.2020.00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160799PMC
April 2020

Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference.

Mol Autism 2019 2;10:42. Epub 2019 Dec 2.

1Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, Victoria Australia.

Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of dysfunction ( and ). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms.
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http://dx.doi.org/10.1186/s13229-019-0292-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889473PMC
June 2020

Cognition in Stroke Rehabilitation and Recovery Research: Consensus-Based Core Recommendations From the Second Stroke Recovery and Rehabilitation Roundtable.

Neurorehabil Neural Repair 2019 11 29;33(11):943-950. Epub 2019 Oct 29.

University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia.

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway.
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http://dx.doi.org/10.1177/1545968319886444DOI Listing
November 2019

The mGluR agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice.

J Psychopharmacol 2019 12 3;33(12):1588-1599. Epub 2019 Oct 3.

Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne Brain Centre, Parkville, VIC, Australia.

Background: Abnormalities in neural oscillations that occur in the gamma frequency range (30-80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists.

Aims: We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR) agonist LY379268.

Methods: C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus.

Results: MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130-180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment.

Conclusions: NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.
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http://dx.doi.org/10.1177/0269881119875976DOI Listing
December 2019

Cognition in stroke rehabilitation and recovery research: Consensus-based core recommendations from the second Stroke Recovery and Rehabilitation Roundtable.

Int J Stroke 2019 10 12;14(8):774-782. Epub 2019 Sep 12.

4University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, Australia.

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway.
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http://dx.doi.org/10.1177/1747493019873600DOI Listing
October 2019

Cognitive deficits in a rat model of temporal lobe epilepsy using touchscreen-based translational tools.

Epilepsia 2019 08 23;60(8):1650-1660. Epub 2019 Jul 23.

Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.

Objective: Cognitive deficits are commonly observed in people with epilepsy, but the biologic causation of these is challenging to identify. Animal models of epilepsy can be used to explore pathophysiologic mechanisms leading to cognitive problems, as well as to test novel therapeutics. We utilized a well-validated animal model of epilepsy to explore cognitive deficits using novel translational assessment tools/automated rodent touchscreen assays.

Methods: To induce epilepsy, adult Wistar rats were subjected to kainic acid-induced status epilepticus or sham control (n = 12/group). Two months following induction, animals underwent the Pairwise Discrimination and Reversal learning touchscreen tasks, novel object recognition, and the Y maze test of spatial memory.

Results: In the Pairwise Discrimination paradigm, only 40% of epilepsy animals acquired the discrimination learning criterion, compared to 100% of sham animals (P = 0.003). Epilepsy and sham animals that successfully acquired the discrimination progressed onto the reversal phase, which measures cognitive flexibility. Of interest, there were no differences in the rate of reversal learning; however, on the first reversal session, epilepsy rats committed more perseverative errors than shams (mean ± SEM: 6.3 ± 0.9 vs 1.8 ± 0.5, P < 0.0001). Additional behavioral analysis revealed that epilepsy rats were significantly impaired in novel object recognition and short-term spatial learning and memory.

Significance: Using translationally relevant behavioral tools in combination with traditional assays to measure cognition in animal models, here we identify impairments in learning and memory, and enhanced perseverative behaviors in rats with epilepsy. These tools can be used in future research to explore biologic mechanisms and treatments for cognitive deficits associated with epilepsy.
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http://dx.doi.org/10.1111/epi.16291DOI Listing
August 2019

Paradoxical effects of exercise on hippocampal plasticity and cognition in mice with a heterozygous null mutation in the serotonin transporter gene.

Br J Pharmacol 2019 09 15;176(17):3279-3296. Epub 2019 Jul 15.

Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Melbourne, VIC, Australia.

Background And Purpose: Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects.

Experimental Approach: Hippocampal long-term potentiation (LTP) and neurogenesis were measured in standard-housed and exercising (wheel running) wild-type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal-dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task.

