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Lecture11_Fortin_4sl - HIPPOCAMPUS II MEMORY PROCESSES WHAT DOES THE HIPPOCAMPUS DO Good question N112A Neuroscience Fundamentals November 2 2011

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Unformatted text preview: HIPPOCAMPUS II - MEMORY PROCESSES WHAT DOES THE HIPPOCAMPUS DO? Good question... N112A: Neuroscience Fundamentals November 2, 2011 OVERVIEW ❖ Why use animals to investigate the role of the hippocampus in learning and memory? ❖ The hippocampus and spatial learning/memory ❖ The hippocampus as a cognitive map ❖ Problems with that theory ❖ The hippocampus and non-spatial learning/memory ❖ So what does the hippocampus do? WHY USE ANIMALS TO INVESTIGATE THE ROLE OF THE HIPPOCAMPUS IN MEMORY? Limitations of memory experiments performed in humans Variability in extent of neurological damage Variability in subjects’ learning history Low spatial and temporal resolution of techniques Advantages of animal models Control extent and timing of brain damage Control information learned before and after brain damage Can use high-precision techniques that are not available in humans WHY USE ANIMALS TO INVESTIGATE THE ROLE OF THE HIPPOCAMPUS IN MEMORY? The brain is very similar across mammalian species, especially the hippocampus Human brain scan Detailed histology of Hippocampus and Medial Temporal Lobes (MTL) Human Rat Chimpanzee WHY USE ANIMALS TO INVESTIGATE THE ROLE OF THE HIPPOCAMPUS IN MEMORY? The brain is very similar across mammalian species, especially the hippocampus Various mammals Human brain scan from Manns & Eichenbaum, 2006 WHY USE ANIMALS TO INVESTIGATE THE ROLE OF THE HIPPOCAMPUS IN MEMORY? Similar pattern of connections between brain structures across mammals OVERVIEW ❖ Why use animals to investigate the role of the hippocampus in learning and memory? ❖ The hippocampus and spatial learning/memory ❖ The hippocampus as a cognitive map ❖ Problems with that theory ❖ The hippocampus and non-spatial learning/memory ❖ So what does the hippocampus do? THE HIPPOCAMPUS AND SPATIAL MEMORY WHY MAZES? Mazes were thought to be an good way to test learning and memory in rats (they live in burrows, use tunnels and paths) a b Figure 2. Complex maze learning (Small, 1901). a, picture of the Hampton Court Palace maze outside London, which served as inspiration (from Google Maps). b, Diagram of one of the maze used by Small (1901). from Fortin, 2008 THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) Theory: The hippocampus builds a faithful map of the environment Experimental evidence: Damage to the hippocampus impairs many spatial tasks “Place cells” in the hippocampus Larger hippocampi in people with advanced navigational capabilities THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) Damage to the hippocampus impairs performance in radial-arm maze in rats a b Radial-arm maze performance Arm baited with food X Arm previously visited X X Figure 4. Radial-arm maze task. a, The maze consists of 8 arms radially extending from a central platform. Before each session, all arms were baited with a food reward and optimal foraging performance would consist of running down the end of each arm only once (Olton and Samuelson, 1976). b, Animals with hippocampal damage were severely impaired in learning the task compared to control groups (McDonald and White, 1993). from Fortin, 2008 THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) Performance of a control animal in the radial-arm maze THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) Performance of a transgenic animal in the radial-arm maze THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) Damage to the hippocampus impairs performance in watermaze in rats a c b Figure 5. Morris watermaze task (Morris, 1981). a, Example swim path of a control rat. b, Example swim path of a rat with damage to the hippocampus. c, Top, performance of rats with hippocampal lesions (filled circles and lines), cortical lesions (filled circle and dashed lines) and normal controls (open circle) in acquiring the watermaze task. Place navigation refers to the condition in which the platform is hidden under the surface, cue navigation refers to a control condition in which the platform is visible to the animals. Bottom, swim path of a control subject on the transfer test in which the platform has been removed, showing a preference for the quadrant where the platform was located, and swim times of the rats in the four different quadrants (Morris et al., 1982). from Fortin, 2008 The Watermaze (Morris, 1981) The most widely used test of memory in rodents THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) A mouse learning the watermaze THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) “Place cells” in the hippocampus Cells firing at high rate when rat is in a specific location in the environment Original report: O’Keefe and Dostrovsky, 1971 THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) “Place cells” in the hippocampus Cells firing at high rate when rat is in a specific location in the environment Firing&rate:& Red&>&yellow&>&green&>&blue& Top view of square environment from O’Keefe and Burgess, 1996 THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) Latest technology: ~ 96-128 electrodes