@prefix vivo: . @prefix edm: . @prefix ns0: . @prefix dcterms: . @prefix dc: . @prefix skos: . vivo:departmentOrSchool "Arts, Faculty of"@en, "Psychology, Department of"@en ; edm:dataProvider "DSpace"@en ; ns0:degreeCampus "UBCV"@en ; dcterms:creator "Seamans, Jeremy Keith"@en ; dcterms:issued "2008-08-20T23:19:11Z"@en, "1993"@en ; vivo:relatedDegree "Master of Arts - MA"@en ; ns0:degreeGrantor "University of British Columbia"@en ; dcterms:description "Anatomical studies have identified major efferent pathways from the hippocampus to the nucleus accumbens (N.Acc.), but the functional significance of this interaction remains unclear. The delayed spatial win-shift radial arm maze task has been used as a selective behavioral measure of damage to the hippocampal system, whereas the cued win-stay version of this task is unaffected by hippocampal lesions, but is disrupted by lesions in the dorsal striatum. The present study utilized these two procedures, along with reversible lidocaine-induced lesions of the N.Acc., to determine whether the N.Acc. is part of the extra-hippocampal system that subserves efficient memory-based foraging behavior. These lesions impaired performance on the spatial win-shift but not the cued win-stay task. Pre-training lesions on the spatial win-shift task did not affect foraging for four pellets during either the training or test phases of the experiment. In contrast, lidocaine-induced lesions, given prior to the test-phase, significantly disrupted retrieval of four pellets on the 8-arm maze. Comparable deficits also were observed in animals trained to forage efficiently for four pellets on an 8-arm maze, without prior win-shift experience. State-dependent drug effects were ruled out by replicating the disruptive effects of lidocaine-infusions into the N.Acc. on spatial win-shift performance in animals receiving this treatment prior to both training and test phases. Collectively, these results indicate that the N.Acc. interacts with the hippocampus in guiding spatial win-shift behavior by allowing information about previously visited spatial locations to influence foraging in a complex radial arm maze environment."@en ; edm:aggregatedCHO "https://circle.library.ubc.ca/rest/handle/2429/1446?expand=metadata"@en ; dcterms:extent "3443278 bytes"@en ; dc:format "application/pdf"@en ; skos:note "SELECTIVE MEMORY IMPAIRMENTS PRODUCED BY TRANSIENT LIDOCAINE-INDUCED LESIONS OF THE NUCLEUS ACCUMBENS.byJEREMY KEITH SEAMANSB.Sc., McGill University, 1991.A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF ARTSinTHE FACULTY OF GRADUATE STUDIES(DEPARTMENT OF PSYCHOLOGY)We accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIAAUGUST 1993© JEREMY KEITH SEAMANS, 1993In presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature)Department of P-5 t/t o (ool The University of British ColumbiaVancouver, CanadaDate 8V,27/ 3DE-6 (2/88)AbstractAnatomical studies have identified major efferent pathways from thehippocampus to the nucleus accumbens (N.Acc.), but the functional significance ofthis interaction remains unclear. The delayed spatial win-shift radial arm maze taskhas been used as a selective behavioral measure of damage to the hippocampalsystem, whereas the cued win-stay version of this task is unaffected byhippocampal lesions, but is disrupted by lesions in the dorsal striatum. The presentstudy utilized these two procedures, along with reversible lidocaine-induced lesionsof the N.Acc. , to determine whether the N.Acc. is part of the extra-hippocampalsystem that subserves efficient memory-based foraging behavior. These lesionsimpaired performance on the spatial win-shift but not the cued win-stay task. Pre-training lesions on the spatial win-shift task did not affect foraging for four pelletsduring either the training or test phases of the experiment. In contrast, lidocaine-induced lesions, given prior to the test-phase, significantly disrupted retrieval of fourpellets on the 8-arm maze. Comparable deficits also were observed in animalstrained to forage efficiently for four pellets on an 8-arm maze, without prior win-shiftexperience. State-dependent drug effects were ruled out by replicating thedisruptive effects of lidocaine-infusions into the N.Acc. on spatial win-shiftperformance in animals receiving this treatment prior to both training and testphases. Collectively, these results indicate that the N.Acc. interacts with thehippocampus in guiding spatial win-shift behavior by allowing information aboutpreviously visited spatial locations to influence foraging in a complex radial armmaze environment.iiTable of ContentsAbstract^ iiList of Tables vList of Figures^ viAcknowledgements ixIntroduction^ 1General Methods 13Experiment 1: The Effects of Intra-N.Acc. Lidocaine Infusions onSpatial Win-Shift and Cued Win-Stay Behavior^ 16Methods^ 17Results 19Discussion^ 26Experiment 2: The Effects of Pre-Training and Pre-Test Intra-N.Acc.Lidocaine Infusions on Spatial Win-Shift Behavior^ 29Methods^ 29Results 31Discussion^ 47Experiment 3: The Effects of Intra-N.Acc. Lidocaine Infusions onRandom Foraging Behavior^ 49Methods^ 49Results 50Discussion^ 60iiiExperiment 4: The Effects of Combined Pre-Training and Pre-TestIntra-N.Acc. Lidocaine Injections on Spatial Win-Shift Behavior:A Test for State Dependency^ 62Methods^ 62Results 63Discussion^ 73The Effects of Intra-N.Acc. Lidocaine Infusions on Locomotor Behavior^74General Discussion^ 77References^ 87ivList of TablesTable 1 Mean latency to approach a food well for tasks on which the lidocainegroup made numerous errors (left column) versus tasks which the lidocaine groupmade no more errors than controls (right column). The left column shows the meanapproach latency for the lidocaine (top) and saline (bottom) groups during the testphase of the spatial win-shift task in Experiment 1 and Experiment 2b and therandom foraging task (Experiment 3). The right column shows the mean approachlatency for the lidocaine (top) and saline (bottom) groups during the training phaseof Experiment 2a and the cued win-stay task of Experiment 1. 2. denotessignificance at p<0.05. Standard errors are shown inbrackets^ 76viList of FiguresFigure 1.1 Mean number of visits to baited arms expressed as a percentage of thetotal number of all arm visits, the day prior to the injection (white) and the day of theinjection (black) for the lidocaine and saline groups during the test phase of thespatial win-shift task in Experiment 1. .- denotes statistical significance at p<0.01.Standard errors are represented by vertical bars^ 21Figure 1.2 Mean number of visits to lit arms expressed as a percentage of all armvisits, the day prior to the injection (white) and the day of the injection (black) for thelidocaine and saline groups during the cued-win-stay task of Experiment 1.Standard errors are represented by vertical bars^ 23Figure 1.3 Schematic representation of the infusion sites for all subjects included inExperiment 1. Black dots represent the location of the cannulae tips. Infusionsspread approximately 0.5mm from the cannulae tips (see text). Illustrated brainsections are computer generated adaptations of plates found in Paxinos andWatson (1982). Histological abbreviations, N.Acc.=nucleus accumbens, cc=corpuscallosum, ac=anterior commisure, CPu=caudate putamen^ 25Figure 2.1 Mean number of visits to baited arms expressed as a percentage of thetotal number of all arm visits, the day prior to the injection (white) and the day of theinjection (black) for the lidocaine and saline groups during the training phase andtest phase of Experiment 2a. Standard errors are represented by verticalbars^ 34Figure 2.2 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during the training phase ofExperiment 2a, on the day of the injection. Standard errors are represented byvertical bars^ 36Figure 2.3 Mean number of visits to baited arms expressed as a percentage of thetotal number of all arm visits, the day prior to the injection (white) and the day of theinjection (black) for the lidocaine and saline groups during the test phase ofExperiment 2b. .* denotes statistical significance at p<0.01. Standard errors arerepresented by vertical bars^ 38Figure 2.4 Mean number of across-delay (hatched) and within-trial (shaded) errorsmade by the lidocaine and saline groups during the test phase of Experiment 2b theday of the injection (see text for details). Standard errors are represented byvertical bars^ 40vi'Figure 2.5 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during the test phase ofExperiment 2b, the day of the injection. denotes a statistically significantdifference from chance at p<0.05. Standard errors are represented by verticalbars^ 42Figure 2.6 Number of arm visits necessary to retrieve 4 pellets on an eight armmaze, by chance (values were mathematically genereated)^44Figure 2.7 Schematic representation of the infusion sites for all subjects included inExperiment 2. Black dots represent the location of the cannulae tips. Infusionsspread approximately 0.5mm from the cannulae tips (see text). Illustrated brainsections are computer generated adaptations of plates found in Paxinos andWatson (1982). Histological abbreviations, N.Acc.=nucleus accum bens, cc=corpuscallosum, ac=anterior commisure, CPu=caudate putamen^ 46Figure 3.1 Mean number of visits to baited arms expressed as a percentage of thetotal number of all arm visits, the day prior to the injection (white) and the day of theinjection (black) for the lidocaine and saline groups during the random foraging task(Experiment 3). ** denotes statistical significance at p<0.01. Standard errors arerepresented by vertical bars^ 53Figure 3.2 Mean number of revisits to baited arms (cross hatched) and non-baitedarms (horizontal lines) for the saline and lidocaine groups during the randomforaging task (Experiment 3) the day of the injection. Standard errors arerepresented by vertical bars^ 55Figure 3.3 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during the random foragingtask (Experiment 3), the day of the injection. denotes a statistically significantdifference from chance at p<0.05. Standard errors are represented by verticalbars^ 57Figure 3.4 Schematic representation of the infusion sites for all subjects included inExperiment 3. Black dots represent the location of the cannulae tips. Infusionsspread approximately 0.5mm from the cannulae tips (see text). Illustrated brainsections are computer generated adaptations of plates found in Paxinos andWatson (1982). Histological abbreviations, N.Acc.=nucleus accumbens, cc=corpuscallosum, ac=anterior commisure, CPu=caudate putamen^ 59Figure 4.1 Mean number of visits to baited arms expressed as a percentage of thetotal number of all arm visits for the saline and lidocaine groups during the trainingphase and test phase in Experiment 4 following pre-training (hatched) and pre-test(black) injections. denotes statistical significance at p<0.01. Standard errors arerepresented by vertical bars^ 66VIIIFigure 4.2 Mean number of across-delay (hatched) and within-trial (shaded) errorsmade by the lidocaine and saline groups during the test phase of Experiment 4, theday of the injection (see text for details). denotes a statistically significantdifference at p<0.05. Standard errors are represented by vertical bars^68Figure 4.3 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during Experiment 4, the dayof the injection. denotes a statistically significant difference from chance atp<0.05. Standard errors are represented by vertical bars^ 70Figure 4.4 Schematic representation of the infusion sites for all subjects included inExperiment 4. Black dots represent the location of the cannulae tips. Infusionsspread approximately 0.5mm from the cannulae tips (see text). Illustrated brainsections are computer generated adaptations of plates found in Paxinos andWatson (1982). Histological abbreviations, N.Acc.