574 results on '"Saksida, Lisa M."'
Search Results
152. Assessment of Glutamate Transporter GLAST (EAAT1)-Deficient Mice for Phenotypes Relevant to the Negative and Executive/Cognitive Symptoms of Schizophrenia
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Karlsson, Rose-Marie, primary, Tanaka, Kohichi, additional, Saksida, Lisa M, additional, Bussey, Timothy J, additional, Heilig, Markus, additional, and Holmes, Andrew, additional
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- 2008
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153. The touchscreen cognitive testing method for rodents: How to get the best out of your rat
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Bussey, Timothy J., primary, Padain, Tina L., additional, Skillings, Elizabeth A., additional, Winters, Boyer D., additional, Morton, A. Jennifer, additional, and Saksida, Lisa M., additional
- Published
- 2008
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154. Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit
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Brigman, Jonathan L., primary, Feyder, Michael, additional, Saksida, Lisa M., additional, Bussey, Timothy J., additional, Mishina, Masayoshi, additional, and Holmes, Andrew, additional
- Published
- 2008
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155. Perirhinal cortex resolves feature ambiguity in configural object recognition and perceptual oddity tasks
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Bartko, Susan J., primary, Winters, Boyer D., additional, Cowell, Rosemary A., additional, Saksida, Lisa M., additional, and Bussey, Timothy J., additional
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- 2007
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156. Scopolamine infused into perirhinal cortex improves object recognition memory by blocking the acquisition of interfering object information
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Winters, Boyer D., primary, Bartko, Susan J., additional, Saksida, Lisa M., additional, and Bussey, Timothy J., additional
- Published
- 2007
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157. PERFORMANCE OF TRANSGENIC TgTau-P301L MICE IN A 5-CHOICE SERIAL REACTION TIME TASK (5-CSRTT) AS A MODEL OF ALZHEIMER'S DISEASE.
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Bharmal, Aamena Valiji, Kent, Brianne A., Bussey, Timothy J., and Saksida, Lisa M.
- Published
- 2015
158. Measuring cognitive deficits in disabled mice using an automated interactive touchscreen system
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Morton, A Jennifer, primary, Skillings, Elizabeth, additional, Bussey, Timothy J, additional, and Saksida, Lisa M, additional
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- 2006
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159. Paradoxical Facilitation of Object Recognition Memory after Infusion of Scopolamine into Perirhinal Cortex: Implications for Cholinergic System Function
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Winters, Boyer D., primary, Saksida, Lisa M., additional, and Bussey, Timothy J., additional
- Published
- 2006
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160. Perirhinal cortex and feature-ambiguous discriminations
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Bussey, Timothy J., primary, Saksida, Lisa M., additional, and Murray, Elisabeth A., additional
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- 2006
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161. No effect of hippocampal lesions on perirhinal cortex-dependent feature-ambiguous visual discriminations
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Saksida, Lisa M., primary, Bussey, Timothy J., additional, Buckmaster, Cindy A., additional, and Murray, Elisabeth A., additional
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- 2006
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162. Object memory and perception in the medial temporal lobe: an alternative approach
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Bussey, Timothy J, primary and Saksida, Lisa M, additional
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- 2005
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163. Functional Specialization in the Human Medial Temporal Lobe
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Barense, Morgan D., primary, Bussey, Timothy J., additional, Lee, Andy C. H., additional, Rogers, Timothy T., additional, Davies, R. Rhys, additional, Saksida, Lisa M., additional, Murray, Elisabeth A., additional, and Graham, Kim S., additional
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- 2005
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164. The touchscreen operant platform for assessing executive function in rats and mice.
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Mar, Adam C, Horner, Alexa E, Nilsson, Simon R O, Alsiö, Johan, Kent, Brianne A, Kim, Chi Hun, Holmes, Andrew, Saksida, Lisa M, and Bussey, Timothy J
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- 2013
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165. Operant Conditioning in Skinnerbots
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Touretzky, David S., primary and Saksida, Lisa M., additional
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- 1997
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166. Pigeons' landmark use as revealed in a ‘feature-positive’, digitized landscape, touchscreen paradigm
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Wilkie, Donald M., primary, Mak, Tippi, additional, and Saksida, Lisa M., additional
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- 1994
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167. A mathematical theory of reinforcement: An unexpected place to find support for analogical memory coding
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Wilkie, Donald M., primary and Saksida, Lisa M., additional
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- 1994
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168. The spatial distribution of pigeons' target detection
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Wilkie, Donald M., primary and Saksida, Lisa M., additional
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- 1994
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169. Properties of time-place learning by pigeons, Columba livia
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Wilkie, Donald M., primary, Saksida, Lisa M., additional, Samson, Piers, additional, and Lee, Anita, additional
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- 1994
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170. Chronic alcohol produces neuroadaptations to prime dorsal striatal learning.
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DePoy, Lauren, Daut, Rachel, Brigman, Jonathan L., MacPherson, Kathryn, Crowley, Nicole, Gunduz-Cinar, Ozge, Pickens, Charles L., Cinar, Resat, Saksida, Lisa M., Kunos, George, Lovinger, David M., Bussey, Timothy J., Camp, Marguerite C., and Holmes, Andrew
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PSYCHOLOGY of alcoholism ,LEARNING ,COGNITION ,PREFRONTAL cortex ,ETHANOL ,DISEASE progression ,LABORATORY rats - Abstract
Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptor-dependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism. [ABSTRACT FROM AUTHOR]
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- 2013
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171. GluN2B in corticostriatal circuits governs choice learning and choice shifting.