in the hippocampus Recording from > 40 place cells at once THE HIPPOCAMPUS AND SPATIAL MEMORY THE HIPPOCAMPUS AS A COGNITIVE MAP (O’KEEFE & NADEL, 1978) People with advanced navigational capabilities may have larger hippocampi Navigation-related structural change in the hippocampi of taxi drivers Eleanor A. Maguire*†, David G. Gadian‡, Ingrid S. Johnsrude†, Catriona D. Good†, John Ashburner†, Richard S. J. Frackowiak†, and Christopher D. Frith† †Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom; and ‡Radiology and Physics Unit, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom Communicated by Brenda Milner, McGill University, Montreal, Canada, January 28, 2000 (received for review November 10, 1999) Structural MRIs of the brains of humans with extensive navigation experience, licensed London taxi drivers, were analyzed and compared with those of control subjects who did not drive taxis. The posterior hippocampi of taxi drivers were significantly larger relative to those of control subjects. A more anterior hippocampal region was larger in control subjects than in taxi drivers. Hippocampal volume correlated with the amount of time spent as a taxi driver (positively in the posterior and negatively in the anterior hippocampus). These data are in accordance with the idea that the posterior hippocampus stores a spatial representation of the environment and can expand regionally to accommodate elaboration of this representation in people with a high dependence on navigational skills. It seems that there is a capacity for local plastic change in the structure of the healthy adult human brain in response to environmental demands. O ne important role of the hippocampus is to facilitate spatial memory in the form of navigation (1). Increased hippocampal volume relative to brain and body size has been reported in small mammals and birds who engage in behavior requiring spatial memory, such as food storing (2). In some species, hippocampal volumes enlarge specifically during seasons when demand for spatial ability is greatest (2, 3). In the healthy human, structural brain differences between distinct groups of subjects (for example, males and females, ref. 4, or musicians and nonmusicians, ref. 5) have been documented. From existing studies, it is impossible to know whether differences in brain anatomy are predetermined or whether the brain is susceptible to plastic change in response to environmental stimulation. Furthermore, although lesion work (6, 7) and functional neuroimaging work (8) confirm the involvement of the human hippocampus in spatial memory and navigation, there is still debate about its precise role. Given the propensity of lower mammalian avian hippocampi to undergo structural change in response to behavior requiring spatial memory (2, 3), the present study addressed whether morphological changes could be detected in the healthy human brain associated with extensive experience of spatial navigation. Our prediction was that the hippocampus would be the most likely brain region to show changes. Taxi drivers in London must undergo extensive training, learning how to navigate between thousands of places in the city. This training is colloquially known as ‘‘being on The Knowledge’’ and takes about 2 years to acquire on average. To be licensed to operate, it is necessary to pass a very stringent set of police examinations. London taxi drivers are therefore ideally suited for the study of spatial navigation. The use of a group of taxi drivers with a wide range of navigating experience permitted an examination of the direct effect of spatial experience on brain structure. In the first instance, we used voxel-based morphometry (VBM) to examine whether morphological changes associated with navigation experience were detectable anywhere in the healthy human brain. VBM is an objective and automatic procedure that identifies regional differences in relative gray matter density in structural MRI brain scans. It allows every point in the brain to be considered in an unbiased way, with no OVERVIEW a priori regions of interest. The data were also analyzed by using a second and completely independent pixel-counting technique within the hippocampus proper. Comparisons were made between the brain scans of taxi drivers, who had all acquired a significant amount of large-scale spatial information (as evidenced by passing the licensing examinations), and those of a comparable group of control subjects who lacked such extensive navigation exposure. Methods Subjects. Right-handed male licensed London taxi drivers (n 16; mean age 44 years; range 32–62 years) participated. All had been licensed London taxi drivers for more than 1.5 years (mean time as taxi driver 14.3 years; range 1.5–42 years). The average time spent training to be a taxi driver before passing the licensing tests fully (i.e., time on The Knowledge) was 2 years (range 10 months to 3.5 years; some trained continuously, some part time). All of the taxi drivers had healthy general medical, neurological, and psychiatric profiles. The scans of control subjects were selected from the structural MRI scan database at the same unit where the taxi drivers were scanned. Those subjects below 32 and above 62 years of age were excluded as were females, left-handed