=nucleus accumbens, cc=corpuscallosum, ac=anterior commisure, CPu=caudate putamen^ 72ACKNOWLEDGMENTSSpecial thanks goes to my thesis supervisor, Dr. Tony Phillips, for hissupport, guidance and extreme patience in helping me with the preparation of thisthesis. I would also like to thank Stan Floresco and Tim Bussey for theirinvolvement in some of the experiments described in this thesis. Finally, I would liketo thank my thesis committee members, Dr. D. Wilkie and Dr. E. Eich for theirhelpful comments and insights.ixIntroduction:Limbic-Striatal Interactions in Motivated BehaviorsThe ventral striatum or nucleus accumbens (N.Acc.) lies at a crossroadsbetween the limbic system and motor output regions of the brain (Nauta &Domesick 1978). This structure receives input from the amygdala, hippocampusand prefontal cortex, and sends indirect projections through the pallidum and\"mesencephalic locomotor region (MLR)\" to motor output regions in the spinalchord (Groenewegen, Berendse, Meredith & Haber, 1991; Mogenson & Yang,1991). Electrophysiological data have demonstrated that activity of the N.Acc. isaffected by hippocampal stimulation, while activity in the MLR is influenced bystimulation of the N.Acc. (Mogenson & Yang 1991; Pennartz, Dolleman-Van DerWeel, Katai & DaSilva 1992; Pennartz & Katai 1991; Yang & Mogenson 1984).The functional importance of this pathway is indicated by behavioral datademonstrating that stimulation of the glutamate NMDA receptor in thehippocampus, or injection of the dopamine (DA) agonist, d-amphetamine into theN.Acc. cause increases in locomotor behavior which can be attenuated byprocaine injections into the subpallidal region or the MLR (Mogenson & Neilson1984; Mogenson & Yang 1991). Based on these and other findings, GordonMogenson and his colleges have proposed that the N.Acc. acts as a limbic-motor interface, allowing limbic inputs to gain access to motor output areas ofthe brain (Mogenson & Yang 1987; Mogenson & Yang 1991).While this theory has been very influential, there is a growing body ofevidence suggesting that the N.Acc. is more than simply a relay site for limbicinput. Heimer, deOlmos, Alhied and Zaborsky (1991) have advanced the ideathat the N.Acc. and related areas make up the \"extended amygdala\" which isessential for gating the ascending and descending output of the entire limbic2system. While it is still unclear as to the nature of this gate, one possibility is thatDA activity in the N.Acc. has a \"gain amplifying\" effect on afferent input from theamygdala (Cador, Robbins, Everitt, Simon, LeMoal & Stinus 1991). Cador et al.(1991) and Cador, Everitt and Robbins (1989) have shown that lesions of thebasolateral nucleus of the amygdala impair the ability to acquire a new operentresponse with conditioned reinforcement, while having a relatively minor effecton operant responding for primary reinforcement. Relative to control subjects,animals with amygdala lesions respond less frequently on a lever which deliversa conditioned stimulus. However, injections of d-amphetamine into the N.Acc. ofanimals with amygdala lesions leads to an increase responding specifically forthe presentation of a conditioned stimulus. Therefore enhanced DAtransmission in the N.Acc. may selectively modulate input received from theamygdala.Electrophysiological data suggest that DA in the N.Acc. may play a similarrole in modulating hippocampal input. Stimulation of discrete areas of thehippocampus activates certain cells in the N.Acc. (DeFrance, Sikes & Chronister,1985; Pennartz & Katai 1991; Pennartz et al. 1992; Yang & Mogenson 1984).Microinjection of DA into the N.Acc., or stimulation of the ventral tegmental area(which causes DA release in the N.Acc.), inhibits these excitatory responses in ause-dependent manner. When the hippocampus is stimulated at 0.5Hz, DAinhibits approximately 75% of the elicited activity in the N.Acc. Conversely, whenthe hippocampus is stimulated at 6 Hz there is no decrease in the evoked activity(DeFrance et al. 1985). DeFrance et al. (1985) have suggested that DA in theN.Acc. may act to \"increase the signal to noise ratio\" of hippocampal input. The\"signal\" is hypothesized to be information arriving at the N.Acc. in the 6 Hzrange. Activity in this range is observed in the hippocampus naturally when ananimal actively explores it's environment (Bland & Vanderwolf 1972).3Furthermore, tetanic stimulation at 6Hz induces long-term potentiation (asynaptic model of memory) in the hippocampus (Bliss & Lynch 1988). Thus, DAactivity in the N.Acc. may selectively enhance the transmission of informationgathered during exploration and learning by inhibiting the transfer of other typesof information. If this theory is expanded to incorporate the hypothesis that theN.Acc. acts as a \"limbic-motor interface\" (Mogenson & Yang 1991), theninformation acquired during exploration may have a preferential influence overongoing behavior. Hence, the interaction between the hippocampus and N.Acc.may be crucial for updating behavior based on newly acquired information.Indeed it has been suggested that the hippocampus and N.Acc. may acttogether to guide flexible modes of responding in the face of environmentalchange (Isaacson 1982 and 1984; Scheel-Kruger & Wilner 1991). Much of theevidence supporting this claim comes from the findings that inflexiblestereotyped modes of responding similar to those observed followinghippocampal damage can also be produced by altering DA activity in the N.Acc.It is quite clear that damage to the hippocampus reduces the variety ofbehavioral responses. Lesions of the hippocampus inhibit spontaneousalternation (for review see Isaacson 1982), and produce a tendency to exhibitwin-stay behavior in the radial arm maze (Packard, Hirsh & White, 1989).Animals with hippocampal damage also sample fewer arm choices in a radialmaze than control subjects and show a decrease in vigilant behaviors, indicating\"fewer shifts in behavior and attention away from routine\" (Devenport, Hale &Stidham 1988). Furthermore, such animals respond over a restricted range ofinter-response intervals in operant paradigms and tend to respond in a rhythmicmanner (Devenport, Devenport & Holloway 1981; Devenport et al. 1988; ).Finally, hippocampal damage produces an inability to inhibit responding during4periods of non-reward in a DRL paradigm (Isaacson 1982; Schmaltz & Isaacson1966).Hippocampal damage also alters DA activity in the N.Acc. (Isaacson1984; Mittleman et al. in press). Hence it follows that many of the impairmentsthat occur following hippocampal lesions may be due in part, to secondarychanges in the DA system at the level of the N.Acc. This theory is supported bythe findings that 6-OHDA lesions of the N.Acc. cause impairments inspontaneous alternation, spatial alternation, reduced exploration of objects orenvironments and great difficulty in reversing previously learned habits(Taghzouti et al. 1985a, 1985b). While the exact interaction between thehippocampus and N.Acc. in guiding flexible modes of responding remainsunclear, it has been suggested that hippocampal damage may lead to aninability to assess properly the relevance of external stimuli which providesignals for an animal to change it's current mode of behavior (Devenport et al.1981; Douglas & Pribram 1969; Isaacson 1982). Likewise, decreased DAactivity in the N.Acc. may also result in an inability to change current modes ofresponding based on external cues (Scheel-Kruger & Wilner 1991; van den Bos,Charria Oritz, Bergman & Cools 1991).The interactive roles of the N.Acc. and hippocampus in guiding flexiblemodes of behavior and in the control of locomotion raise the question as towhether the N.Acc. participates in other functions thought to be mediated by thehippocampus. The most extensively studied behavioral function of thehippocampus is its role in learning and memory. This work began in the 1950'swith the discovery that bilateral removal of the medial temporal lobes produces asevere anterograde amnesia, and relatively mild retrograde amnesia ( for reviewsee Corkin 1984; Scoville & Milner 1957). Since that time there has been a5great deal of interest in the memory-related functions of medial temporal lobestructures and in particular the hippocampus.In the early 1970's O'Keefe and Dostrovsky (1971) demonstrated theexistence of \"place cells' in the hippocampus. These cells fire when an animal isin a place in it's environment as specified by the combination of allocentric cuesthat surround the animal (O'Keefe & Speakman 1987). The integrated activity ofa network of place cells in the hippocampus has been hypothesized to form thebasis of an enduring internal representation of an animal's environment (O'Keefe& Nadel 1978). In accordance with this theory, hippocampal lesions produceimpairments in a variety of tasks that require an ability to acquire knowledgeabout spatial locations (Goodlett, Nichols, Holloran & West 1989; Jarrard 1983;Nadel & McDonald 1980). Taken together, these data suggest that thehippocampus is involved in spatial learning and memory.A second view of hippocampal function was put forward by Olton, Becker& Handelmann (1980), who suggested that the hippocampus is involved inworking memory, whether it be for spatial or non-spatial information. In oneexperiment, Olton reported that rats with hippocampal lesions, were unable tolearn which arms of a radial maze contained food and which did not based solelyon the patterns of the arms (Olton & Feustle 1981). A second task requiredanimals to learn that certain arms of a radial maze always contained food, andothers never contained food. The location of these arms were signaled by theirrelationship to extra-maze cues. Hence, it was a spatial task, with twocomponents which Olton termed \"working memory\" (WM) and 'referencememory\" (RM). The working memory component assessed the ability toremember which arms were visited within a trial,while the reference memorycomponent assessed the ability to remember which four arms always containedfood across many trials. Rats with hippocampal lesions were able to learn the6reference memory component but not the working memory component, therebydemonstrating that although these animals had a memory deficit they couldacquire some types of spatial information (Davis, Baranowski, Pulsinelli & Volpe1986; Olton et al. 1980; Olton & Papas 1979). These data have been supportedby other demonstrations that rats with hippocampal lesions are impaired inspecific non-spatial cued radial arm maze tasks which involve a working memorycomponent (Jarrard Okaichi, Steward & Goldschmidt 1984). Furthermore,lesions of the hippocampus in monkeys have produced impairments in non-spatial tasks such as delayed non-matching to sample, concurrent objectdiscrimination and object-reward association tasks (Squire 1992). Takentogether, these data demonstrate that the role of the hippocampus in memoryappears to extend beyond the ability to learn about and utilize spatial features ofan external environment.Specific regions of the hippocampal formation are also involved in certainaspects of learning and memory. Patients with CA1 damage resulting from anischemic episode have severe memory impairments, especially in learning newmaterial (Zola-Morgan, Squire & Amaral 1986). Animals with this type ofdamage are deficient on spatial navigation tasks, such as the spatial win-shifttask, described below and in a delayed non-matching to sample task (Auer,Murray & Whishaw 1989; Wood, Bussey & Phillips 1992; Wood, Mumby, Pinel &Phillips 1991). Damage to the subiculum, or its main output pathway, the fornix(Brodal 1968) also causes spatial navigation and working memory impairmentsin the radial arm maze (Goodlett et al. 1989: Jarrard et al. 1984). Lesions of thefornix produce deficits