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Brigman, Jonathan L, Daut, Rachel A, Wright, Tara, Gunduz-Cinar, Ozge, Graybeal, Carolyn, Davis, Margaret I, Jiang, Zhihong, Saksida, Lisa M, Jinde, Seiichiro, Pease, Matthew, Bussey, Timothy J, Lovinger, David M, Nakazawa, Kazu, and Holmes, Andrew
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IMMUNOCYTOCHEMISTRY ,MICRODIALYSIS ,PREFRONTAL cortex ,NEURONS ,GLUTAMATE receptors - Abstract
A choice that reliably produces a preferred outcome can be automated to liberate cognitive resources for other tasks. Should an outcome become less desirable, behavior must adapt in parallel or it becomes perseverative. Corticostriatal systems are known to mediate choice learning and flexibility, but the molecular mechanisms of these processes are not well understood. We integrated mouse behavioral, immunocytochemical, in vivo electrophysiological, genetic and pharmacological approaches to study choice. We found that the dorsal striatum (DS) was increasingly activated with choice learning, whereas reversal of learned choice engaged prefrontal regions. In vivo, DS neurons showed activity associated with reward anticipation and receipt that emerged with learning and relearning. Corticostriatal or striatal deletion of Grin2b (encoding the NMDA-type glutamate receptor subunit GluN2B) or DS-restricted GluN2B antagonism impaired choice learning, whereas cortical Grin2b deletion or OFC GluN2B antagonism impaired shifting. Our convergent data demonstrate how corticostriatal GluN2B circuits govern the ability to learn and shift choice behavior. [ABSTRACT FROM AUTHOR]
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- 2013
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172. Depletion of Perineuronal Nets Enhances Recognition Memory and Long-Term Depression in the Perirhinal Cortex.
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Romberg, Carola, Sujeong Yang, Melani, Riccardo, Andrews, Melissa R., Horner, Alexa E., Spillantini, Maria G., Bussey, Timothy J., Fawcett, James W., Pizzorusso, Tommaso, and Saksida, Lisa M.
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NEURONS ,RECOGNITION (Psychology) ,MEMORY ,MENTAL depression ,CEREBRAL cortex ,EXTRACELLULAR matrix ,PROTEIN structure - Abstract
Perineuronal nets (PNNs) are extracellular matrix structures surrounding cortical neuronal cell bodies and proximal dendrites and are involved in the control of brain plasticity and the closure of critical periods. Expression of the link protein Crtll/Haplnl in neurons has recently been identified as the key event triggering the formation of PNNs. Here we show that the genetic attenuation of PNNs in adult brain Crtl 1 knock-out mice enhances long-term object recognition memory and facilitates long-term depression in the perirhinal cortex, a neural correlate of object recognition memory. Identical prolongation of memory follows localized digestion of PNNs with chondroiti-nase ABC, an enzyme that degrades the chondroitin sulfate proteoglycan components of PNNs. The memory-enhancing effect of chon-droitinase ABC treatment attenuated over time, suggesting that the regeneration of PNNs gradually restored control plasticity levels. Our findings indicate that PNNs regulate both memory and experience-driven synaptic plasticity in adulthood. [ABSTRACT FROM AUTHOR]
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- 2013
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173. Dissociation between memory retention across a delay and pattern separation following medial prefrontal cortex lesions in the touchscreen TUNL task
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McAllister, Kathryn A.L., Saksida, Lisa M., and Bussey, Timothy J.
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DISSOCIATION (Psychology) , *PREFRONTAL cortex , *NEURONS , *COGNITIVE neuroscience , *SHORT-term memory , *HIPPOCAMPUS (Brain) , *LABORATORY rats - Abstract
Abstract: The neural structures that support the retention of memories over time has been a subject of intense research in cognitive neuroscience. However, recently much attention has turned to pattern separation, the putative process by which memories are stored as unique representations that are resistant to confusion. It remains unclear, however, to what extent these two processes can be neurally dissociated. The trial-unique delayed nonmatching-to-location (TUNL) task was developed to assess spatial working memory and pattern separation function using trial-unique locations on a touch-sensitive screen (Talpos, McTighe, Dias, Saksida, & Bussey, 2010). Using this task, Talpos et al. (2010) showed that lesions of the hippocampus led to both impairments with a 6s delay, and impairments in pattern separation. The present study shows that lesions of the medial prefrontal cortex lead to a different pattern of effects: impairment at the same, 6s delay, but no hint of impairment in pattern separation. In addition, rats with medial prefrontal lesions were more susceptible to interference in this task. When compared with previously published results, these data show that whereas the prefrontal cortex and hippocampus likely interact in the service of working memory across a delay, only the hippocampus and not the medial prefrontal cortex is essential for pattern separation. [Copyright &y& Elsevier]
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- 2013
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174. Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior.