Key Results: SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard-housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest.

Conclusions And Implications: Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise-induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal-dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5-HT homeostasis.
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http://dx.doi.org/10.1111/bph.14760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692575PMC
September 2019

Colonic dilation and altered ex vivo gastrointestinal motility in the neuroligin-3 knockout mouse.

Autism Res 2020 05 19;13(5):691-701. Epub 2019 Apr 19.

Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia.

Gastrointestinal (GI) dysfunction is commonly reported by people diagnosed with autism spectrum disorder (ASD; autism) but the cause is unknown. Mutations in genes encoding synaptic proteins including Neuroligin-3 are associated with autism. Mice lacking Neuroligin-3 (Nlgn3 ) have altered brain function, but whether the enteric nervous system (ENS) is altered remains unknown. We assessed for changes in GI structure and function in Nlgn3 mice. We found no significant morphological differences in villus height or crypt depth in the jejunum or colon between wildtype (WT) and Nlgn3 mice. To determine whether deletion of Nlgn3 affects enteric neurons, we stained for neural markers in the myenteric plexus. Nlgn3 mice had similar numbers of neurons expressing the pan-neuronal marker Hu in the jejunum, proximal mid, and distal colon regions. We also found no differences in the number of neuronal nitric oxide synthase (nNOS+) or calretinin (CalR+) motor neurons and interneurons between WT and Nlgn3 mice. We used ex vivo video imaging analysis to assess colonic motility under baseline conditions and observed faster colonic migrating motor complexes (CMMCs) and an increased colonic diameter in Nlgn3 mice, although CMMC frequency was unchanged. At baseline, CMMCs were faster in Nlgn3 mice compared to WT. Although the numbers of neuronal subsets are conserved in Nlgn3 mice, these findings suggest that Neuroligin-3 modulates inhibitory neural pathways in the ENS and may contribute to mechanisms underlying GI disorders in autism. Autism Res 2020, 13: 691-701. © 2019 The Authors. Autism Research published by International Society for Autism Research published byWiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gut problems. Many gene mutations associated with autism affect neuronal activity. We studied mice in which the autism-associated Neuroligin-3 gene is deleted to determine whether this impacts gut neuronal numbers or motility. We found that although mutant mice had similar gut structure and numbers of neurons in all gut regions examined, they had distended colons and faster colonic muscle contractions. Further work is needed to understand how Neuroligin-3 affects neuron connectivity in the gastrointestinal tract.
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http://dx.doi.org/10.1002/aur.2109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317711PMC
May 2020

Hypoxia-Induced MicroRNA-210 Targets Neurodegenerative Pathways.

Noncoding RNA 2018 Mar 27;4(2). Epub 2018 Mar 27.

Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.

Hypoxia-regulated microRNA-210 (miR-210) is a highly conserved microRNA, known to regulate various processes under hypoxic conditions. Previously we found that miR-210 is also involved in honeybee learning and memory, raising the questions of how neural activity may induce hypoxia-regulated genes and how miR-210 may regulate plasticity in more complex mammalian systems. Using a pull-down approach, we identified 620 unique target genes of miR-210 in humans, among which there was a significant enrichment of age-related neurodegenerative pathways, including Huntington's, Alzheimer's, and Parkinson's diseases. We have also validated that miR-210 directly regulates various identified target genes of interest involved with neuronal plasticity, neurodegenerative diseases, and miR-210-associated cancers. This data suggests a potentially novel mechanism for how metabolic changes may couple plasticity to neuronal activity through hypoxia-regulated genes such as miR-210.
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http://dx.doi.org/10.3390/ncrna4020010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027187PMC
March 2018

Connecting the dots in mental illness: The synapse as the intersection of brain function and disease.

Prog Neuropsychopharmacol Biol Psychiatry 2018 06;84(Pt B):305

Florey Institute of Neuroscience and Mental Health, Florey Department of Neuroscience, University of Melbourne, Parkville Victoria Australia.