that are often very similar to deficits produced by damageto the entire hippocampus, namely problems in spatial navigation and workingmemory (Becker, Walker & Olton 1980; Jarrard et al. 1984: Meck, Church &Olton 1984; Olton et al. 1980; Olton, Walker & Wolf 1982; Olton & Werz 1978).Damage to the anterior columns of the fornix in humans may be partiallyresponsible for the pathology of the amnesic syndrome of Korsakoff (Heilman &Sypert 1977). Patients with this disorder show a marked anterograde amnesiaand possibly a temporally graded retrograde amnesia (Albert, Butters & Levin1979). Finally cortical areas closely related to the hippocam pus also playimportant roles in learning and memory processes. Zola-Morgan, Squire,Amaral & Suzuki (1989) have demonstrated that lesions of the perirhinal,parahippocampal, or entorhinal cortices in monkeys produce impairments in theperformance of delayed non-matching to sample and concurrent objectdiscrimination tasks. It is therefore quite evident that the hippocampus andrelated regions of the overlying cortex play a critical role in many types ofmemory processes.Anatomical evidence demonstrates that the N.Acc. receives either director indirect input from most of the medial temporal lobe regions discussed above.The dorsolateral or \"core\" area of the N.Acc. receives input from intermediaryareas of the subiculum, the perirhinal cortex, and the anterior entorhinal cortexwhile the more ventral medial 'shell\" region receives input from the ventralsubiculum, temporal regions of the CA1 subfield, medial and posterior regions ofthe entorhinal cortex, prelimbic cortex, and anterior cingulate cortex(Groenewegan, Beredse, Wolters & Loman 1990; Groenewegan, Vermeulen-Van Der Zee, Kortschot & Witter 1987; Kelly & Domesick 1982; McGeorge &Faull 1989; Newman & Winas 1980; Swanson & Cowan 1977; Walaas 1981).These anatomical data therefore raise the possibility that the N.Acc. may indeedplay a role in the memory-related functions of the hippocampus. However thebehavioral data supporting this speculation are sparse and in many casesinconclusive.78Two tasks which are impaired by hippocampal lesions, namely acquisitionof the spatial Morris water maze task and spatial reversal in the T-maze are alsoimpaired by exocitotoxic lesions of the N.Acc. (Annett, McGregor & Robbins1989; Sutherland & Rodriguez 1989; Brandesis, Brandys & Yehuda 1989;Goodlett et al. 1989; Isaacson 1982). Scheel-Kruger & Wilner (1991) have alsoshown that microinjections of glutamate antagonists into the N.Acc. produceimpairments in a spatial water maze task both during initial training and when thetask is well learned. While these data suggest a functional interaction betweenthe hippocampus and N.Acc. with regards to learning and memory processes,other data do not support this hypothesis. Microinjection of a glutamateantagonist into the N.Acc. produces impairments in the reference memorycomponent of the WM/RM radial arm maze described previously, whereashippocampal lesions do not (Davis et al. 1986; Olton & Papas 1979; Schacter,Yang, Innis & Mogenson 1989). The reference memory component of this taskis however sensitive to damage of the caudate nucleus (Packard & White 1990;Colombo, Davis & Volpe 1989). Furthermore disruption of dorsal striatal functionalso results in impairments in spatial reversal in the T-maze (Divac 1971) andspatially mediated behavior in the Morris water maze (Whishaw, Mittleman,Bunch & Dennett 1987; Scheel-Kruger & Wilner 1991). Therefore, based onthese data it may be argued that the N.Acc. is involved in memory processesmediated by either the caudate nucleus or the hippocampal formation.Any attempt to explore the role of the N.Acc. in behaviors linked tohippocampal function, must use tasks which are sensitive to lesions of thehippocampal formation and not to damage to other areas of the brain. Onecandidate is the spatial win-shift 8-arm radial maze task developed by Packardet al. (1989) and Packard and White (1991). The task consists of a trainingphase and test phase separated by a delay period. During the training phase9four arms are blocked and the animal must explore four open arms of the mazeto find food in each. During the test phase the animal must avoid the arms itvisited during the previous training phase and visit the four remaining arms. Thistask has an inherent working memory component in that the animal mustremember previous arm choices both within a test phase and across a delay. Italso requires a knowledge of spatial locations as the location of the arms aresignaled by the constellation of allocentric spatial cues surrounding the maze.Finally the task requires an ability to respond in a flexible manner as the animalmust explore a novel set of arms each day as well as avoid arms previouslyvisited both within a trial and across a delay. This task therefore encompassesmany of the functions ascribed to the hippocampus discussed above. Perhapsthe most important feature of the spatial win-shift task is its sensitivity to lesionsof the hippocampus but not to damage of the caudate nucleus or amygdala(McDonald & White 1993).As noted above, hypotheses concerning the function of the N.Acc. mustalso pay particular attention to its possible involvement in the memory-relatedfunctions of the caudate nucleus. Indeed anatomists have suggested that theN.Acc. is in a position to influence the activity of the caudate nucleus indirectly byaffecting the activity of the substantia nigra, the main source of DA input to thecaudate nucleus (Groenewegen et al. 1991; Groenewegen & Russchen 1984;Fallon 1988; Nauta, Smith, Faull & Domesick 1978). If disruption of neuralactivity in the N.Acc. results in the modification of striatal function, this may bemanifested by disrupted behavior on a task sensitive to lesions of the caudatenucleus, such as the cued win-stay task also developed by Packard et al. (1989)and Packard and White (1991). In this task the animal must learn to approacharms on a radial maze which are illuminated in order to obtain food reward. Thecued win-stay task appears to be sensitive to several functions ascribed to the10striatum, including the association of a response with a stimulus, referencememory, habit learning, and memory for a visual stimulus (Columbo et al 1989;Cook & Kesner 1988; Hikosaka 1986; Mitchell, Channell & Hall 1985; Packard etal 1989; Packard & McGaugh 1992; Packard & White 1990). Importantly, thecued win-stay task is disrupted by lesions of the caudate nucleus but not of thehippocampus or amygdala (McDonald & White 1993). Therefore the cued win-stay task serves as viable behavioral test for memory functions thought to bemediated by the dorsal striatum.Purpose of Present Research The purpose of the present series of experiments was to examine thepossible contribution of the N.Acc. to behaviors controlled by the hippocampusand the caudate nucleus, using the spatial win-shift and win-stay procedures justdescribed. In contrast to the majority of lesion studies referred to above, thepresent study employed transient lesions of the N.Acc. produced by intracranialinjections of the local anesthetic lidocaine. Local anesthetics, such as lidocaineor procaine have been used by electrophysiologists to block temporarily theactivity of a brain area under investigation. As discussed above, Mogenson andYang (1991) have used this technique to examine the role of the hippocampal-MLR pathway in locomotion. This technique has also been used to block theactivity of cerebellar nuclei transiently during the performance of a conditionedeye blink task (Chapman, Steinmetz, Sears & Thompson 1990; Knowlton &Thompson 1988; Welsh & Harvey 1991).There are a number of reasons for choosing this technique over methodswhich produce permanent lesions. First lidocaine lesions can be made quicklyand easily therefore the animals do not have to forgo training for many days toallow time for surgery and recovery. Furthermore, permanent lesions causechanges in other structures which receive projections from the lesioned area,11making it difficulty to make accurate structure/function assessments (Isaacson1984). Although, at present there is no direct evidence that similar effects do notoccur with lidocaine lesions, this technique does not produce any long-termimpairments in the performance of a variety of responses on the radial arm maze(personal observations). Finally the use of permanent lesions poses difficulty inassessing accurately which component of memory has been affected by thelesion, i.e. rule acquisition, versus the acquisition, storage, and/or retrieval ofwithin-trial information.The choice of the reversible lesion technique focused my experiments onthe ability to acquire and use trial-unique information. Animals, with indwellingcanulae aimed at the N.Acc. were trained daily on the spatial win-shift and cuedwin-stay tasks. Once the behaviors were well learned, lidocaine injections weremade into the N.Acc. of these animals, at different points of the daily learningtrials. Electrophysiological data indicate that the time necessary for theanesthetic effects of lidocaine on neural tissue to commence is approximately 2min while the effects dissipate in approximately 20-30 min (Crawford, Hallock,Truant & Wilder 1960; Sandkuhler, Maish & Zimmerman 1987; Welsh & Harvey1991). This technique therefore allowed animals to be trained with a transientN.Acc. lesion and tested drug-free or trained drug-free and tested with a N.Acc.lesion, thereby permitting a dissociation of the role of the N.Acc. in theacquisition as compared to the retreival of information that was unique to a giventrial.The present study was divided into four experiments. Experiment 1examined the effects of intra-N.Acc. lidocaine infusions on the performance of aspatial win-shift task and a cued win-stay task, while all subsequent experimentsaddressed the role of the N.Acc. in specific aspects of spatial win-shift behavior.In Experiment 2, transient N.Acc. lesions were delivered prior to the training12phase (2a) or prior to the test phase (2b) of this task to determine whether theN.Acc. is involved in the acquisition and/or use of newly acquired information.Experiment 3 examined the effects of transient N.Acc. lesions on a randomforaging task. As this task was identical to the test phase of the spatial win-shifttask, it permited an assessment of the effects of transient N.Acc. lesions onacquisition and/or use of information solely within the test phase. Experiment 4provided a necessary control for a state-dependency phenomenon, given thatthe animals in Experiments 1 and 2 were either trained in a drug free state andtested under the influence of lidocaine or vice versa.General MethodsSubjectsThe subjects were 104 male Long Evans rats (350-550 g), housedindividually in a temperature and light-controlled (12;12-hr light-dark cycle)colony. All subjects were given free access to water and were reduced to 80%of their free feeding weight, prior to the first day of food training. Once the ratsbegan to eat on the maze, they were maintained at 85% of their free-feedingweight by providing approximately 25-30g of Purina lab chow pellets once daily.All animals were tested during their light cycle between 2-8 pm daily.SurgeryPrior to surgery animals were anesthetized with 1 mg/kg ketaminehydrochloride and 0.33 mg/kg xylazine. Twenty two gauge stainless steel guidecannulae were aimed at the N.Acc. bilaterally using standard stereotaxicprocedures. The cannulae were aimed at the ventromedial region of the N.Acc.This area was choosen because it receives a large input from medial temporallobe structures, as discussed above. The stereotaxic coordinates obtained fromPaxinos and Watson (1982) were, AP.