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Ryan, Tomás J, Kopanitsa, Maksym V, Indersmitten, Tim, Nithianantharajah, Jess, Afinowi, Nurudeen O, Pettit, Charles, Stanford, Lianne E, Sprengel, Rolf, Saksida, Lisa M, Bussey, Timothy J, O'Dell, Thomas J, Grant, Seth G N, and Komiyama, Noboru H
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GENOMES ,VERTEBRATES ,MAMMALS ,BIOCHEMISTRY ,PHYSIOLOGY - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2013
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175. Synaptic scaffold evolution generated components of vertebrate cognitive complexity.
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Nithianantharajah, Jess, Komiyama, Noboru H, McKechanie, Andrew, Johnstone, Mandy, Blackwood, Douglas H, Clair, David St, Emes, Richard D, van de Lagemaat, Louie N, Saksida, Lisa M, Bussey, Timothy J, and Grant, Seth G N
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VERTEBRATES ,ANIMAL cognition ,GENOMES ,GENES ,ANIMAL psychopathology - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2013
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176. Predator-induced opioid and non-opioid mediated analgesia in young meadow voles: sex differences and developmental changes
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Saksida, Lisa M., primary, Galea, Liisa A.M., additional, and Kavaliers, Martin, additional
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- 1993
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177. Impaired Attention in the 3xTgAD Mouse Model of Alzheimer's Disease: Rescue by Donepezil (Aricept).
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Romberg, Carola, Mattson, Mark P., Mughal, Mohamed R., Bussey, Timothy J., and Saksida, Lisa M.
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ALZHEIMER'S patients ,COGNITIVE ability ,DISABILITIES ,ATTENTION-deficit hyperactivity disorder ,GENETIC mutation ,MICE ,ENZYMES - Abstract
Several mouse models of Alzheimer's disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD. [ABSTRACT FROM AUTHOR]
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- 2011
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178. Application of a model of instrumental conditioning to mobile robot control.
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Saksida, Lisa M. and Touretzky, D. S.
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- 1997
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179. Skinnerbots.
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Touretzky, David S. and Saksida, Lisa M.
- Published
- 1996
180. Functional Dissociations within the Ventral Object Processing Pathway: Cognitive Modules or a Hierarchical Continuum?
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Cowell, Rosemary A., Bussey, Timothy J., and Saksida, Lisa M.
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DISSOCIATION (Psychology) ,COGNITIVE ability ,VISUAL discrimination ,CEREBRAL cortex ,VISUAL perception - Abstract
We examined the organization and function of the ventral object processing pathway. The prevailing theoretical approach in this field holds that the ventral object processing stream has a modular organization, in which visual perception is carried out in posterior regions and visual memory is carried out, independently, in the anterior temporal lobe. In contrast, recent work has argued against this modular framework, favoring instead a continuous, hierarchical account of cognitive processing in these regions. We join the latter group and illustrate our view with simulations from a computational model that extends the perceptual-mnemonic feature-conjunction model of visual discrimination proposed by Bussey and Saksida [Bussey, T. J., & Saksida, L. M. The organization of visual object representations: A connectionist model of effects of lesions in perirhinal cortex. European Journal of Neuroscience, 15, 355-364, 2002]. We use the extended model to revisit early data from Iwai and Mishkin [Iwai, E., & Mishkin, M. Two visual foci in the temporal lobe of monkeys. In N. Yoshii & N. Buchwald (Eds.), Neurophysiological basis of learning and behavior (pp. 1-11). Japan: Osaka University Press, 1968]; this seminal study was interpreted as evidence for the modularity of visual perception and visual memory. The model accounts for a double dissociation in monkeys' visual discrimination performance following lesions to different regions of the ventral visual stream. This double dissociation is frequently cited as evidence for separate systems for perception and memory. However, the model provides a parsimonious, mechanistic, single-system account of the double dissociation data. We propose that the effects of lesions in ventral visual stream on visual discrimination are due to compromised representations within a hierarchical representational continuum rather than impairment in a specific type of learning, memory, or perception. We argue that consideration of the nature of stimulus representations and their processing in cortex is a more fruitful approach than attempting to map cognition onto functional modules. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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181. The representational–hierarchical view of amnesia: Translation from animal to human
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Saksida, Lisa M. and Bussey, Timothy J.
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AMNESIA , *ANIMAL memory , *HIPPOCAMPUS (Brain) , *TEMPORAL lobe , *EXPLICIT memory , *VISUAL discrimination ,ANIMAL models of memory disorders - Abstract
Abstract: Animal research has, in our opinion, made an invaluable contribution to our understanding of human amnesia. In this article we summarise our and others’ work in this area, focusing on a new view of amnesia we refer to as the representational–hierarchical view. According to this view—and in contrast to the prevailing paradigm in the field—the brain is best understood as a hierarchically organized continuum of representations, each of which is useful for a variety of cognitive functions. We focus our review on four visual discrimination paradigms that have been successfully translated into the human arena: configural concurrent discriminations, pair-wise “morph” discriminations, oddity discriminations, and configural oddity discriminations. The data from the animal studies are first reviewed, followed by illustrations of how the tasks have been utilized in human research. We then turn to the canonical impairment in animal models of amnesia, object recognition, and show how impairments in object recognition can be understood within the representational–hierarchical framework. This is followed by a discussion of predictions of the view related to classic issues in amnesia research, namely whether amnesia is due to a deficit of encoding, storage or retrieval, and the related issue of the role of interference in amnesia. Finally, we provide evidence from animal and human studies that even the hippocampus—almost universally regarded as a module for memory—may be better understood within the representational–hierarchical paradigm. [Copyright &y& Elsevier]
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- 2010
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182. Implications of animal object memory research for human amnesia
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Winters, Boyer D., Saksida, Lisa M., and Bussey, Timothy J.