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http://dx.doi.org/10.1016/j.pnpbp.2018.03.025DOI Listing
June 2018

Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence.

Cell Rep 2017 Oct;21(3):679-691

Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK; Genes to Cognition Programme, Centre for Clinical Brain Science, University of Edinburgh, Edinburgh, UK. Electronic address:

Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function.
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http://dx.doi.org/10.1016/j.celrep.2017.09.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656750PMC
October 2017

Using Animal Models to Study the Role of the Gut-Brain Axis in Autism.

Curr Dev Disord Rep 2017 12;4(2):28-36. Epub 2017 May 12.

School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC 3083 Australia.

Purpose Of Review: Individuals with autism spectrum disorders (ASD) commonly also suffer from gastrointestinal (GI) dysfunction; however, few animal model studies have systematically examined both ASD and GI dysfunction. In this review, we highlight studies investigating GI dysfunction and alterations in gut microbiota in animal models of ASD with the aim of determining if routinely used microbiology and enteric neurophysiology assays could expand our understanding of the link between the two.

Recent Findings: Gut-brain axis research is expanding, and several ASD models demonstrate GI dysfunction. The integration of well-established assays for detecting GI dysfunction into standard behavioural testing batteries is needed.

Summary: Advances in understanding the role of the gut-brain axis in ASD are emerging; however, we outline standard assays for investigating gut-brain axis function in rodents to strengthen future phenotyping studies. Integrating these findings to the field of animal behaviour is one of the next major challenges in autism research.
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http://dx.doi.org/10.1007/s40474-017-0111-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488132PMC
May 2017

Local NMDA receptor hypofunction evokes generalized effects on gamma and high-frequency oscillations and behavior.

Neuroscience 2017 09 1;358:124-136. Epub 2017 Jul 1.

Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria, Australia. Electronic address:

The NMDA receptor (NMDAr) hypofunction theory of schizophrenia suggests that aberrant signaling through NMDAr underlies the pathophysiology of this disease. This is commonly modeled in rodents via treatment with NMDAr antagonists, which causes a range of behavioral effects that represent endophenotypes related to schizophrenia. These drugs also disrupt high-frequency neural oscillations within the brain, also potentially relevant to disease. We studied the effect of localized NMDAr hypofunction on the generation of neural oscillations occurring both locally and in distant brain regions, and on behaviors routinely used as endophenotypes to model psychosis in rodents. Wistar rats were implanted with local field potential recording electrodes in the prefrontal cortex, dorsal hippocampus and nucleus accumbens, as well as cannulae in these regions to facilitate drug infusion. Rats received bilateral infusions of MK801 (0, 5μg, 20μg, 50μg) into one of the three target regions and their behavior measured in an open field. We also assessed the effects of systemic MK801 injection (0.16mg/kg sc). Electrophysiological signals were recorded continuously, allowing assessment of gamma oscillations (30-80Hz) and high-frequency oscillations (HFO: 130-180Hz) occurring as a result of infusions. Regardless of MK801 infusion location, gamma oscillations and HFOs significantly and consistently increased in all three regions studied, similar to that observed following systemic injection. Locomotor activity, stereotypies and ataxia were also observed following infusion into all regions. We conclude that localized regions exhibiting NMDAr hypofunction are sufficient to disrupt local as well as diffuse neural circuits and global brain function, and concomitantly cause psychosis-related behavioral effects.
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http://dx.doi.org/10.1016/j.neuroscience.2017.06.039DOI Listing
September 2017

Cognitive components in mice and humans: combining genetics and touchscreens for medical translation.

Neurobiol Learn Mem 2013 Oct 22;105:13-9. Epub 2013 Jun 22.

Centre for Clinical Brain Sciences and Centre for Neuroregeneration, Edinburgh University, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.