+1.9 mm, ML=1.4 mm, from bregma andDV=-6.3 mm from cortex. Solid steel 26 gauge stylets, the same length as theguide cannulae, were inserted and left in place until the injections were made.After surgery animals were allowed to recover for at least 10 days prior tobehavioral testing.Injection ProcedureThe injections for all experiments were made only on the day after eachanimal attained criterion performance. All animals were injected in their homecages in the rooms which contained the test apparatus. For each injection thesolid steel stylets were removed and a 26 gauge inner cannulae was insertedwhich extended .8mm beyond the end of the guide. 1 p1 of Lidocaine1314hyrochloride (2%, Astra Phamaceuticals) or 1pl of isotonic saline was deliveredat a rate of 1 p1 / 2 min by a Sage instruments model 341 syringe pump. Theinjection cannulae were left in place for an additional 60 s to allow for diffusion.Animals were allowed an additional 120 s in their home cages prior to beingplaced on the maze to ensure sufficient tissue anesthetization.ApparatusTwo similar 8-arm radial mazes were used for all behavioral testing. Bothmazes had octagonal center platforms measuring 40cm in diameter. Radiatingout from these platforms were eight arms each 50cm x 9cm, with 1cm (height) x3cm (diameter) cylindrical food cups at the ends of maze 1 and 0.5cm (depth) x1cm (diameter) food wells at the ends of maze 2. Maze 1 had eight six watt lightbulbs mounted on Plexiglas sheets (6cm x 10cm) located directly above the foodcups. Metal doors 9cm (width) x 13cm (height) which laid flat against each arm,could be raised to block the entrance to each arm of maze 1 while arms wereblocked in maze 2 using 9cm (width) x 13cm (height) pieces of removableopaque plastic.In Experiment 1, maze 1 was used for both the spatial win-shift and cuedwin-stay tasks. For the spatial win-shift task the maze was elevated 40cm off theground and surrounded by several extra maze cues. For the cued win-stay task,the maze was placed on a large opaque cylindrical platform, surrounded on allsides by curtains to obscure the animal's view of extra-maze cues. Animalswere monitored by an overhead video camera. The lights at the ends of thearms were operated by a remote switch box. All other experiments wereconducted using maze 2. This maze was elevated 40 cm off the ground andsurrounded by several extra maze cues.15HistologyAfter behavioral testing the animals were sacrificed in a carbon dioxidechamber. Brains were removed and fixed in a 10% formaline solution. Thebrains were then frozen and sliced in 40pm sections prior to being mounted andstained using the Kluver-Barrera method (Luna 1960). Cannulae placementswere verified with reference to the stereotaxic atlas of Paxinos and Watson(1982). Histological results are shown in Fig. 1.3 for Experiment 1, Fig. 2.7 forExperiment 2, Fig. 3.4 for Experiment 3 and Fig. 4.4 for Experiment 4. Thesefigures show the location of the cannulae tips for each animal included inExperiments 1 through 4. Albert and Madryga (1980) demonstrate that thefunctional spread of lidocaine in the occulomotor nucleus is approximately 0.5mm from the site of infusion . However Welsh & Harvey (1991) have shown thatlidocaine has a functional spread of up to 1.4 mm in the cerebellum. Based onhistological analysis in the present study, tissue damage resulting from lidocaineinfusions into the N.Acc. extended no greater than 1 mm from the tip of theinjection cannulae. Subjects whose injections diffused out of the N.Acc. were notincluded in the above figures or data analysis. The placements were largelyconfined within the N.Acc. with the exception of two animals in Experiment 1,four animals in Experiment 2 and four animals in Experiment 4.16Experiment 1:The Effects of Intra-N.Acc. Lidocaine Infusions on Spatial Win-Shift and CuedWin-Stay Behavior.As discussed in the introduction, the N.Acc. participates in tasks thoughtto be mediated by the hippocampus and caudate nucleus. A number ofbehavioral investigations have shown that damage to, or inhibition of DA orglutamatergic transmission in the N.Acc., impairs performance on the spatialMorris water maze task and spatial reversal in a T-maze (Annett et al. 1989;Scheel-Krugar & Wilner 1991; Taghoutzi, Simon Louilot, Herman & LeMoal1985a, Taghoutzi, Louilot, Herman, LeMoal & Simon 1985b; Sutherland &Rodriguez 1989). However, as these tasks are sensitive to both hippocampallesions (Brandesis et al. 1989; Goodlett et al. 1989; Isaacson 1982) and lesionsof the caudate nucleus (Divac 1971; Scheel-Krugar & Wilner 1991; Whishaw etal. 1987) it is difficult to conclude whether the N.Acc. interacts specifically withthe hippocampus or caudate nucleus in guiding these behaviors. RecentlyPackard et al. (1989), Packard and White (1991) and McDonald and White(1993) have shown that the memory-related functions of the hippocampus andcaudate nucleus can be dissociated using two radial arm maze tasks. Theydemonstrated that performance of a spatial win-shift task was sensitive tolesions of the hippocampus but not the caudate nucleus while performance ofthe cued win-stay task was impaired by lesions of the caudate nucleus, but notthe hippocampus. These tasks therefore provide viable behavioral assays of thememory-related functions of the hippocampus and caudate nucleus. Thepurpose of the present experiment was to examine the effects of transient N.Acc.lesions on the spatial win-shift and cued win-stay tasks, in an attempt to gain17insight into as to whether this structure interacts with the hippocampus orcaudate nucleus in guiding radial arm-maze behavior.Methods The spatial win-shift and cued win-stay paradigms used in the presentstudy were variations of tasks used by Packard et al. (1989), and Packard andWhite (1991) with a 5 min inter-phase interval. The procedure for the spatialwin-shift task was as follows. On the first two days of behavioral testing, animalswere placed on the maze for 10 min, with no food available. Upon returning totheir home cages they were given five Biosery pellets (Holton Industries Co.,Frenchtown, NJ). Daily learning trials were divided into a training phase and atest phase separated by a delay. Prior to the training phase a set of four armschosen quasi-randomly were blocked and a food pellet was placed in the foodcups of the four remaining open arms. During the training phase the animal wasrequired to retrieve the four pellets from the four baited arms within 10 min. Onthe first day of training four pellets were also placed on the center platform andone pellet was placed in the center as well as on the food cup of the four openarms during the training phase. After the first training session, food was onlyplaced in the food cups. During the test phase of each daily trial, all arms wereopen, but only the arms that were blocked during the training phase were baited.The animals were given 10 min to retrieve the four pellets during the test phase.A 5 min delay separated the training and test phases in this experiment.Criterion performance was attained when the animals could retrieve all 4 pelletsduring the training phase, and 4 pellets in 5 or fewer choices during the testphase, for 3 consecutive days.The day after criterion performance was attained the animals were againallowed to retrieve all 4 pellets during the training phase, but were then removedfrom the maze to receive injections of either saline or lidocaine, into the N.Acc.18as described above. After a 5 min delay, the animals were placed on the mazefor the test phase. The percentage of correct arm choices out of the totalnumber of all arm choices during the test phase was computed for the day priorto the injection and the day of the injection. A correct choice was scored as anentry into a baited arm and consumption of the food pellet.While the cued win-stay task used the same maze as the spatial win-shifttask, the maze was placed on a large circular platform surrounded by curtains,with lights at the ends of the arms to signal the presence of food. The initial twodays of training for the cued win-stay task were similar to the spatial win-shifttask, in that the animals were allowed to explore the maze for 10 min with nofood available and were given 5 pellets in their home cages after being removedfrom the maze. Each subsequent day of training consisted of two similarsessions separated by a 5 min delay. This procedure was used to mimic thetemporal design of the spatial win-shift task, as well as to allow time for aninjection between identical training sessions. This procedure therefore allowed adirect comparison of performance during a transient N.Acc. lesion to drug-freeperformance 5 min. earlier. During the first daily session the lights of four armschosen quasi-randomly were turned on and the food cups located beneath theselights, were baited. Each rat was given 10 min. to retrieve the pellets from thefood cups of the four lit arms. Once a pellet was retrieved the light locatedabove it, was turned off. The animals were then removed from the maze andplaced in their home cages for 5 min. After the delay the procedure outlinedabove was repeated.Criterion performance was attained when eight pellets over 2 dailysessions could be obtained in 10 or fewer choices, for 3 consecutive days. Theday after criterion performance was demonstrated, the animals were injectedwith either saline or lidocaine, in the manner described above, between the two19training sessions. Arm choices were recorded, and the number of correctchoices (visits to lit arms) as a percentage of the total number of choices wascalculated for the drug-free and injection trial.ResultsTransient lidocaine induced lesions of the N.Acc. produce severeimpairments in test phase performance of the spatial win-shift task while leavingcued win-stay behavior intact. The effects of intra-N.Acc. lidocaine injections onspatial win-shift and cued win-stay behavior is shown in Fig. 1.1 and 1.2respectively. A two-way repeated measures ANOVA was performed on thescores obtained the during the test phase of the spatial win-shift task on the dayprior to the injection, and on the day of the injection. A significant group effect(sal R=84%, lido R=69.5%, F(1,18)=9.05, p=0.008) and a day x groupinteraction effect (F(1,18)=24.91, p<0.05), was observed and followed by simplemain effect analysis which yielded no significant difference between the groupsthe day prior to the injection (sal R=88%, lido R=94% F(1,18)=1.8, p=0.19) buta significant difference between the groups the day of the injection, (sal R=74%,lido R=45.2%), F(1,18)=25.37, p<0.001). A two-way repeated measuresANOVA was computed on the choice scores for the two trials, the day of theinjection for the cued win-stay task. No significant difference was observedbetween the saline ( R=83.6%) and lidocaine ( R=90%) groups F(1,14)=1.168,p=0.298 overall or between the trial prior to the injection versus the trialimmediately following the injection F(1,14)=0.331, p=0.574 for either saline orlidocaine groups.Histological results for all animals included in the spatial win-shift andcued win stay tasks in Experiment 1 are shown in Fig. 1.3.20Figure 1.1 Mean number of visits to baited arms expressed as a percentage ofthe total number of all arm visits, the day prior to the injection (white) and the dayof the injection (black) for the lidocaine and saline groups during the test phaseof the spatial win-shift task in Experiment 1. ** denotes statistical significance atp<0.01. Standard errors are represented by vertical21day prior to injectionday of injection100 TT804.44,L.o`^60*0^40•20Lidocaine Group^Saline GroupFigure 1.2 Mean number of visits to lit arms expressed as a percentage of allarm visits, the day prior to the injection (white) and the day of the injection(black) for the lidocaine and saline groups during the cued-win-stay task ofExperiment 1. Standard errors are represented by vertical bars.22TT23prior to injectioninjectionI^I10080.6•VoL..o 600200Lidocaine Group^Saline Group24Figure 1.3 Schematic representation of the infusion sites for all subjectsincluded in Experiment 1. Black dots represent the location of the cannulae tips.Infusions spread approximately 0.5mm from the cannulae tips (see text).Illustrated brain sections are computer generated adaptations of plates found inPaxinos and Watson (1982). Histological abbreviations, N.Acc.