males, and those with any health problems. After the application of these exclusion criteria, the scans of 50 healthy right-handed males who did not drive taxis were included in the analyses for comparison with the taxi drivers. Both the mean age and the age range did not differ between the taxi driver and control groups. We were also careful to ensure an even spread of subjects in each decade (for example, 41–50 years or 51–60 years) up to the upper limit of the oldest taxi driver, such that subjects were not clustered at one end of the age scale. Image Acquisition. Structural MRI scans were obtained with a 2.0 Tesla Vision system (Siemens GmbH, Erlangen, Germany) by using a T1-weighted three-dimensional gradient echo sequence (TR 9.7 ms; TE 4 ms; flip angle 12°; field of view 256 mm; 108 partitions; partition thickness 1.5 mm; voxel size 1 1 1.5 mm). Image Analysis Method 1: VBM. Data were analyzed by using VBM implemented with Statistical Parametric Mapping (SPM99, Wellcome Department of Cognitive Neurology) executed in MATLAB (Mathworks, Sherborn, MA). Detailed descriptions of the technique are given elsewhere (9, 10). Briefly, the subjects’ data were spatially normalized into stereotactic space (11) by registering each of the images to the same template image by minimizing the residual sums of squared differences between them. The template ❖ Why use animals to investigate the role of the hippocampus in learning and memory? ❖ The hippocampus and spatial learning/memory Abbreviations: VBM, voxel-based morphometry; ICV, intracranial volume. *To whom reprint requests should be addressed. E-mail: e.maguire@fil.ion.ucl.ac.uk. ❖ The hippocampus as a cognitive map ❖ Problems with that theory 4398 – 4403 PNAS April 11, 2000 vol. 97 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073 pnas.070039597. Article and publication date are at www.pnas.org cgi doi 10.1073 pnas.070039597 no. 8 ❖ The hippocampus and non-spatial learning/memory ❖ So what does the hippocampus do? REPORTS THE HIPPOCAMPUS AND SPATIAL MEMORY ing bath solution, which were neClamp 500 amplifier (Axon City, CA) interfaced with a water at 0°C, which was addchamber at the end of each d the expected large depolarCa2 and Cl channels [B. D. mann, R. W. Davis, E. P. Spal114, 1327 (1997)], a test of ent. Leigh, A. J. Miller, Proc. Natl. , 10510 (1996). between an inserted electrode ermits a depolarizing current to and M. H. M. Goldsmith, Planta effect of which may be to un0 to 50 mV [W. Gassmann and nt Physiol. 105, 1399 (1994)]. agnitude would shift each of ts, the most positive of which lues more negative than 230 to pH 5.7 with CaOH. Roots were incubated for 10 25. Supported by the Department of Energy (DOE)/NSF/ containing 4 COGNITIVE USDA Collaborative Research Biology PROBLEMS min, in DSmM Rb( Rb)ClmM NH Clwashed two times MAP THEORY to in Plant from the ProWITH THE and then and 10 M, 100 M or 1 gram (BIR-9220331), funds R.E.H. NIH 86 4 for 10 min each in ice-cold DS. Radioactivity was measured by detection of Cerenkov radiation. 23. J. I. Schroeder, J. M. Ward, W. Gassmann, Annu. Rev. Biophys. Biomol. Struct. 23, 441 (1994); W. Gassmann, J. M. Ward, J. I. Schroeder, Plant Cell 5, 1491 (1993). 24. Y. Cao, A. D. M. Glass, N. M. Crawford, Plant Physiol. 102, 983 (1993); F. R. Vale, W. A. Jackson, R. J. Volk, ibid. 84, 1416 (1987); F. R. Vale, R. J. Volk, W. A. Jackson, Planta 173, 424 (1988). University of Wisconsin Cellular and Molecular Biology Training Grant (GM07215), to M.R.S. from DOE (DEFG02-88ER13938) and NSF (DCB-90-04068), and to E.P.S. from the NASA/NSF Network for Research on Plant Sensory Systems (IBN-9416016). We thank T. Janczewski and R. Meister for technical assistance and P. Krysan, W. Robertson, J. Satterlee, and J. Young for helpful comments on the manuscript. Many other brain regions are involved in processing spatial info e.g., fMRI studies in humans navigating a virtual environment Knowing Where and Getting There: A Human Navigation Network Eleanor A. Maguire,* Neil Burgess, James G. Donnett, Richard S. J. Frackowiak, Christopher D. Frith, John O’Keefe The neural basis of navigation by humans was investigated with functional neuroimaging of brain activity during navigation in a familiar, yet complex virtual reality town. Activation of the right hippocampus was strongly associated with knowing accurately where places were located and navigating accurately between them. Getting to those places quickly was strongly associated with activation of the right caudate nucleus. These two right-side brain structures function in the context of associated activity in right inferior parietal and bilateral medial parietal regions that support egocentric movement through the virtual town, and activity in other left-side regions (hippocampus, frontal cortex) probably involved in nonspatial aspects of navigation. These findings outline a network of brain areas that support navigation in humans and link the functions of these regions to physiological observations in other mammals. Where am I? Where are other places in the environment? How do I get there? Questions such as these reflect the essential .sciencemag.org on May 13, 2011 rtically on Petri plates contain1 mM KCl, and 1 mM CaCl2 in 4 to 5 days. Root protoplasts utting the root about 150 m cromanipulator-mounted razor. ere infiltrated with an enzyme Cellulysin (12 mg/ml) (Calbiomg/ml) (Sigma), and bovine sel) (Sigma) dissolved in 10 mM M MES, and 300 mM sorbitol -bis[tris(hydroxymethyl)methyl)} using a vacuum produced by fter 2 hours of incubation, the d in the solution without ent 4°C or placed in a 500- l ontaining 10 mM CaCl2, 30 mM nd 120 to180 mM sorbitol (pH oplasts of nonepidermal cells t end of the otherwise undigesttes were filled with 130 mM KTA, 5 mM Hepes, and 4 mM sphate (Mg-ATP) (pH 7.0 with quipment and procedures were Cho and E. P. Spalding Proc. . 