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ANIMAL memory , *AMNESIA , *TEMPORAL lobe , *RECOGNITION (Psychology) , *EXPLICIT memory , *LABORATORY monkeys , *LABORATORY rats ,ANIMAL models of memory disorders - Abstract
Abstract: Damage to structures in the human medial temporal lobe causes severe memory impairment. Animal object recognition tests gained prominence from attempts to model ‘global’ human medial temporal lobe amnesia, such as that observed in patient HM. These tasks, such as delayed nonmatching-to-sample and spontaneous object recognition, for assessing object memory in non-human primates and rodents have proved invaluable as animal models of specific aspects of human declarative memory processes. This paper reviews research in non-human primates and rats using object recognition memory tasks to assess the neurobiological bases of amnesia. A survey of this research reveals several important implications for our understanding of the anatomical basis of memory and the medial temporal lobe amnesic syndrome. First, research with monkeys and rats reveals that the contributions of medial temporal lobe structures such as the hippocampus and perirhinal cortex to memory processes are dissociable, with particular structures contributing to specific tasks on the basis of the specific type of information that a structure is optimized to process. Second, the literature suggests that cognitive tasks requiring integration of different types of information, such as in the case of complex, multimodal declarative memory, will recruit structures of the medial temporal lobe in an interactive manner. The heterogeneity of function within the medial temporal lobe, as well as the multimodal and complex nature of human declarative memory, implies that animal tests of object recognition memory, once believed to be comprehensive models for the study of human global amnesia, model just one important facet of human declarative memory. Finally, in light of the research reviewed here, it is apparent that the specific nature of amnesia observed in an individual with medial temporal lobe damage will depend on the particular medial temporal lobe regions affected and their specific representational capacities. [Copyright &y& Elsevier]
- Published
- 2010
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183. Running enhances spatial pattern separation in mice.
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Creer, David J., Romberg, Carola, Saksida, Lisa M., Van Praag, Henriette, and Bussey, Timothy J.
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PHYSIOLOGICAL aspects of running ,NEUROPLASTICITY ,DEVELOPMENTAL neurobiology ,HIPPOCAMPUS physiology ,DENTATE gyrus ,LABORATORY mice ,SPACE perception ,NEURAL physiology - Abstract
Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions. [ABSTRACT FROM AUTHOR]
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- 2010
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184. Assessment of Glutamate Transporter GLAST (EAAT1)-Deficient Mice for Phenotypes Relevant to the Negative and Executive/Cognitive Symptoms of Schizophrenia.
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Karlsson, Rose-Marie, Tanaka, Kohichi, Saksida, Lisa M, Bussey, Timothy J, Heilig, Markus, and Holmes, Andrew
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GLUTAMIC acid ,SCHIZOPHRENIA ,COGNITION ,ANHEDONIA ,NEUROPSYCHOPHARMACOLOGY - Abstract
Glutamatergic dysfunction is increasingly implicated in the pathophysiology of schizophrenia. Current models postulate that dysfunction of glutamate and its receptors underlie many of the symptoms in this disease. However, the mechanisms involved are not well understood. Although elucidating the role for glutamate transporters in the disease has been limited by the absence of pharmacological tools that selectively target the transporter, we recently showed that glial glutamate and aspartate transporter (GLAST; excitatory amino-acid transporter 1) mutant mice exhibit abnormalities on behavioral measures thought to model the positive symptoms of schizophrenia, some of which were rescued by treatment with either haloperidol or the mGlu2/3 agonist, LY379268 the mGlu2/3 agonist, LY379268. To further determine the role of GLAST in schizophrenia-related behaviors we tested GLAST mutant mice on a series of behavioral paradigms associated with the negative (social withdrawal, anhedonia), sensorimotor gating (prepulse inhibition of startle), and executive/cognitive (discrimination learning, extinction) symptoms of schizophrenia. GLAST knockout (KO) mice showed poor nesting behavior and abnormal sociability, whereas KO and heterozygous (HET) both demonstrated lesser preference for a novel social stimulus compared to wild-type littermate controls. GLAST KO, but not HET, had a significantly reduced acoustic startle response, but no significant deficit in prepulse inhibition of startle. GLAST KO and HET showed normal sucrose preference. In an instrumental visual discrimination task, KO showed impaired learning. By contrast, acquisition and extinction of a simple instrumental response was normal. The mGlu2/3 agonist, LY379268, failed to rescue the discrimination impairment in KO mice. These findings demonstrate that gene deletion of GLAST produces select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia.Neuropsychopharmacology (2009) 34, 1578–1589; doi:10.1038/npp.2008.215; published online 10 December 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2009
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185. Impaired Fear Extinction Learning and Cortico-Amygdala Circuit Abnormalities in a Common Genetic Mouse Strain.