=nucleusaccumbens, cc=corpus callosum, ac=anterior commisure, CPu=caudateputamen.25AP +2.2mmAP +1.7mmAP +1.2mmAP+0.7mm11112^1^0^1^2^3113^26Discussion The results of this experiment demonstrate that intra-N.Acc. lidocaineinfusions spare cued win-stay behavior. In contrast, this manipulation produceda severe impairment in performance on the test phase of the spatial win-shifttask. In view of the results obtained by Packard et al. 1989, the present datasuggest that the N.Acc. is involved preferentially in tasks thought to be mediatedby the hippocampus rather than those linked to the caudate nucleus. However,Schacter et al. (1989) report that microinjections of a glutamate antagonist intothe N.Acc. impairs the the reference memory component but not the workingmemory component of the WM/RM radial arm maze task (described above). Asimilar impairment is observed following permanent lesions of the caudatenucleus, while hippocampal lesions impair only the working memory component(Colombo et al. 1989; Davis et al. 1986; Olton 1982; Packard & White 1990)suggesting that the N.Acc. is involved in tasks mediated by the caudate nucleusrather than the hippocampus. A second interpretation of these data is that theN.Acc. is involved in spatially mediated tasks. Given that the cued win-stay taskis not spatially mediated, transient N.Acc. lesions would be expected to havelittle effect on this behavior.Although animals with permanent or transient N.Acc. lesions are impairedon the initial acquisition of the spatial Morris water maze task, they caneventually learn to find a hidden platform using spatial cues (Annett et al. 1989;Seamans, Floresco & Phillips in preparation). Therefore N.Acc. lesions do notseem to abolish completely the ability to form a spatial map (O'keefe & Nadel1978). These lesions may however impair the ability to use newly acquiredinformation about specific aspects of a spatial environment. This interpretation isin accordance with the results of the present experiment demonstrating animpairment in the ability to use newly acquired information about the location of27four food pellets on an 8-arm spatially cued maze following transient N.Acc.lesions.A second major difference between the cued win-stay and spatial win-shifttask is that the former does not require a flexible mode of responding. In thistask the animal must, under all circumstances, visit arms that are illuminated.Conversely, in the spatial win-shift task the animal must use a variety of cues tonavigate among arms in a non-repetitive manner. Transient N.Acc. lesions maytherefore produce an impairment in the ability to respond in a flexible manner.Taghzouti et al. (1985a, 1985b) have reported that 6-OHDA lesions of the N.Acc.impair the ability to perform spatial reversals in a T-Maze, as lesioned animalstend to perseverate in their previous response tendencies. However it is unlikelythat such an impairment is responsible for the deficits observed in the presentinvestigation as the animals were responding randomly and rarely revisited thesame arm or arm sequence in succession (personal observations). Annett et al.(1989) have observed random modes of responding in a spatial T-mazeparadigm following excitotoxic lesions of the N.Acc. These authors suggest thatN.Acc. lesions impair the ability to choose the correct response strategynecessary to solve the task. It is possible that the animals receiving transientN.Acc. lesions in the present experiment were unable to use the correct or welllearned behavioral strategy (i.e. win-shift) and as a result began to respond in arandom manner. Moreover, it is clear that this type of impairment is limited towin-shift radial arm maze behavior as no such impairment is observed inemploying a win-stay strategy.Finally, the amount of new information acquired daily is clearly differentfor the spatial win-shift and cued win-stay tasks. In the former case, up to eightprevious arm choices must be remembered, whereas no previous dailyinformation must be retained in the latter task. In contrast the cued win-stay task28requires an ability to use the well learned rule that a light signals the location offood. Lights are turned off following a visit, and thus information aboutpreviously visited arms can be forgotten. Hence trial-unique information must beacquired and used only in spatial win-shift task and not the cued win-stay task.Therefore, the deficit produced by transient N.Acc. lesions may be attributed toan inability to acquire and/or use trial-unique information efficiently .29Experiment 2:The Effects of Pre-Training and Pre-Test Intra-N.Acc. Lidocaine Infusions onSpatial Win-Shift Behavior.Transient lesions of the N.Acc. delivered prior to the test phase of thespatial win-shift task in Experiment 1 impaired test phase performance.However the results of Experiment 1 provided little insight into the role of theN.Acc. in the acquisition as opposed to the use of trial-unique information in thespatial win-shift task. Experiment 2a was designed to address this issue byexploiting the transient anesthetiq properties of lidocaine on neuronal tissue.Intra-N.Acc. lidocaine infusions were delivered prior to the training phase of thespatial win-shift task. In this experiment the test phase followed 30 min. laterwhen the anesthetic effects of the drug had dissipated, hence the animals weretrained under the influence of the drug, but tested drug free. This procedurepermitted an analysis of the role played by the N.Acc. specifically in theacquistion of trial-unique information during the training phase of the spatial win-shift task. The role of the N.Acc. in the ability to use information acquiredpreviously during the training phase of the spatial win-shift task was addressedin Experiment 2b. In this experiment a transient N.Acc. lesion was delievered atthe end of the 30 min. inter-phase interval, prior to the commencement of thetest phase. Collectively Experiments 2a and 2b were conducted in an attempt togain insight into the role of the N.Acc. in the acquisition as opposed to theretrieval of information obtained during the training phase of the spatial win-shifttask.MethodsThe behavioral procedure for this experiment was similar to that outlinedabove for the spatial win-shift task. However, injections were made the day after30an animal successfully retrieved four pellets during the training phase and fourpellets in five or fewer choices during the test phase for two consecutive days ata five min. inter-phase interval, then at a 30 min. inter-phase interval. InExperiment 2a, the day after criterion performance was demonstrated, theanimals received either a saline or lidocaine injection, in the manner describedabove, prior to the training phase. After the injection, the animals completedboth the training phase and the test phase 30 min. later. A 30 min. post-injectioninterval is sufficient time for the anesthetic effects of lidocaine to dissipate(Crawford et al. 1960; Sandkuhler et al. 1987; Welsh & Harvey 1991). Hencethe animals acquired information during the training phase under the influence oflidocaine but were tested drug free during the test phase.Experiment 2b used the same procedure as Experiment 2a. However anintra-N.Acc. infusion of saline or lidocaine was delivered prior to the test phaserather than prior to the training phase. On the day of the injections, the animalswere required to complete the training phase as usual. They were then returnedto their home cages, where 25 min. later they were given intra-N.Acc. lidocaineor saline injections, in the manner described above (the injections took 5 min,making a total delay of 30 min). After the injections the animals were placedback on the maze for the test phase.The number of correct choices (visits to baited arms) expressed as apercentage of the total number of arm choices was calculated for the trainingphase and test phase of Experiment 2a and the test phase of Experiment 2b.The type of errors made, i.e. across-delay errors (revisits to arms visited duringthe training phase), and within-trial errors (revisits to arms visited previouslyduring the test phase) was calculated for the test phase of Experiment 2b.Finally the number of choices required to retrieve each pellet was obtained forthe training phase of Experiment 2a and test phase of Experiment 2b.31ResultsIn Experiment 2a transient lidocaine-induced lesions of the N.Acc.delivered prior to the training phase of the spatial win-shift task, did not impairtraining phase performance or test phase performance 30 min. later when theanesthetic effects of the drug had dissipated (Fig. 2.1, Fig 2.2). In contrast pre-test intra-N.Acc. lidocaine infusions disrupted performance during the test phaseof the spatial win-shift task in Experiment 2b (Fig 2.3). Animals receiving thismanipulation made an equal number of across-delay and within trial errors (Fig.2.4). Furthermore their performance was similar to the saline group in retrievingthe first two pellets but approached chance when they attempted to retrievepellets 3 and 4 (Fig. 2.5, Fig. 2.6).A two-way repeated measures ANOVA was computed on the number oferrors made during the training phase of Experiment 2a. There was nosignificant difference between the day prior to the injection versus the day of theinjection F(1,14)=1.79, p=0.20 or between the lidocaine ( )1=96%) and salinegroups ( R=93.3%) F(1,14)=0.27, p=0.61. A two-way repeated measuresANOVA was computed on the performance scores during the test phase ofExperiment 2a. Again there was no significant difference in the percentage ofcorrect choices made by the lidocaine ( R=84.9%) and saline ( R=85.7%) groups(F(1,14)=0.01, p=0.92). Fig. 2.2 shows the mean number of arm visits made bythe lidocaine and saline groups to retrieve pellets 1 to 4 during the training phaseof Experiment 2a. No differences were observed between the groups on thechoices taken to retrieve each pellet (pellet 1, R=1, pellet 2, R=1.08, pellet 3,R=1, pellet 4 R=1.48, F(3,42)=1.47, p=0.236).A two-way repeated measures ANOVA was computed on theperformance scores during the test phase of Experiment 2b. A significant groupeffect (sal R=82.5%, lido R=63.5% ) and day x group interaction effect32F(1,14)=7.36 p<0.05 was observed . This was followed by simple main effectanalyses which yielded no significant difference between the groups on the dayprior to the injection F(1,14)=2.333, p=0.149, but a significant difference wasobserved between the groups on the day of the injection (saline R=74%,lidocaine R=41.75%) F(1,14)=17.69, p=0.001.A two-way repeated measures ANOVA conducted on the types of errorsmade by the saline and lidocaine groups revealed a significant overall groupdifference (sal R=1.4, lido R=3, F(1,14)=10.8, p=0.005). No differences wereobserved in the types of errors made by the lidocaine group (across-delayerrors R=3, within-trial errors R=4.8, F(1,7)=2.16, p=0.185) while the salinegroup made slightly more across-delay errors ( R=1.54) than within-trial errors( R=0.32) ( F(1,7)=4.667, p=0.06).Fig. 2.5 shows the number of arm choices (visits) required to retrieveeach pellet (choices are non-cumulative) while chance values are shown in Fig.2.6. The chance values generated mathematically are: 2 choices to retrieve thefirst pellet, 2.67 to retrieve the second, 4 to retrieve the third, and 8 choices toretrieve the final pellet. Two chi-square analyses were conducted on the numberof arm visits taken to retrieve pellet 1 and 2 and the number arm visits taken toretrieve pellet 3 and 4. There was no significant difference from chance levelson the number of choices necessary to retrieve pellet 1 and 2 for the salinegroup (pellet 1, R=1.5, pellet 2, R=1.13, x2(1)=0.88, p>0.1) or lidocaine group(pellet 1, R=1.25, pellet 2, .R=2, x2(1)=0.38, p>0.1). The saline group wassignificantly different from chance in retrieving pellets 3 ( R=1.25) and 4( R=1.88) (x2(1)=6.58, p<0.05), whereas the lidocaine group was not (pellet3, R=2.38, and pellet 4, R=5.125, x2(1)=1.657, p>0.1).Histological results for all subjects included in Experiments 2 are shown inFig. 