Human disorders of cognition arise from hundreds of gene mutations and mice serve as models for developing and testing therapeutic approaches. Recent advancements using touchscreen psychological tests that measure similar components of cognition in mice and humans can be combined with genetics. These experiments formally demonstrate that different components of cognition in humans and mice are not merely analogous, but homologous, sharing common descent and genetic constitution. They also show that it is possible to genetically dissect different behaviours and identify their underlying molecular mechanisms. Using these methods as standardised approaches offers the prospect of understanding the genetic architecture of the cognitive repertoire and the identification of new targets for drug development. Rigorously defining homologous mechanisms using genetics and touchscreen tests may also improve drug trial design. Recommendations for mouse clinical trial protocols combined with human genetics are proposed.
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http://dx.doi.org/10.1016/j.nlm.2013.06.006DOI Listing
October 2013

Synaptic scaffold evolution generated components of vertebrate cognitive complexity.

Nat Neurosci 2013 Jan 2;16(1):16-24. Epub 2012 Dec 2.

Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh, UK.

The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report, to our knowledge, the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2's role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness.
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http://dx.doi.org/10.1038/nn.3276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131247PMC
January 2013

Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior.

Nat Neurosci 2013 Jan 2;16(1):25-32. Epub 2012 Dec 2.

Genes to Cognition Programme, Wellcome Trust Sanger Institute, Cambridge, UK.

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C-terminal domains (CTDs). To identify shared ancestral functions and diversified subunit-specific functions, we exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock-in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit-specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long-term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 genes.
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http://dx.doi.org/10.1038/nn.3277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979286PMC
January 2013

TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function.

J Neurosci 2012 Oct;32(40):13987-99

Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom.

Traf2 and NcK interacting kinase (TNiK) contains serine-threonine kinase and scaffold domains and has been implicated in cell proliferation and glutamate receptor regulation in vitro. Here we report its role in vivo using mice carrying a knock-out mutation. TNiK binds protein complexes in the synapse linking it to the NMDA receptor (NMDAR) via AKAP9. NMDAR and metabotropic receptors bidirectionally regulate TNiK phosphorylation and TNiK is required for AMPA expression and synaptic function. TNiK also organizes nuclear complexes and in the absence of TNiK, there was a marked elevation in GSK3β and phosphorylation levels of its cognate phosphorylation sites on NeuroD1 with alterations in Wnt pathway signaling. We observed impairments in dentate gyrus neurogenesis in TNiK knock-out mice and cognitive testing using the touchscreen apparatus revealed impairments in pattern separation on a test of spatial discrimination. Object-location paired associate learning, which is dependent on glutamatergic signaling, was also impaired. Additionally, TNiK knock-out mice displayed hyperlocomotor behavior that could be rapidly reversed by GSK3β inhibitors, indicating the potential for pharmacological rescue of a behavioral phenotype. These data establish TNiK as a critical regulator of cognitive functions and suggest it may play a regulatory role in diseases impacting on its interacting proteins and complexes.
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http://dx.doi.org/10.1523/JNEUROSCI.2433-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978779PMC
October 2012

Retinal dysfunction, photoreceptor protein dysregulation and neuronal remodelling in the R6/1 mouse model of Huntington's disease.

Neurobiol Dis 2012 Mar 11;45(3):887-96. Epub 2011 Dec 11.

Department of Anatomy and Cell Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.