93, 8134 (1996)]. Our proce- 26 November 1997; accepted 27 March 1998 poral context (3, 6). By contrast, the role of the hippocampus in human navigation has remained controversial, and the wider neu- Author's personal copy Navigation and Episodic-Like THE HIPPOCAMPUS AND Memory in Mammals 393 SPATIAL MEMORY PROBLEMS WITH THE COGNITIVE MAP THEORY 978) original description. they were shown to scale their size to reflect changes in the size of the environment (Muller and Kubie, map is a two-dimensional 1987; O’Keefe and Burgess, 1996). Third, once estabhe environment, in that it Examples oflished, the spatial representation of a specific virtual reality mazes used in human studies ations of distances and environment coded by place cell is stable over long nt stimuli (See Chapters periods of time (at least 5 months; Thompson and Best, 1990). cells in the hippocampus At the conceptual level, a place cell is thought to vidence supporting the construct the notion of a place in the environment by hippocampus. 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Each place cell is hypothesized existence to represent the position ofto represent the position of the rat at hypothesized the rat at ce field (Figure 6(a)). Their existence called the place field (Figure 6(a)). 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In addition to cue in the environment. requires other brain systems as well. In addition to requires environment. For instance, place cell place THE HIPPOCAMPUS is role of sensory systems theprocess and represent to process and represent cell firing is maintained even iffiring AND SPATIAL to role of sensory systems the maintained even if MEMORY individual distal THE COGNITIVE MAP cues andenvironmental stimuli, and the involvement of the tal cues are removed, orWITHcuescuesremoved, or if all distalTHEORY involvement of the environmental stimuli, the PROBLEMS if all distal are are field rotates with the prefrontal cortex in providing executive control of a unit (the place rotated as a unit (the place field rotates with the prefrontal cortex in providing executive control of cues; O’Keefe and Best, 1978; Miller and and response selection and planning through interactions and Conway, 1978; Miller and Conway, response selection Best,planning through interactions are involved in with cortico-striatal loops 1980; Hill and Best, cells d Best, Many other brain regionswith cortico-striatal loops (e.g., De Bruin spatial info De Bruin et al., 1994; 1981). Second, many place 1981). Second, many place cells processing et al., 1994; (e.g., Alexander et ), number reflect the overall topographyAlexander et al., 1986;as of the environment, Dunnett et al., 2005al.,a1986; Dunnett et al., 2005), a number erall topography of the environment, as e.g., “Grid cells” are found in a subregion of the entorhinal cortex, but not the hippocampus (b) (b) 60 Firing rate (spikes/s) Firing rate (spikes/s) (a) 40 20 0 0 60 (c) (c) 60 40 20 0 120 180 240 0300 60 360 120 180 240 300 Head direction (deg) Head direction (deg) 360 “Place Neurons with spatial firing properties. (a) showing ancell” ininentorhinal cortex rons with spatialFigure 6 cell” (a) Place cell: Hippocampal neuron Place cell: Hippocampal neuron showing an increase in firing rate whenever firing properties. in hippocampus “Grid increase firing rate whenever the animal enters the North-West corner of an open-field environment. Adapted from O’Keefe J and Burgess N (1996) rs the North-West corner of an open-field environment. Adapted from O’Keefe J and Burgess N (1996) Geometric determinants of the place Nature 381(6581): 425–428, with permission from 425–428, with permission from rminants of the place fields of hippocampal neurons. fields of hippocampal neurons. Nature 381(6581): Macmillan Publishers Ltd. lishers Ltd. (b) Head-directioncells” are(b) Head-direction cell: Postsubicular whenever the animal’s head is whenever the animal’s head is “Grid cell: Postsubicular neuron increasing its firing rate neuron increasing info rate much less influenced by non-spatial its firing lar direction (60 facing a particular direction (60 degrees). Taken from Taube JS (2007) The head direction signal: Origins and sensory-motor degrees). Taken from Taube JS (2007) The head direction signal: Origins and sensory-motor integration. Annu. Rev. Neurosci. that “place cells” 30: 181–207, with permission from the Annual Review u. Rev. Neurosci. 