2.733Figure 2.1 Mean number of visits to baited arms expressed as a percentage ofthe total number of all arm visits, the day prior to the injection (white) and the dayof the injection (black) for the lidocaine and saline groups during the trainingphase and test phase of Experiment 2a. Standard errors are represented byvertical bars.34day prior to injectionday of injectiontraining^test^training^test^Lidocaine Group Saline GroupFigure 2.2 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during the training phaseof Experiment 2a, on the day of the injection. Standard errors are representedby vertical bars.3536 saline grouplidocaine group1 0 -9 -8 -7 -6 -o 50^4 -3 -2 -10 ^pellet 1^pellet 2^pellet 3^pellet 4Pellet Number37Figure 2.3 Mean number of visits to baited arms expressed as a percentage ofthe total number of all arm visits, the day prior to the injection (white) and the dayof the injection (black) for the lidocaine and saline groups during the test phaseof Experiment 2b. ** denotes statistical significance at p<0.01. Standard errorsare represented by vertical bars.100804.•00b.%.o 6004.0C6 40oL.oa.200TT* *11-38day prior to injectionday of injectionLidocaine Group Saline Group39Figure 2.4 Mean number of across-delay (hatched) and within-trial (shaded)errors made by the lidocaine and saline groups during the test phase ofExperiment 2b the day of the injection (see text for details). Standard errors arerepresented by vertical bars.across delay errorswithin trial errorsI-0a..LIJOa.OEzLidocaine Group^Saline GroupFigure 2.5 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during the test phase ofExperiment 2b, the day of the injection. * denotes a statistically significantdifference from chance at p<0.05. Standard errors are represented by verticalbars.41saline4210 -9 -8 -7 -0^6 -et.)._.o^5-0^4 -3 -2 -1 -0 lidocaine pellet 1^pellet 2^pellet 3^pellet 4Pellet Number43Figure 2.6 Number of arm visits necessary to retrieve 4 pellets on an eight armmaze, by chance (values were mathematically genereated).44pellet 1^pellet 2^pellet S^pellet 4Pellet Number45Figure 2.7 Schematic representation of the infusion sites for all subjectsincluded in Experiment 2. Black dots represent the location of the cannulae tips.Infusions spread approximately 0.5mm from the cannulae tips (see text).Illustrated brain sections are computer generated adaptations of plates found inPaxinos and Watson (1982). Histological abbreviations, N.Acc.=nucleusaccumbens, cc=corpus callosum, ac=anterior commisure, CPu=caudateputamen.46AP +2.2mmAP +1.7mmAP +1.2mmAP+0.7mm}1^0 2^33^247Discussion Experiment 2a demonstrates that pre-training intra-N.Acc. lidocaineinjections have no effect on foraging behavior on a four arm maze (trainingphase). Furthermore, this manipulation has no effect on acquisition of newinformation during the training phase, as this information can be used effectivelyduring the test phase, when the anesthetic effects of lidocaine have dissipated.Experiment 2b demonstrates that intra-N.Acc. lidocaine infusions prior to the testphase of the spatial win-shift task, produce a severe impairment in test phaseperformance.The error distribution shown in Fig. 2.4, illustrates two points. 1) Thesaline group made significantly fewer errors overall than the lidocaine group. 2)The saline group made slightly more across-delay errors than within-trial errors,while the lidocaine group made an equal number of both. Therefore thelidocaine group was equally impaired at using information acquired prior to adelay, as in using information acquired earlier within a trial.The number of arm visits necessary to retrieve each pellet during the testphase of Experiment 2b, shown in Fig. 2.5, illustrates that the performance of thelidocaine group departed from the saline group and approached chance levelsduring the retrieval of pellets 3 and 4. The chance values shown in Fig. 2.6indicate that there is a lower probability of retrieving pellets 3 and 4 by chancethan pellets 1 and 2. Hence the impairment following a transient N.Acc. lesionmay be dependent on task difficulty. This hypothesis is supported by theobservation that the lidocaine group performed above chance during the trainingphase of Experiment 2a (Fig. 2.2) which is much easier than the test phase.During the test phase in which eight arms are open, and only four are baited theanimal must potentially remember many more previous arm choices than duringthe training phase and must use this information to navigate through twice as48many arms. Optimal performance during the test phase also requires the animalto use information acquired across a delay. As the lidocaine group made anequal number of across-delay and within-trial errors in Experiment 2b (Fig. 2.4),it is difficult to determine whether the lidocaine-induced deficit is attributable toan inability to acquire and/or use information within a trial or in the ability to useinformation acquired prior to a delay.49Experiment 3:The Effects of Intra-N.Acc. Lidocaine Infusions on Random Foraging Behavior.As noted, it was unclear as to whether the inefficient retrieval of fourpellets on an 8-arm maze observed in Experiment 2b was the result of aninability to use information acquired prior to a delay or an inability to useinformation acquired within a trial. The present random foraging task wasdesigned to address this question. In this task animals were required to foragefor four randomly placed pellets, on an 8-arm maze. Hence it was identical tothe test phase of the spatial win-shift task used in Experiments 1 and 2 above.However, since there was no training phase the animals were not required touse information acquired prior to a delay. Thus, this task permitted aninvestigation of the effects of transient N.Acc. lesions solely on the ability toacquire and/or use within-trial information to forage for four pellets on an 8-armmaze.MethodsEach day the animals were allowed to explore the maze freely to retrievea food pellet from four quasi-randomly chosen arms. The animals were trainedin this manner for 15 days, approximately the same amount of training receivedby the animals in Experiment 2. Criterion performance was attained when theanimals could retrieve the 4 pellets in 5 or fewer choices, for 3 consecutive days.The day after criterion were attained, a saline or lidocaine intra-N.Acc. infusion,was delivered to the animals in the manner described above, prior to beingplaced on the maze.Three measures of performance were calculated for the day prior to theinjection and the day of the injection, 1) the number of visits to baited armsexpressed as a percentage of total arm visits, 2) the number of revisits to baited50arms versus the number of revisits to non-baited arms and 3) the number of armvisits required to obtain each pellet.ResultsIn this experiment transient lidocaine-induced lesions of the N.Acc.produced impairments in the ability to forage for four randomly placed pellets onan eight arm maze (Fig. 3.1). Furthermore, the lidocaine group revisitedpreviously baited and previously non-baited arms equally (Fig. 3.2). Finally, thelidocaine group and saline groups made a similar number of arm visits whenretrieving the first two pellets but the lidocaine group approached chance levelswhen they attempted to retrieve pellets 3 and 4 (Fig. 3.3, Fig. 2.6).A two way repeated measures ANOVA was computed on the number ofvisits to baited arms expressed as a percent of the total number of arm choices,and revealed a significant difference between the groups on the day of theinjection (sal R=56%, lido )7=34% F=16.82, p=0.001).These data were also compared to the results obtained in Experiment 2b(exp 2b) (Fig. 2.3) using a four way repeated measures ANOVA. The overalltest revealed a significant group difference (sal R=69%, lido )7=55%,F(3,26)=18.605, p=0.000) and a significant day x group interaction effect(F(3,26)=4.657, p<0.05). This was followed by two, two-way repeated measuresANOVAs. A significant difference was found between the saline group fromExperiment 2b ( R=82.5%) and the saline group from Experiment 3 ( R=56%)(F(1,13)=20.173, p=0.001). A significant overall difference was also foundbetween the lidocaine groups (exp 2b R=63.5%, exp 3 R=48.5%,(F(1,13)=17.203=0.001) as was a significant day x experiment interaction effect(F(1,13)=4.46, p=0.05). This interaction effect was followed by two simple maineffect analyses which yielded a significant difference between the lidocainegroups on the day prior to the injection (exp 2b R=85%, exp 3 R=61%51F(1,13=21.137, p<0.01) but no significant difference on the day of the injection(exp 2b R=42%, exp 3 R=34% F(1,10)=1.93, p=0.189).A two way repeated measures ANOVA was computed on the number ofrevisits to baited and non-baited arms (Fig. 3.2) and revealed a significantoverall difference in the mean number of errors made by the lidocaine ( R=2.14)and saline groups ( g=0.71) (F(1,12)=22.64, p<0.01), but no significant overalldifference in the number of revisits to baited arms versus the number of revisitsto non-baited arms (F(1,12)=0.049, p=0.828) and no group x error interactioneffect (F(1,12)=0.049, p=0.828).Fig. 3.3 shows the mean number of choices to retrieve each pellet,(chance values are shown in Fig. 2.6). A Chi-square analysis on the meannumber of choices to retrieve pellets 1 and 2 showed no significant differencefrom chance for the saline group (pellet 1 R=2.14, pellet 2 g=1.43, x 2(1)=0.58,p>0.05) or lidocaine group (pellet 1 R=2.57, pellet 2 R=2, x2(1)=0.32, p>0.05).However a similar analysis on the mean number of choices to retrieve pellets 3and 4 revealed a significant difference from chance for the saline group (pellet3 R=2.1, pellet 4 R=2.03 x2(1)=5.35, p<0.05) but no significant difference fromchance for the lidocaine group (pellet 3 R=2.86, pellet 4 R=4.14 x 2(1). 2.18,p>0.1).Histological results for all subjects included in the random foragingexperiment are shown in Fig. 3.4.52Figure 3.1 Mean number of visits to baited arms expressed as a percentage ofthe total number of all arm visits, the day prior to the injection (white) and the dayof the injection (black) for the lidocaine and saline groups during the randomforaging task (Experiment 3). s-* denotes statistical significance at p<0.01.Standard errors are represented by vertical bars.day prior to injectionday of injection5310080V.I.1.o ^60200 T**ILidocaine Group Saline GroupFigure 3.2 Mean number of revisits to baited arms (cross hatched) and non-baited arms (horizontal lines) for the saline and lidocaine groups during therandom foraging task (Experiment 3) the day of the injection. Standard errorsare represented by vertical bars.5455saline grouplidocaine groupSOL0VW0L.AE=zrevisits to baited arms revisits to nonbaited armsWithin Trial ErrorsFigure 3.3 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during the randomforaging task (Experiment 3), the day of the injection. * denotes a statisticallysignificant difference from chance at p<0.05. Standard errors are representedby vertical bars.560 -9 -a -7 -6 -5 -4 -3 -2 -1 -01••.05.eCYPellet Number58Figure 3.4 Schematic representation of the infusion sites for all subjectsincluded in Experiment 3. Black dots represent the location of the cannulae tips.Infusions spread approximately 0.5mm from the cannulae tips (see text).Illustrated brain sections are computer generated adaptations of plates found inPaxinos and Watson (1982). Histological abbreviations, N.Acc.