- Author
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Hefner, Kathryn, Whittle, Nigel, Juhasz, Jaynann, Norcross, Maxine, Karlsson, Rose-Marie, Saksida, Lisa M., Bussey, Timothy J., Singewald, Nicolas, and Holmes, Andrew
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FEAR & society ,AMYGDALOID body ,ANXIETY disorders treatment ,NEURAL transmission ,MICE ,ANIMAL models in research - Abstract
Fear extinction is a form of new learning that results in the inhibition of conditioned fear. Trait deficits in fear extinction are a risk factor for anxiety disorders. There are few examples of naturally occurring animal models of impaired extinction. The present study compared fear extinction in a panel of inbred mouse strains. This strain survey revealed an impairment in fear extinction in 129/SvImJ (129S1). The phenotypic specificity of this deficit was evaluated by comparing 129S1 and C57BL/6J for one-trial and multitrial fear conditioning, nociception, and extinction of conditioned taste aversion and an appetitive instrumental response. 129S1 were tested for sensitivity to the extinction-facilitating effects of extended training, as well as D-cycloserine and yohimbine treatment. To elucidate the neural basis of impaired 129S1 fear extinction, c-Fos and Zif268 expression was mapped after extinction recall. Results showed that impaired fear extinction in 129S1 was unrelated to altered fear conditioning or nociception, and was dissociable from intact appetitive extinction. Yohimbine treatment facilitated extinction in 129S1, but neither extended extinction training nor D-cycloserine treatment improved 129S1 extinction. After extinction recall, 129S1 showed reduced c-Fos and Zif268 expression in the infralimbic cortex and basolateral amygdala, and elevated c-Fos or Zif268 expression in central nucleus of the amygdala and medial paracapsular intercalated cell mass, relative to C57BL/6J. Collectively, these data demonstrate a deficit in fear extinction in 129S1 associated with a failure to properly engage corticolimbic extinction circuitry. This common inbred strain provides a novel model for studying impaired fear extinction in anxiety disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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186. Object recognition memory: Neurobiological mechanisms of encoding, consolidation and retrieval
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Winters, Boyer D., Saksida, Lisa M., and Bussey, Timothy J.
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CEREBRAL cortex , *ARCHIPALLIUM , *SENSORIMOTOR cortex , *MEMORY - Abstract
Abstract: Tests of object recognition memory, or the judgment of the prior occurrence of an object, have made substantial contributions to our understanding of the nature and neurobiological underpinnings of mammalian memory. Only in recent years, however, have researchers begun to elucidate the specific brain areas and neural processes involved in object recognition memory. The present review considers some of this recent research, with an emphasis on studies addressing the neural bases of perirhinal cortex-dependent object recognition memory processes. We first briefly discuss operational definitions of object recognition and the common behavioural tests used to measure it in non-human primates and rodents. We then consider research from the non-human primate and rat literature examining the anatomical basis of object recognition memory in the delayed nonmatching-to-sample (DNMS) and spontaneous object recognition (SOR) tasks, respectively. The results of these studies overwhelmingly favor the view that perirhinal cortex (PRh) is a critical region for object recognition memory. We then discuss the involvement of PRh in the different stages – encoding, consolidation, and retrieval – of object recognition memory. Specifically, recent work in rats has indicated that neural activity in PRh contributes to object memory encoding, consolidation, and retrieval processes. Finally, we consider the pharmacological, cellular, and molecular factors that might play a part in PRh-mediated object recognition memory. Recent studies in rodents have begun to indicate the remarkable complexity of the neural substrates underlying this seemingly simple aspect of declarative memory. [Copyright &y& Elsevier]
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- 2008
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187. Perceptual Functions of Perirhinal Cortex in Rats: Zero-Delay Object Recognition and Simultaneous Oddity Discriminations. .
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Bartko, Susan J., Winters, Boyer D., Cowell, Rosemary A., Saksida, Lisa M., and Bussey, Timothy J.
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TEMPORAL lobe ,VISUAL perception ,LABORATORY rats ,MEMORY ,VISUAL discrimination ,AMNESIA - Abstract
The perirhinal cortex (PRh) is widely accepted as having an important role in object recognition memory in humans and animals. Contrary to claims that PRh mediates declarative memory exclusively, previous evidence suggests that PRh has a role in the perceptual processing of complex objects. In the present study, we conducted an examination of the possible role of PRh in perceptual function in rats. We examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus postrhinal cortices) in the rat would cause deficits in a zero-delay object-recognition task and a simultaneous oddity discrimination task. Both of these tasks measured spontaneous (untrained, unrewarded) behavior, and the stimuli in these experiments were manipulated to produce varying levels of perceptual difficulty. As predicted by simulations using a computational model, rats with PPRh lesions were impaired in object recognition when the stimuli to be discriminated were manipulated to share many features in common. Furthermore, rats with PPRh and PRh lesions were impaired in a simultaneous oddity discrimination task when the stimuli to be discriminated were manipulated explicitly to be more perceptually similar. These findings provide support for the idea that PRh in the rat is important for the perceptual processing of complex objects, in addition to its well established role in memory. [ABSTRACT FROM AUTHOR]
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- 2007
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188. Double Dissociation between the Effects of Peri-Postrhinal Cortex and Hippocampal Lesions on Tests of Object Recognition and Spatial Memory: Heterogeneity of Function within the Temporal Lobe.
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Winters, Boyer D., Forwood, Suzanna E., Cowell, Rosemary A., Saksida, Lisa M., and Bussey, Timothy J.