30: 181–207, with permission from the Annual Review of Neuroscience. (c) Grid cell: of Neuroscience. (c) Grid cell: Dorsocaudal exhibiting multiple spatial firing exhibiting multiple spatial firing fields arranged in a edial entorhinal cortex neuron medial entorhinal cortex neuronfields arranged in a hexagonal grid in an open field. hexagonal grid in an open field. Taken from Hafting T, Fyhn M, Molden S, Microstructure Moser EI (2005) in the entorhinal fting T, Fyhn M, Molden S, Moser MB, and Moser EI (2005)Moser MB, and of a spatial map Microstructure of a spatial map in the entorhinal THE HIPPOCAMPUS AND SPATIAL MEMORY PROBLEMS WITH THE COGNITIVE MAP THEORY But the biggest problems for the theory are that: Damage to the hippocampus impairs non-spatial memory tasks Hippocampal cells code non-spatial information as well We’ll talk about a few of those examples now OVERVIEW ❖ Why use animals to investigate the role of the hippocampus in learning and memory? ❖ The hippocampus and spatial learning/memory ❖ The hippocampus as a cognitive map ❖ Problems with that theory ❖ The hippocampus and non-spatial learning/memory ❖ So what does the hippocampus do? THE HIPPOCAMPUS AND NON-SPATIAL MEMORY FLEXIBILITY OF EXPRESSION OF NON-SPATIAL REPRESENTATIONS Hippocampal damage impairs “flexibility of expression” of non-spatial memory representations (“~non-spatial maps”) But the biggest problems for the theory are that: Damage to the hippocampus impairs non-spatial memory tasks Hippocampal cells code non-spatial information as well 7112 7112 Psychology: Dusek and Eichenbaum Psychology: Dusek and Eichenbaum Proc. Natl. Acad. Sci. USA 94 (1997) Proc. Natl. Acad. Sci. USA 94 (1997) Bunsey & Eichenbaum (1996) FIG. 2. ( A ) The mean number of trials required to reach the criterion for each phase of premise training. Error bars represent SE above the mean. ( B ) Mean each phase of premise training. Error bars represent SE above the FIG. 2. ( A ) The mean number of trials required to reach the criterion for response accuracy ( SE) on each of the four premise pairs during the test sessions. mean. ( B ) Mean response accuracy ( SE) on each of the four premise pairs during the test sessions. across both pairs, performance did notUSA above chance levels hoc Psychology: Dusek and Eichenbaum Proc. Natl. Acad. Sci. performance 7112 comparisons indicated and Eichenbaum 94 (1997) was Psychology: Dusek that control USA Proc. Natl. Acad. Sci. rise 94 (1997) better than that of both the PRER (P ⌅ 0.01) and rise above chance levels subjects (P ⇥ 0.10) or FX rats (P ⇥ 0.10). PRER in control across both pairs, performance did not FX (P ⌅ hoc comparisons indicated that control performance was 0.01) ⌅ subjects better than that of both the PRER (P ⌅ 0.01) and FX (P groups, which did not significantly 0.10) or FXeach other 0.10). PRER performed significantly [t(5) ⇤ 2.988; P ⌅ 0.05], albeit in control subjects (P ⇥ differ from rats (P ⇥ (P ⇥ 0.10). slightly, 0.01) groups, which did not significantly differ from each other In addition,performed significantly [t(5) ⇤ 2.988; P ⌅ 0.05], albeit better than chance (Fig. 3B). ANOVA confirmed that subjects by contrast to the performance of other there were no significant group differences on new probe (P ⇥ 0.10). In addition, by contrast to the performance FX subjects, the two better than chance from 3B). ANOVA confirmed that of other slightly, subjects removed (Fig. the FX group because performance [F(2, 15) ⇤ 0.221; P ⇥ 0.10]. Furthermore, FX subjects, the two subjects removed from the FX group of ineffective lesions significant group differencesof new probe there were no performed within the range on control controls because of ineffective lesions performed within the range ofperformance on BD[F(2,and 80%0.221; P ⇥ 0.10]. Furthermore, performed significantly better on BD trials than on performance (70 15) ⇤ correct). A further analysis of performed significantly better on BD trials new odor pairs [t(7) ⇤ 3.529; P ⌅ 0.01] whereas PRER and FX control performance on BD (70 and 80% correct). controls transitivity examined performance on than on the on presentation [t the 3.529; P ⌅ 0.01] may be A further analysis of transitivity examined performancevery first new odor pairs of(7) ⇤ BD pair, whichwhereas PRERrats did not (Ps ⇥ 0.10). The contrast between robust perforand FX the very first presentation of the BD pair, which considered a ‘‘pure’’ test ofPs ⇥ 0.10). responding uncontam-robustmance on BD over new odor pairs in control rats strongly may be rats did not ( inferential The contrast between perforinated by considered a ‘‘pure’’ test of inferential responding uncontam- reinforcement on repeated probe trials. Of control rats indicates that their judgments on the BD pairs reflected mance on BD over new odor pairs in control strongly choose that their the first BD presentation inferential inated by reinforcement on repeated probe trials. Ofsubjects, 88% indicatescorrectly on judgments on the BD pairs reflected capacity. Conversely, the absence of a significant control (binomial 0.05) whereas only Conversely, the absence of difference subjects, 88% choose correctly on the first BD presentation P ⌅inferential capacity. 