=nucleusaccumbens, cc=corpus callosum, ac=anterior commisure, CPu=caudateputamen.AP +2.2mmAP +1.7mmAP +1.2mmAP+0.7mm5960Discussion The results of the random foraging experiment demonstrate that intra-N.Acc. lidocaine infusions impaired the ability to retrieve four randomly placedpellets on an 8-arm maze. Hence this manipulation impairs the ability to useinformation acquired within a trial. Furthermore, the foraging behavior of thelidocaine group in the present experiment and Experiment 2b was similar. Thisindicates that subjects in that experiment were completely unable to useinformation acquired 30 min previously during the training phase. Therefore,transient lesions of the N.Acc. impair both the ability to use of informationacquired prior to a delay and within a trial to forage for 4 pellets on an 8-armmaze.Despite differences in the frequency of errors, the types of errors made bycontrol animals and animals receiving intra-N.Acc. lidocaine infusions are similarin that they equally likely to be revisits to an arm which previously contained foodas one that did not. Therefore, although the lidocaine group visited more non-baited arms overall than the saline group their pattern of responding was similar.Thus these data demonstrate that transient N.Acc. lesions do not cause animalsto perseverate in previously reinforced choices as is the case following 6-OHDAlesions of the N.Acc. (Taghoutzi et al.1985a, 1985b).Both the saline and lidocaine groups made the same number of choicesto retrieve pellets 1 and 2. However, the performance of the lidocaine groupdiffered from the saline group and began to approach chance levels during theretrieval of pellets 3 and 4. As already discussed (see Fig. 2.6) there is a muchlower probability of retrieving pellets 3 and 4 by chance than pellets 1 and 2.Thus the retrieval of the final two pellets is a more difficult task than retrieval ofthe first two pellets. As the random foraging task progresses there are greaterdemands placed on the animal as it must remember an increasing number of61subsequent arm choices. The large number of errors made by the lidocainegroup in retrieving pellets 3 and 4 therefore supports the conclusion reached inExperiment 2 that the impairments produced by transient N.Acc. lesions arerelated to task difficulty.The results of the present experiment are very similar to those obtained inExperiment 2b and together they suggest that transient N.Acc. lesions impair theability use within-trial and across-delay information to forage on an 8-arm maze.Experiment 4:The Effects of Combined Pre-Training and Pre-Test Intra-N.Acc. lidocaineInjections on Spatial Win-Shift Behavior: A Test For State-DependencyConger (1951) postulates that alterations on tasks assessing memoryfunctions following single pre-training or pre-test drug administrations may beattributable to an impairment in stimulus generalization resulting from a changein drug state between training and test. Conger's theory of state-dependentlearning is now a well established phenomenon (see Overton 1991 for review)and should be considered in any learning experiment employing single drugadministration. The deficits observed in Experiments 1, 2b, and 3 above, maytherefore have been due to a state-dependency effect, as the animals learnednew information in one drug-state and were tested in another. To eliminate thispossibility, animals were trained and tested on the spatial win-shift task in thesame drug state.Methods In the present experiment animals were trained in an identical manner tothat used in Experiment 2. However on the day after criterion performance wasdemonstrated, intra-N.Acc. lidocaine or saline infusions were delivered prior toboth the training phase and the test phase. The animal's behavior wasassessed the day of the injection using three measures; 1) percent correctperformance during the training phase and test phase, 2) the number of across-delay errors versus the number of within-trial errors during the test phase, and 3)the number of arm visits required to obtain each pellet, during the test phase.62ResultsExperiment 4 demonstrates that pre-training intra-N.Acc. lidocaineinfusions do not impair training phase performance, while pre-test infusionsseverely impair test phase performance on the spatial win-shift task (Fig. 4.1).These results argue against the suggestion that state dependent learning wasresponsible for the impairments observed in Experiments 1-3. In the presentexperiment the saline group made more across-delay than within-trial errorswhile the lidocaine group made an equal number of both (Fig. 4.2).Furthermore, the performance of the lidocaine group was similar to that of thesaline group in retrieving the first two pellets but approached chance when theyattempted to retrieve pellets 3 and 4 (Fig. 4.3, Fig. 2.6).A two-way repeated measures ANOVA was conducted on the data shownin Fig. 4.1 and revealed an overall group effect (sal R=79%, lido 37=59%,F(1,10)=14.76, p=0.003) and a significant phase x group interaction effect(F(1,10)=11.32, p<0.05). This was followed by simple main effect analysis whichyielded no significant difference between the groups for the training phase(sal R=90%, lido R=82% F(1,10)=1.364, p=0.27), but a significant differenceduring the test phase (sal R=67%, lido R=36%, F(1,10)=15.07, p=0.003).A two way repeated measure ANOVA was computed on the number ofacross-delay and within-trial errors made by the lidocaine and saline groups (Fig.4.2). A significant group effect (sal 57=0.81, lido R=2.38 F(1,10)=7.9, p=0.016)was observed as was a significant interaction effect (F(1,10)=4, p=0.06). Simplemain effect analysis revealed that the lidocaine group made an equal number ofboth types of errors (across-delay errors R=3.14, within-trial errors g=4(F(1,6)=0.76, p=0.42), whereas the saline infused group made significantly moreacross-delay errors ( R=1.9) than within-trial errors ( R=0.57) (F(1,6)=9.346,p=0.02).6364Two chi-square analyses were computed on the mean number of choicestaken to retrieve pellets 1 and 2 and the mean number of choices to retrievepellets 3 and 4 (Fig. 4.3). Chance values are represented in Fig. 2.6 . Neitherthe saline (x2(1)=0.73, p>0.05) or lidocaine (x2(1)=0.66, p>0.05) groups differedfrom chance performance in retrieving pellets 1 and 2. The saline animalsdiffered from chance in retrieving pellets 3 ( R=1.71 choices) and 4( R=1.86choices)(x2(1)=6, p<0.05), whereas the lidocaine animals did not (pellet 3 g=3and pellet 4 R=5.14, x2(1)=1.27, p>0.05).Histological results for all animals included in Experiment 4 are shown inFig. 4.4.Figure 4.1 Mean number of visits to baited arms expressed as a percentage ofthe total number of all arm visits for the saline and lidocaine groups during thetraining phase and test phase in Experiment 4 following pre-training (hatched)and pre-test (black) injections. ** denotes statistical significance at p<0.01.Standard errors are represented by vertical bars.6566pre training intectionpretest injectionLidocaine Group^Saline Group67Figure 4.2 Mean number of across-delay (hatched) and within trial (shaded)errors made by the lidocaine and saline groups during the test phase ofExperiment 4, the day of the injection (see text for details). denotes astatistically significant difference at p<0.05. Standard errors are represented byvertical bars.68across delay errorsSaline GroupLidocaine Groupwithin trial errors69Figure 4.3 Mean number of arm visits made by the saline group (shaded) andlidocaine group (black) to retrieve each of four pellets during Experiment 4, theday of the injection. * denotes a statistically significant difference from chance atp<0.05. Standard errors are represented by vertical bars.70 salinelidocaine1 0 -9 -8 -7 -6 -•'a\"^50 43 -2 -1 -0 pellet 1^pellet 2^pellet S^pellet 4Pellet Number71Figure 4.4 Schematic representation of the infusion sites for all subjectsincluded in Experiment 4. Black dots represent the location of the cannulae tips.Infusions spread approximately 0.5mm from the cannulae tips (see text).Illustrated brain sections are computer generated adaptations of plates found inPaxinos and Watson (1982). Histological abbreviations, N.Acc.=nucleusaccumbens, cc=corpus callosum, ac=anterior commisure, CPu=caudateputamen.AP +2.2mmAP +1.7mmAP +1.2mmAP+0.7mm7273DiscussionThe results of this experiment demonstrate that pre-training lidocaineinjections do not have a significant effect on training phase performance, whilesubsequent pre-test infusions in these animals do affect test phase performance.These results argue against a state-dependency interpretation of the deficitsreported in the previous experiments, as the animals in this experiment weretrained and tested in the same drug state. The results of this experiment alsoreplicate the findings of Experiment 2a & 2b demonstrating that pre-trainingintra-N.Acc. infusions do not impair training phase performance whereas pre-testinjections impair test phase performance.The lidocaine group made more errors than the saline group overall, butmade the same number of across-delay errors as within-trial errors. The salinegroup however made significantly more across-delay errors than within-trialerrors. As discussed in Experiment 2, animals receiving transient N.Acc. lesionsare equally deficient at using information acquired within the test phase, as theyare at using information acquired 30 min. earlier during the training phase.However, the deficits in the ability to use information acquired within a trial seemto be severe enough to mask additional impairments in the ability to useinformation acquired prior to a delay (see Experiment 3). Finally as observed inExperiment 2 and 3 the performance of the lidocaine group approaches chancelevels when retrieving pellets 3 and 4, but not pellets 1 and 2. Taken together,the results of the present experiment are in accordance with those reported inExperiments 1-3. Furthermore the present experiment demonstrates that astate-dependency phenomenon cannot account for the results of thoseexperiments.74The Effects of Intra-N.Acc. Lidocaine Infusions on Locomotor BehaviorThere are numerous reports that the N.Acc. plays an important role inlocomotor behavior (Mittleman et al. in press; Mogenson & Neilson 1984;Mogenson & Yang 1991; Schacter et al. 1989). However, the N.Acc. does notseem to be involved in all types of motoric behavior, but rather plays a specificrole in goal-directed locomotion (Kelley & Stinus 1985; Salamone 1992;Whishaw & Kornelsen in press). In an attempt to gain insight into the impact ofintra-N.Acc. lidocaine infusions on goal-directed locomotion, approach latencieswere compared between experimental and control groups in each experiment.Approach latency was defined as the time (in seconds) required to reach thefood cup of the first arm visited by the animal after being placed on the maze.Hence this measure was used to assess the latency to reach a goal locationrather than simply the time to initiate any type of locomotor behavior. Table 1illustrates that lidocaine infusions produced a significant increase in the latencyto approach a food well in the spatial win-shift task of Experiment 1, Experiment2b and Experiment 3 (F(1,44)=5.55, p<0.05). A two-way ANOVA revealed thatthe lidocaine groups in the cued win-stay task of Experiment 1 and Experiment2a did not differ from the control groups in approach latency (F(1,28)=3.7,p>0.05), or in task performance (see Experiment 1 and 2a above). Collectively,these data indicate that when task performance was impaired by