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TEMPORAL lobe ,MEMORY ,HIPPOCAMPUS (Brain) ,CEREBRAL cortex ,HOMOGENEITY - Abstract
It is widely believed that declarative memory is mediated by a medial temporal lobe memory system consisting of several distinct structures, including the hippocampus and perirhinal cortex. The strong version of this view assumes a high degree of functional homogeneity and serial organization within the medial temporal lobe, such that double dissociations between individual structures should not be possible. In the present study, we tested for a functional double dissociation between the hippocampus and peri-postrhinal cortex in a single experiment. Rats with bilateral excitotoxic lesions of either the hippocampus or peri- postrhinal cortex were assessed in tests of spatial memory (radial maze) and object recognition memory. For the latter, the spontaneous object recognition task was conducted in a modified apparatus designed to minimize the potentially confounding influence of spatial and contextual factors. A clear functional double dissociation was observed: rats with hippocampal lesions were impaired relative to controls and those with peripostrhinal cortex lesions on the spatial memory task, whereas rats with peri-postrhinal lesions were impaired relative to the hippocampal and control groups in object recognition. These results provide strong evidence in favor of heterogeneity and independence of function within the temporal lobe. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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189. The touchscreen operant platform for testing learning and memory in rats and mice
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Horner, Alexa E, Heath, Christopher J, Hvoslef-Eide, Martha, Kent, Brianne A, Kim, Chi Hun, Nilsson, Simon R O, Alsiö, Johan, Oomen, Charlotte A, Holmes, Andrew, Saksida, Lisa M, and Bussey, Timothy J
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An increasingly popular method of assessing cognitive functions in rodents is the automated touchscreen platform, on which a number of different cognitive tests can be run in a manner very similar to touchscreen methods currently used to test human subjects. This methodology is low stress (using appetitive rather than aversive reinforcement), has high translational potential and lends itself to a high degree of standardization and throughput. Applications include the study of cognition in rodent models of psychiatric and neurodegenerative diseases (e.g., Alzheimer's disease, schizophrenia, Huntington's disease, frontotemporal dementia), as well as the characterization of the role of select brain regions, neurotransmitter systems and genes in rodents. This protocol describes how to perform four touchscreen assays of learning and memory: visual discrimination, object-location paired-associates learning, visuomotor conditional learning and autoshaping. It is accompanied by two further protocols (also published in this issue) that use the touchscreen platform to assess executive function, working memory and pattern separation.
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- 2013
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190. The touchscreen operant platform for testing working memory and pattern separation in rats and mice
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Oomen, Charlotte A, Hvoslef-Eide, Martha, Heath, Christopher J, Mar, Adam C, Horner, Alexa E, Bussey, Timothy J, and Saksida, Lisa M
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The automated touchscreen operant chamber for rats and mice allows for the assessment of multiple cognitive domains within the same testing environment. This protocol presents the location discrimination (LD) task and the trial-unique delayed nonmatching-to-location (TUNL) task, which both assess memory for location. During these tasks, animals are trained to a predefined criterion during ∼20–40 daily sessions. In LD sessions, touching the same location on the screen is rewarded on consecutive trials, followed by a reversal of location-reward contingencies. TUNL, a working memory task, requires animals to 'nonmatch' to a sample location after a delay. In both the LD and TUNL tasks, spatial similarity can be varied, allowing assessment of pattern separation ability, a function that is thought to be performed by the dentate gyrus (DG). These tasks are therefore particularly useful in animal models of hippocampal, and specifically DG, function, but they additionally permit discernment of changes in pattern separation from those in working memory.
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- 2013
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191. Neuroanatomical and cognitive biomarkers of alpha‐synuclein propagation in a mouse model of synucleinopathy prior to onset of motor symptoms.
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Tullo, Stephanie, Miranda, Aline S., del Cid‐Pellitero, Esther, Lim, Mei Peng, Gallino, Daniel, Attaran, Anoosha, Patel, Raihaan, Novikov, Vladislav, Park, Megan, Beraldo, Flavio H., Luo, Wen, Shlaifer, Irina, Durcan, Thomas M., Bussey, Timothy J., Saksida, Lisa M., Fon, Edward A., Prado, Vania F., Prado, Marco A. M., and Chakravarty, M. Mallar
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PARKINSON'S disease , *MAGNETIC resonance imaging , *CELLULAR pathology , *LABORATORY mice , *ANIMAL disease models - Abstract
Significant evidence suggests that misfolded alpha‐synuclein (aSyn), a major component of Lewy bodies, propagates in a prion‐like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha‐synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human‐relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF‐injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human‐relevant pre‐clinical measures and suggest that these pre‐clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease. [ABSTRACT FROM AUTHOR]
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- 2024
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192. Operant conditioning in skinnerbots.
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Touretzky, David S. and Saksida, Lisa M.
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OPERANT conditioning , *ROBOT programming - Abstract
Presents the use of model on operant conditioning to train a robot. Similarity between operant and reinforcement learning; Delayed match-to-sample task to study working memory in rats and monkeys; Differences between animal and robot learning.