50% of the FX and PRER a significant on this comparison, combined with intact perforsubjects (binomial P ⌅ 0.05) whereas only 50% of the FX and PRER were successful on the initial BD judgment (binomial intactmance on the AE pair, emphasizes the selective loss of the difference on this comparison, combined with perforP ⇥ 0.10). capacity subjects were successful on the initial BD judgment (binomial mance on the AE pair, emphasizes the selective loss of the for transitive inference in FX and PRER rats. Analyses ofcapacity for transitive inference of probe trials performance on other types in FX and PRER rats. P ⇥ 0.10). demonstrated the selectivity of the deficit in transitive inferAnalyses of performance on other types of probe trials DISCUSSION ence in demonstrated the selectivity of the deficit in transitive infer- rats with hippocampal region damage. All rats perDISCUSSION Previous studies have demonstrated that several animal speformed ence in rats with hippocampal region damage. All rats per- extremely well on the AE trials, which can be solved cies can without Previous studies (Fig. 3B), and there was no formed extremely well on the AE trials, which can be solved a transitive judgment have demonstrated that several animal spe-learn an overlapping series of discrimination problems and demonstrate a capacity for transitive inference (15, 26– cies can ishin in up without a transitive judgment (Fig. 3B), and there significant6groupedifferenceanroverlapping series this problem was © 199 Natur Publlearng G operformance on of discrimination problems no FIG. 2. ( A ) The mean number of trials required to reach the criterionIG. 2. ( Aphase of⇤ 0.595;training. Error bars represent the criterion for each phase of premise training. Error bars represent SEregion the F for each (2, 15) premise P of above as [ANOVA: F) The mean number ⇥ trials required to reach groups the 32). The present results Conversely, all SE above and demonstrate ( capacity for transitive premise pairs during significant group difference in performance on this problem ) Mean response accuracy a 0.10]. on each of the four inference (15, 26– the test sessions. identify the hippocampal mean. ( B ) Mean response accuracy ( SE) on each of the four premise pairsBduring the test sessions. mean. ( SE) showed critical to 32). The present results identify the hippocampal region as transitive inference and indicate that the hippocam[ANOVA: F(2, 15) ⇤ 0.595; P ⇥ 0.10]. Conversely, all groups minimal evidence of learning during presentations of © 1996 Nature Publishing Group pus plays showed minimal evidence of learning during presentationscomparisons indicated that inference performance that levels across both pairs, performance did not rise or flexible expresof critical to transitive control and performance hoc comparisons indicated that control performance was the new odor pairs (WX and YZ). Combining theabove chance the hippocam- a critical role in the developmentabove chance levels hoc across both pairs, performance did not rise indicate was the new odor pairs (WX and YZ). 0.01) and FX P ⌅ better than that of both the⇥ 0.10) ( in⌅ rats and FX (P PRER in control subjects (P ⇥ 0.10) or FX rats (P ⇥ 0.10). PRER pus plays P PRER or the development or flexible expresbetter than that of both the PRER (P ⌅ Combining the(performance control subjectsa(critical role P FX0.01) (P ⇥ 0.10). ⌅ in 0.01) groups, which did not significantly differ from each other 0.01) subjects which did not significantly(5) ⇤ 2.988; each0.05], albeit subjects performed significantly [t(5) ⇤ 2.988; P ⌅ 0.05], albeit groups, performed significantly [t differ from P ⌅ other (P ⇥ 0.10). In addition, by contrast to the performance of other (P ⇥ 0.10). In better than chance (Fig. 3Bperformance of other that slightly, better than chance (Fig. 3B). ANOVA confirmed that slightly, addition, by contrast to the ). ANOVA confirmed FX subjects, the two subjects removed from the FX group FX subjects, the no significantremoveddifferences FX groupprobe there were no significant group differences on new probe there were two subjects group from the on new because of ineffective lesions performed within the range of because of ineffective(2, 15) ⇤ 0.221; Pwithin the range of performance [F lesions performed ⇥ 0.10]. Furthermore, performance [F(2, 15) ⇤ 0.221; P ⇥ 0.10]. Furthermore, control performance on BD (70 and 80% correct). control performance on BD (70 and 80% correct). trials than on controls performed significantly better on BD trials than on controls performed significantly better on BD A further analysis of transitivity examined performance on A further analysis [of transitivityPexamined performance on FX new odor pairs [t(7) ⇤ 3.529; P ⌅ 0.01] whereas PRER and FX new odor pairs t(7) ⇤ 3.529; ⌅ 0.01] whereas PRER and the very first presentation of the BD pair, which may be the very did not (Ps ⇥ 0.10). The contrast between robustbe rats first presentation of the BD pair, which may perfor- rats did not (Ps ⇥ 0.10). The contrast between robust perforconsidered a ‘‘pure’’ test of inferential responding uncontam- considered a on BD test of inferential responding uncontammance ‘‘pure’’ over new odor pairs in control rats strongly mance on BD over new odor pairs in control rats strongly inated by reinforcement on repeated probe trials. Of control inated by reinforcement on repeated probe trials. Of control indicates that their judgments on the BD pairs reflected indicates that their judgments on the BD pairs reflected subjects, 88% choose correctly on the first BD presentation subjects, 88% choose correctly on thethe absence of a significant inferential capacity. Conversely, the