Huntington's disease (HD) is a progressive neurological disease characterised by motor dysfunction, cognitive impairment and personality changes. Previous work in HD patients and animal models of the disease has also highlighted retinal involvement. This study characterised the changes in retinal structure and function early within the progression of disease using the R6/1 mouse model of HD. The retinal phenotype was observed to occur at the same time in the disease process as other neurological deficits such as motor dysfunction (by 13 weeks of age). There was a specific functional deficit in cone response to the electroretinogram and using immunocytochemical techniques, this dysfunction was found to be likely due to a progressive and complete loss of cone opsin and transducin protein expression by 20 weeks of age. In addition, there was an increase in Müller cell gliosis and the presence of ectopic rod photoreceptor terminals. This retinal remodelling is also observed in downstream neurons, namely the rod and cone bipolar cells. While R6/1 mice exhibit significant retinal pathology simultaneously with other more classical HD alterations, this doesn't lead to extensive cell loss. These findings suggest that in HD, cone photoreceptors are initially targeted, possibly via dysregulation of protein expression or trafficking and that this process is subsequently accompanied by increased retinal stress and neuronal remodelling also involving the rod pathway. As retinal structure and connectivity are well characterised, the retina may provide a useful model tissue in which to characterise the mechanisms important in the development of neuronal pathology in HD.
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http://dx.doi.org/10.1016/j.nbd.2011.12.004DOI Listing
March 2012

Mechanisms mediating brain and cognitive reserve: experience-dependent neuroprotection and functional compensation in animal models of neurodegenerative diseases.

Prog Neuropsychopharmacol Biol Psychiatry 2011 Mar 26;35(2):331-9. Epub 2010 Nov 26.

Wellcome Trust Sanger Institute, Cambridge, UK.

'Brain and cognitive reserve' (BCR) refers here to the accumulated neuroprotective reserve and capacity for functional compensation induced by the chronic enhancement of mental and physical activity. BCR is thought to protect against, and compensate for, a range of different neurodegenerative diseases, as well as other neurological and psychiatric disorders. In this review we will discuss BCR, and its potential mechanisms, in neurodegenerative disorders, with a focus on Huntington's disease (HD) and Alzheimer's disease (AD). Epidemiological studies of AD, and other forms of dementia, provided early evidence for BCR. The first evidence for the beneficial effects of enhanced mental and physical activity, and associated mechanistic insights, in an animal model of neurodegenerative disease was provided by experiments using HD transgenic mice. More recently, experiments on animal models of HD, AD and various other brain disorders have suggested potential molecular and cellular mechanisms underpinning BCR. We propose that sophisticated insight into the processes underlying BCR, and identification of key molecules mediating these beneficial effects, will pave the way for therapeutic advances targeting these currently incurable neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.pnpbp.2010.10.026DOI Listing
March 2011

The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders.

Prog Neurobiol 2009 Dec 9;89(4):369-82. Epub 2009 Oct 9.

Howard Florey Institute, Florey Neuroscience Institutes, University of Melbourne, Victoria 3010, Australia.

The concept of 'cognitive reserve', and a broader theory of 'brain reserve', were originally proposed to help explain epidemiological data indicating that individuals who engaged in higher levels of mental and physical activity via education, occupation and recreation, were at lower risk of developing Alzheimer's disease and other forms of dementia. Subsequently, behavioral, cellular and molecular studies in animals (predominantly mice and rats) have revealed dramatic effects of environmental enrichment, which involves enhanced levels of sensory, cognitive and motor stimulation via housing in novel, complex environments. Furthermore, increasing levels of voluntary physical exercise, via ad libitum access to running wheels, can have significant effects on brain and behavior, thus informing the relative effects of mental and physical activity. More recently, animal models of brain disorders have been compared under environmentally stimulating and standard housing conditions, and this has provided new insights into environmental modulators and gene-environment interactions involved in pathogenesis. Here, we review animal studies that have investigated the effects of modifying mental and physical activity via experimental manipulations, and discuss their relevance to brain and cognitive reserve (BCR). Recent evidence suggests that the concept of BCR is not only relevant to brain aging, neurodegenerative diseases and dementia, but also to other neurological and psychiatric disorders. Understanding the cellular and molecular mechanisms mediating BCR may not only facilitate future strategies aimed at optimising healthy brain aging, but could also identify molecular targets for novel pharmacological approaches aimed at boosting BCR in 'at risk' and symptomatic individuals with various brain disorders.
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http://dx.doi.org/10.1016/j.pneurobio.2009.10.001DOI Listing
December 2009