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- 1996
193. The continuous performance test (rCPT) for mice: a novel operant touchscreen test of attentional function
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Kim, Chi Hun, Hvoslef-Eide, Martha, Nilsson, Simon RO, Johnson, Mark R, Herbert, Bronwen R, Robbins, Trevor W, Saksida, Lisa M, Bussey, Timothy J, Mar, Adam C, Robbins, Trevor [0000-0003-0642-5977], and Apollo - University of Cambridge Repository
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Male ,BASAL FOREBRAIN ,Mouse ,Drug Evaluation, Preclinical ,SELECTIVE ATTENTION ,Discrimination Learning ,DBA/2J MICE ,17 Psychology And Cognitive Sciences ,Mice ,Discrimination, Psychological ,Piperidines ,Species Specificity ,MOUSE MODELS ,Animals ,Humans ,Attention ,Donepezil ,Pharmacology & Pharmacy ,Nootropic Agents ,2 INBRED STRAINS ,Psychiatry ,REACTION-TIME-TASK ,Pharmacology ,Science & Technology ,Neurosciences ,11 Medical And Health Sciences ,CHOLINERGIC MECHANISMS ,Touchscreen operant chamber ,SENSITIVITY DECREMENT ,Mice, Inbred C57BL ,ALZHEIMERS-DISEASE ,Mouse strain differences ,Mice, Inbred DBA ,Indans ,Visual Perception ,Conditioning, Operant ,Cholinesterase Inhibitors ,Neurosciences & Neurology ,SUSTAINED ATTENTION ,Continuous performance test ,Life Sciences & Biomedicine ,Psychomotor Performance - Abstract
RATIONALE: Continuous performance tests (CPTs) are widely used to assess attentional processes in a variety of disorders including Alzheimer's disease and schizophrenia. Common human CPTs require discrimination of sequentially presented, visually patterned 'target' and 'non-target' stimuli at a single location. OBJECTIVES: The aims of this study were to evaluate the performance of three popular mouse strains on a novel rodent touchscreen test (rCPT) designed to be analogous to common human CPT variants and to investigate the effects of donepezil, a cholinesterase inhibitor and putative cognitive enhancer. METHODS: C57BL/6J, DBA/2J and CD1 mice (n = 15-16/strain) were trained to baseline performance using four rCPT training stages. Then, probe tests assessed the effects of parameter changes on task performance: stimulus size, duration, contrast, probability, inter-trial interval or inclusion of flanker distractors. rCPT performance was also evaluated following acute administration of donepezil (0-3 mg/kg, i.p.). RESULTS: C57BL/6J and DBA/2J mice showed similar acquisition rates and final baseline performance following rCPT training. On probe tests, rCPT performance of both strains was sensitive to alteration of visual and/or attentional demands (stimulus size, duration, contrast, rate, flanker distraction). Relative to C57BL/6J, DBA/2J mice exhibited (1) decreasing sensitivity (d') across the 45-min session, (2) reduced performance on probes where the appearance of stimuli or adjacent areas were changed (size, contrast, flanking distractors) and (3) larger dose- and stimulus duration-dependent changes in performance following donepezil administration. In contrast, CD1 mice failed to acquire rCPT (stage 3) and pairwise visual discrimination tasks. CONCLUSIONS: rCPT is a potentially useful translational tool for assessing attention in mice and for detecting the effects of nootropic drugs.
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194. The role of the dorsal hippocampus in two versions of the touchscreen automated paired associates learning (PAL) task for mice
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Kim, Chi Hun, Heath, Christopher J., Kent, Brianne A., Bussey, Timothy J., Saksida, Lisa M., and Apollo - University of Cambridge Repository
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Male ,Touch screen operant chamber ,Pharmacology ,Dose-Response Relationship, Drug ,Mouse ,Paired-associate learning ,Muscimol ,Motor Activity ,Hippocampus ,Mice, Inbred C57BL ,Automation ,Mice ,Reward ,Animals ,Conditioning, Operant ,Noise ,GABA Agonists ,Photic Stimulation ,Psychomotor Performance ,Original Investigation - Abstract
Rationale\ud The CANTAB object-location paired-associate learning (PAL) test can detect cognitive deficits in schizophrenia and Alzheimer’s disease. A rodent version of touch screen PAL (dPAL) has been developed, but the underlying neural mechanisms are not fully understood. Although there is evidence that inactivation of the hippocampus following training leads to impairments in rats, this has not been tested in mice. Furthermore, it is not known whether acquisition, as opposed to performance, of the rodent version depends on the hippocampus. This is critical as many mouse models may have hippocampal dysfunction prior to the onset of task training. \ud Objectives\ud The objectives of this study are to examine the effects of dorsal hippocampal (dHp) dysfunction on both performance and acquisition of mouse dPAL and to determine if hippocampal task sensitivity could be increased using a newly developed context-disambiguated PAL (cdPAL) paradigm. \ud Methods\ud In experiment 1, C57Bl/6 mice received post-acquisition dHp infusions of the GABA agonist muscimol. In experiment 2, C57Bl/6 mice received excitotoxic dHp lesions prior to dPAL/cdPAL acquisition. \ud Results\ud Post-acquisition muscimol dose-dependently impaired dPAL and cdPAL performance. Pre-acquisition dHp lesions had only mild effects on both PAL tasks. Behavioural challenges including addition of objects and degradation of the visual stimuli with noise did not reveal any further impairments. \ud Conclusions\ud dPAL and cdPAL performance is hippocampus-dependent in the mouse, but both tasks can be learned in the absence of a functional dHp.
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195. Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS–FTD.
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Kim, Eosu, White, Matthew A., Phillips, Benjamin U., Lopez-Cruz, Laura, Kim, Hyunjeong, Heath, Christopher J., Lee, Jong Eun, Saksida, Lisa M., Sreedharan, Jemeen, and Bussey, Timothy J.