absence of a significant inferential capacity. Conversely, first BD presentation (binomial P ⌅ 0.05) whereas only 50% of the FX and PRER (binomial P ⌅ 0.05)this comparison, combined with intact perfor- difference on this comparison, combined with intact perfordifference on whereas only 50% of the FX and PRER subjects were successful on the initial BD judgment (binomial subjects wereon the AE on theemphasizes judgment (binomial the mance on the AE pair, emphasizes the selective loss of the mance successful pair, initial BD the selective loss of P ⇥ 0.10). P ⇥ 0.10). capacity for transitive inference in FX and PRER rats. capacity for transitive inference in FX and PRER rats. Analyses of performance on other types of probe trials Analyses of performance on other types of probe trials demonstrated the selectivity of the deficit in transitive infer- demonstrated the selectivity of the deficit in transitive inferDISCUSSION DISCUSSION ence in rats with hippocampal region damage. All rats per- ence in rats with hippocampal region damage. All rats perPrevious studies on the AE trials, which can be solved formed extremely well on the AE trials, which can be solved formed extremely wellhave demonstrated that several animal spe- Previous studies have demonstrated that several animal species transitive overlapping series ), and there was no without a transitive judgment (Fig. 3B), and there was no without acan learn anjudgment (Fig. 3Bof discrimination problems cies can learn an overlapping series of discrimination problems and group difference in performance on this problem significant group difference in performance on this problem significantdemonstrate a capacity for transitive inference (15, 26– and demonstrate a capacity for transitive inference (15, 26– hippocampal region as [ANOVA: F(2, 15) ⇤ 0.595; P ⇥ 0.10]. Conversely, all groups [ANOVA:The present0.595;accuracy (⇧SE) for the average performance32).premise pairs BC and CD and for the critical test pair BD during F(2, 15) ⇤ results identify the hippocampal region as on The present results identify FIG.32). ( A ) Mean response P ⇥ 0.10]. Conversely, all groups 3. the test minimal Response accuracy ( CD and presentations pair AE critical to showed minimal evidence ofresponse accuracy (presentations of showedsessions. onevidencepairs BC and ⇧SE) forfor thatcritical test pair BD during transitive inference and the new control pairs (WX and critical to transitive of learning during control probe of FIG. 3. ( A ) Mean learning during ⇧SE) for the average performance ( B )premise inference and indicate the the hippocam-and the average response accuracy for indicate that the hippocamYZ). pair AE and the average in the development or flexible expres- pus and the test sessions. ( B ) YZ). Combining (⇧ performance the new odor pairs (WX roleYZ). Combining the performance the new odor pairs (WX and Response accuracy theSE) for control probe pus plays a critical and response accuracy for the new control pairs (WXplays a critical role in the development or flexible expres- 7112 THE HIPPOCAMPUS AND NON-SPATIAL MEMORY MEMORY FOR RELATIONSHIPS AMONG NON-SPATIAL ITEMS Hippocampal damage impairs “transitive inference” in non-spatial representations (analogous to thinking of a new trajectory between 2 locations) 7110 Psychology: Dusek and Eichenbaum Hippocampal rats can learn set of overlapping pairs of odors as well as Eichenbaum 7110 Psychology: Dusek and tests Table 1. Stages of training and probecontrols © 1996 Nature Publishing Group Table 1. Hipocampal rats cannot express the “hidden” Proc. Natl. Acad. Sci. USA 94 (1997) relationship among the 5 items Proc. Natl. Acad. Sci. USA 94 (1997) were combined in the analyses below and they were designated as the control group. Premise pair training Stages of training and probe tests were combined in the analyses below and they were rats were Apparatus and Shaping. During initial shaping, designated A B as the with a group. providedcontrol 4-oz Nalgene plastic cup (6.4 cm high ⇥ 6.2 cm Premise pair training B C Apparatus and Shaping. of sand and shaping, onto a diameter) filled with 110 g During initial mounted rats were A BC D provided with a ⇥ 3.5 in). A plastic baited with high ⇥ food Plexiglas base (6.54-oz Nalgenecup was cup (6.4 cm several 6.2 cm B CD E diameter) filled with 110 g of sand and mounted were rewards (Froot Loops, Kellogg’s, Battle Creek, MI) that onto a C D Ordered representation Plexiglas base in and on top of the sand, placed several food partially buried (6.5 ⇥ 3.5 in). A cup was baited within one end A B C “hidden” relationshipDD E E items among Both groups can expressrat’s a simpler relationship removed whenMI) rewards ofrewards (Froot Loops, and then Battle Creek, no that were the the home cage, Kellogg’s, Ordered Probe testsrepresentationYZ). in a control conditionin and on subjects were presented in one end partially buried were visible. Subsequently, top of the sand, placed with unB A D: testC transitivity vs. B of D E of the rat’s home cage, and then removed when base, and scented sand in two cups mounted onto the Plexiglas no rewards Probe E: nontransitive novel pairing tests A vs. were visible. Subsequently, rewards. Pretraining continued only one cup contained food subjects were presented with unB vs. D: test of transitivity scented sand in two cups mounted onto the Plexiglas base, and with a simple odor discrimination task in which the discrimiA vs. E: nontransitive novel pairing no memory deficit whereas severe memory deficits are observed when the damage includes the cortical regions adjacent tono memory deficit whereas severe memory deficits are obthe hippocampus in both rats (16, 17) and monkeys (18–20). served when have led some to suggest that the hippocampus These findings the damage includes the cortical regions adjacent to the hippocampus in bothunimportant role in memory (20) rats itself plays & Eichenbaum (1998) (16, 17) and monkeys (18–20). Dusek either a relatively orThese findingsto spatial memory suggestwhereas the adjacent a role limited have led some to (6, 10) that the hippocampus itself plays either a relatively a broader role, in memory (20) parahippocampal cortex plays unimportant roleincluding non- only one cup contained food rewards. Pretraining into the native stimuli consisted of common food spices mixedcontinued with a each of two discrimination task in which the discrimisand. Onsimple odor 10-trial sessions, subjects were presented native cups consisted of common food spices mixed into the with twostimuliof sand; one containing celery was baited with a sand. On each reward, and the other containing thyme was single buried of two 10-trial sessions, subjects were presented with two cups of response was defined as the first cup in unbaited. A choicesand; one containing celery was baited with a single buried reward, and the other rat was permitted was which a subject began to dig although the containing thyme to unbaited. A choice response was defined as the first cup in FIG. 3. ( A ) Mean response accuracy (⇧SE) for the average performance 3. premise pairs BC and CD and (for thefor the average performance on premise pairs BC and CD and for the critical test pair BD during FIG. on ( A ) Mean response accuracy ⇧SE) critical test pair BD during the test sessions. ( B ) Response accuracy (⇧SE) for control probe pairthe test sessions. ( B ) Response accuracy for SE) newcontrol probe (WXAE and the average response accuracy for the new control pairs (WX and AE and the average response accuracy (⇧ the for control pairs pair and YZ). YZ). WHAT ARE THESE CELLS CODING FOR? •  Damage'to'the'hippocampus'leads'to'deficits'in'non4spatial' paradigms'as'well' •  Transitive'inference'(Dusek'and'Eichenbaum,'1997)' •  Neurons'in'the'hippocampus'code'for'more'than'spatial'location' •  “Splitter'cells"'in'T4maze'alternation'task'(e.g.,'Wood'et'al.,'2000)' •  “Odor'cells”,'“match/non4match'cells”,…'(e.g.,'Wood'et'al.,'1999)' •  Neurons'in'other'structures'show'spatial'coding'as'well' Wood et al (2000) THE HIPPOCAMPUS AND NON-SPATIAL MEMORY HIPPOCAMPAL CELLS ENCODE MORE THAN JUST SPATIAL INFO •  Damage'to'the'hippocampus'leads'to'deficits'in'non4spatial' paradigms'as'well' •  Transitive'inference'(Dusek'and'Eichenbaum,'1997)' •  Neurons'in'the'hippocampus'code'for'more'than'spatial'location' •  “Splitter'cells"'in'T4maze'alternation'task'(e.g.,'Wood'et'al.,'2000)' •  “Odor'cells”,'“match/non4match'cells”,…'(e.g.,'Wood'et'al.,'1999)' •  Neurons'in'other'structures'show'spatial'coding'as'well' Wood et al (2000) THE HIPPOCAMPUS AND NON-SPATIAL MEMORY HIPPOCAMPAL CELLS ENCODE MORE THAN JUST SPATIAL INFO Hippocampal cells also code for non-spatial info in a non-spatial task (Task: “Does current odor match the odor from the last trial?”) d(hippocampal(neurons( s(perform(a(match/non5 (judgment(at(different( ons(in(an(environment( ll (( Place(cell( Place cells Match/nonmatch(cell( Approach cells Approach(cell( Odor cells •  Damage'to'the'hippocampus'leads'to'deficits'in'non4spatial' paradigms'as'well' Match/nonmatch cells •  Transitive'inference'(Dusek'and'Eichenbaum,'1997)' •  Neurons'in'the'hippocampus'code'for'more'than'spatial'location' •  “Splitter'cells"'in'T4maze'alternation'task'(e.g.,'Wood'et'al.,'2000)' •  “Odor'cells”,'“match/non4match'cells”,…'(e.g.,'Wood'et'al.,'1999)' •  Neurons'in'other'structures'show'spatial'coding'as'well' enko,(and(Eichenbaum,(1999( Wood et al (1999) THE HIPPOCAMPUS AND NON-SPATIAL MEMORY HIPPOCAMPAL CELLS ENCODE MORE THAN JUST SPATIAL INFO Recording single neurons in humans subjects (very rare!) Individual neurons coding for specific experiences (more on that next lecture) OVERVIEW ❖ Why use animals to investigate the role of the hippocampus in learning and memory? ❖ The hippocampus and spatial learning/memory ❖ The hippocampus as a cognitive map ❖ Problems with that theory ❖ The hippocampus and non-spatial learning/memory ❖ So what does the hippocampus do? SO WHAT DOES THE HIPPOCAMPUS DO? PUTTING IT ALL TOGETHER: THE “RELATIONAL MEMORY THEORY” The hippocampus is important for creating a “relational network”, in which spatial and non-spatial info is encoded and can be flexibly expressed The hippocampus encodes relations among spatial stimuli The hippocampus encodes relations among non-spatial stimuli It’s a “memory space”, not memory for space! ...
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This note was uploaded on 12/13/2011 for the course BIOSCI 93 taught by Professor Staff during the Fall '11 term at UC Irvine.

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