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- 2020
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196. Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine.
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Nilsson, Simon R. O., Heath, Christopher J., Takillah, Samir, Didienne, Steve, Fejgin, Kim, Nielsen, Vibeke, Nielsen, Jacob, Saksida, Lisa M., Mariani, Jean, Faure, Philippe, Didriksen, Michael, Robbins, Trevor W., Bussey, Timothy J., and Mar, Adam C.
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- 2018
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197. Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome
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Nilsson, Simon Ro, Fejgin, Kim, Gastambide, Francois, Vogt, Miriam A, Kent, Brianne A, Nielsen, Vibeke, Nielsen, Jacob, Gass, Peter, Robbins, Trevor W, Saksida, Lisa M, Stensbøl, Tine B, Tricklebank, Mark D, Didriksen, Michael, and Bussey, Timothy J
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cognition ,Male ,animal model ,copy number variation ,Mice, Transgenic ,Neuropsychological Tests ,3. Good health ,Cohort Studies ,Mice, Inbred C57BL ,Translational Research, Biomedical ,Disease Models, Animal ,Executive Function ,Inhibition, Psychological ,Discrimination, Psychological ,Phenotype ,Memory ,22q11.2 deletion syndrome ,Drug Discovery ,DiGeorge Syndrome ,Animals ,Learning ,Attention ,Female - Abstract
A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.
198. A Touchscreen Motivation Assessment Evaluated in Huntington's Disease Patients and R6/1 Model Mice
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Heath, Christopher J, O'Callaghan, Claire, Mason, Sarah L, Phillips, Benjamin U, Saksida, Lisa M, Robbins, Trevor W, Barker, Roger A, Bussey, Timothy J, and Sahakian, Barbara J
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motivation ,progressive ratio ,translational ,Huntington's disease ,apathy ,touchscreen ,3. Good health - Abstract
Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients (n = 23) and age-matched healthy controls (n = 20), and male R6/1 mice (n = 23) and wildtype controls (n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions.
199. Longitudinal evaluation of Tau-P301L transgenic mice reveals no cognitive impairments at 17 months of age
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Kent, Brianne A, Heath, Christopher J, Kim, Chi Hun, Ahrens, Rosemary, Fraser, Paul E, St George-Hyslop, Peter, Bussey, Timothy J, and Saksida, Lisa M
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Behavior, Animal ,Mice, Transgenic ,tau Proteins ,Alzheimer's disease ,recognition memory ,frontotemporal dementia ,attention ,Disease Models, Animal ,Mice ,P301L ,Cognition ,Tauopathies ,Reaction Time ,Animals ,Cognitive Dysfunction ,tau ,10. No inequality - Abstract
INTRODUCTION: Tau is a microtubule-associated binding protein implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD). These diseases result in the intracellular accumulation of hyperphosphorylated tau in the form of neurofibrillary tangles, the presence of which is associated with cognitive deficits. METHODS: We conducted a longitudinal behavioral study to provide a profile of the TgTau(P301L)23027 transgenic mouse in multiple cognitive domains across multiple ages. P301L is the tau mutation most frequently observed in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and this mouse model recapitulates the progressive development of glial and neurofibrillary tangles, and associated cerebral atrophy observed in patients. We examined frontal cortex-dependent executive function and attention with the touchscreen 5-choice serial reaction time test (5-CSRTT) and assessed the function of temporal cortical structures using novel object recognition (OR). RESULTS: Despite using sensitive tasks, there were no apparent changes in executive function, attention, or recognition memory in the transgenic mice from 5 to 17 months of age. CONCLUSIONS: This study represents the first comprehensive longitudinal analysis of cognition in the TgTauP301L mouse model and suggests that this model is not ideal for studying early attention and recognition memory impairments associated with tauopathy. However, spatial and object recognition memory impairments were observed during follow-up assessments when the mice were 18 and 21 months, respectively. These impairments are consistent with previous publications, and with a dementia-like phenotype in these mice when aged.
200. Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology
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Yang, Sujeong, Cacquevel, Matthias, Saksida, Lisa M., Bussey, Timothy J., Schneider, Bernard L., Aebischer, Patrick, Melani, Riccardo, Pizzorusso, Tommaso, Fawcett, James W., Spillantini, Maria Grazia, Fawcett, James [0000-0002-7990-4568], Spillantini, Maria [0000-0002-8544-7332], and Apollo - University of Cambridge Repository
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Cerebral Cortex ,Male ,Neuronal Plasticity ,Object recognition TEST ,Chondroitinase ABC ,Microtubule-associated protein ,Regular Article ,Mice, Transgenic ,Memory dementia perineuronal net ,Chondroitin ABC Lyase ,Mice, Inbred C57BL ,Mice ,Tauopathy ,Organ Culture Techniques ,Tauopathies ,Developmental Neuroscience ,Neurology ,Memory ,Animals ,Humans ,Nerve Net ,Injections, Intraventricular - Abstract
Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3 month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1 week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders., Highlights • Progressive tau pathology in the perirhinal cortex impairs object recognition memory. • ChABC treatment improves plasticity and object recognition memory in mice with tau pathology. • The improvement of object recognition memory by ChABC is temporary and related to ChABC expression.
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