transientN.Acc. lesions, approach latency was also increased whereas when taskperformance was unimpaired, approach latency was unaffected. Oneinterpretation of these results is that enhanced approach latency may reflect astate of confusion in the animal that is manifested in impaired task performance.However as approach latencies are highly variable (as shown by the largestandard errors in Table 1), this interpretation should be taken with caution.75Table 1 Mean latency to approach a food well for tasks which the lidocainegroup made numerous errors (left column) versus tasks which the lidocainegroup made no more errors than controls (right column). The left column showsthe mean approach latency for the lidocaine (top) and saline (bottom) groupsduring the test phase of the spatial win-shift task in Experiment 1 andExperiment 2b and the random foraging task (Experiment 3). The right columnshows the mean approach latency for the lidocaine (top) and saline (bottom)groups during the training phase of Experiment 2a and the cued win-stay task ofExperiment 1. * denotes significance at p<0.05. Standard errors are shown inbrackets.76Pre-test 14 (Exp 1-3)Pre-training Inj. (Exp 2a)Cued win-stay (Exp 1)LidocaineSalineR=88 (±22.8)* sec. R=23 (±9) sec.R=36.9 (±9.6) sec. 3Z=68.6 (±21) sec.General DiscussionThe results of the present study demonstrate that lidocaine injections intothe N.Acc. have no effects on cued win-stay behavior or the ability to forage for,and learn the spatial location of 4 pellets on a 4-arm radial maze. Thismanipulation does, however, cause severe impairments in test phaseperformance of the spatial win-shift task.As discussed above, there is a selective effect of the transient N.Acc.lesions on locomotor behavior. The results of the present series of experimentsindicate that if task performance is impaired by the lesions so to is approachlatency, whereas if task performance is unimpaired no such increase inapproach latency is observed. However once the animals showing enhancedapproach latencies initiate movement toward a food cup they are able to moveabout the radial arm maze environment with little or no difficulty, and in fact visitmany more arms than control animals. Therefore, a generalized locomotorimpairment cannot account for the impairments observed in Experiment 1-4.Numerous authors have proposed a role for the N.Acc. in motivatedbehaviors (Mogenson, Jones & Yim 1980; Phillips et al. 1991; Salamone 1992).Thus it may be argued that the lesioned animals in the present study were lessmotivated to retrieve the food pellets and as a result entered arms in a randommanner. This is unlikely as animals receiving transient N.Acc. lesions retrievedand consumed all the food pellets in every task, despite making numerouserrors. Furthermore lesioned animals were unimpaired on the cued win-staytask and the training phase of the spatial win-shift task in which they had toretrieve the same number of pellets (i.e. 4) as during the test phase of the spatialwin-shift task. Therefore, impairments in goal-directed behavior following the7778transient N.Acc. lesions are dependent on task complexity and the cues used tonavigate towards a goal.A generalized perceptual impairment also cannot account for theimpairment in test phase performance, as lesioned animals performed the cuedwin-stay task adequately, as well as the training phase of the spatial win-shifttask which required them to use spatial cues to navigate on the maze.Finally, based on the results from Experiment 4, poor performance by thelidocaine-treated animals on the test phase of the spatial win-shift task cannot beattributed to state-dependent learning. Animals receiving both pre-training andpre-test infusions were impaired only during the test phase, thereby indicatingthat this manipulation does not induce a \"state\" that must be re-establishedduring the test phase in order to use previously acquired information.No impairments were observed in the cued win-stay task followingtransient N.Acc. lesions suggesting that this structure is not involved in the abilityto recognize and respond to specific non-spatial cues which have beenpreviously and consistently associated with reward. Past work hasdemonstrated that lesions of the caudate nucleus but not of the hippocampus oramygdala produce impairments in cued win-stay behavior (McDonald & White;1993; Packard et al 1989). Therefore the results of Experiment 1 suggest thatthe N.Acc. does not act synergistically with the caudate nucleus to guide cuedwin-stay behavior. In contrast, lesions of the N.Acc. or caudate nucleus produceimpairments on tasks such as spatial reversal in the T-maze, reference memoryperformance on the radial arm maze, and the spatial Morris water maze(Taghoutzi et al. 1985a, 1985b; Divac 1971; Packard & White 1990; Colombo etal. 1989; Schacter et al. 1989; Scheel-Krugar & Wilner 1991; Whishaw et al1987). As each of these tasks has a spatial component that is not present in the79cued win-stay task, it may be argued that the N.Acc. is involved preferentially inspatially-mediated behaviors.This conclusion is supported by data demonstrating that ibotenic acid orelectrolytic lesions of the N.Acc. impair the acquisition of a spatial Morris watermaze task (Annett et al. 1989; Sutherland & Rodriguez 1989). However whilethis task is mediated by spatial cues, decrements in task performance followingN.Acc. lesions may not be the result of an impairment in the ability to form aspatial map (O'Keefe & Nadel 1978). If an animal is unable to learn its positionin space relative to surrounding extra-maze cues, then performance of thespatial Morris water maze task would be severely affected. However exocitoxicN.Acc. lesions do not completely abolish the acquisition of the task, as lesionedanimals are eventually able to swim to the hidden platform in a manner that doesnot differ from controls (Annett et al.; 1989). Furthermore, although Sutherland& Rodriguez (1989) reported that electrolytic lesions of the N.Acc produced aninitial deficit in task performance, they also demonstrated that pre-trained ratscould find a hidden platform as accurately as controls, following electrolyticlesions of the N.Acc. Taken together these data suggest that animals withN.Acc. lesions are able to localize their position in space relative to a set ofconsistent extra-maze cues. Hence it is unlikely that the impairments in spatialwin-shift behavior following transient N.Acc. lesions observed in the presentseries of experiments were the result of an inability to acquire a spatial map.This is supported further by the observation that no impairments were observedduring the training phase of the spatial win-shift task in Experiment 2a followingtransient N.Acc. lesions. Although fewer arms are used in the training phasethan in the test phase, animals must still be able to forage for four pellets using aconsistent set of extra-maze cues. However, the impairment in test phaseperformance observed in Experiments 1-4 may have been the result of an80inability to learn, store or use daily information regarding the location of food in afamiliar environment.The results of Experiment 2a argue against the possibility that transientN.Acc. lesions produced a specific impairment in the acquisition of newinformation. Lidocaine-induced N.Acc. lesions delivered prior to the trainingphase did not disrupt performance 30 min. later during the test phase when theanesthetic effects of the drug had dissipated. This suggests that these lesionsspared the ability to learn about and encode the location of four randomly placedpellets on a 4-arm maze.Another possibility that must be considered is that the deficits in testphase performance may be attributed to an impairment in the consolidation ofnewly acquired information. There is evidence that the mesolimbic DA system(the source of DA input to the N.Acc.) is involved in the processes underlyingmemory consolidation, as delivery of peripheral or intra-hippocampal infusions ofDA receptor agonists post-training, improves test phase performance on thespatial win-shift task (Packard & White 1991; White, Packard & Seamans inpress). It is therefore possible that the lidocaine infusions interfered with theactivity of the mesolimbic DA system in the N.Acc. and impaired some aspect ofthe consolidation of newly acquired information. However this possibility is notsupported by the results of Experiment 2b. Here the saline group rarely enteredthe previously baited arms during the test phase, suggesting that 25 min. issufficient time for consolidation of newly acquired information. Therefore, it maybe assumed that the lidocaine group had also consolidated the informationacquired during the training phase prior to receiving the injection. This suggeststhat unless the transient N.Acc. lesions altered the processes underlyingconsolidation in a retroactive manner, it is unlikely that this manipulation had anyeffect on memory consolidation.81Conversely, the lidocaine-induced impairment in test phase performanceduring the spatial win-shift task may have been the result of a deficit in memoryretrieval. This hypothesis cannot be refuted by the present data set. Infusionsof lidocaine into the N.Acc. prior to the test phase reliably and consistentlyproduced an impairment in test phase performance in all experiments reportedhere. Test phase data from Experiments 1-4 demonstrated that the animal'sbehavior approaches chance levels following transient N.Acc. lesions.Furthermore, Figs. 2.4, 4.2 show that these animals made an equal number ofacross-delay and within-trial errors suggesting that they were unable to userecently acquired information regarding the location of baited and unbaited armsto guide their subsequent choices of arms that may contain food.This inability to use previously acquired information following transientN.Acc lesions is not absolute, as it is dependent on task complexity. TransientN.Acc. lesions produced no impairments in training phase performance(Experiment 2a) but caused severe impairments in test phase performance(Experiments 1, 2b, 3, & 4). The training phase differs from the test phase inseveral important respects. In contrast to the test phase, the training phasedoes not assess the ability to use information acquired prior to a delay. Acomparison of Figs. 2.3 and 3.1 shows that animals given transient N.Acc.lesions were as impaired on the random foraging task as they were during thetest phase of Experiment 2b. Hence information that was acquired during thetraining phase was of no use to the lidocaine group during the test phase ofExperiment 2b. A second difference between the training and test phase relatesto the use of four out of four baited arms in the former condition and four out ofeight baited arms in the latter. The effects of transient lesions of the N.Acc. areonly manifested in the more complex 8-arm situation. Therefore it is conceivablethat the observed deficits are related to the amount of information that must be82either processed or retained in order to forage efficiently when encountering fourrandomly baited arms on an 8-arm maze. If transient N.Acc. lesions impair theability to remember a large number of arm choices then impairments in testphase performance should be most apparent at the end of the trial. This patternmay be seen in Figs. 2.5, 3.3, 4.3 where both saline and lidocaine-infusedanimals do not differ when retrieving pellets 1 and 2, but performance of thelidocaine group falls dramatically when retrieving pellets 3 and 4. These resultssuggest that when the amount of newly acquired information exceeds a certainlimit, the capacity to use this information is severely impaired by transient N.Acc.lesions. It therefore follows that the failure to observe disruptive effects followingtransient N.Acc. lesions during the training phase of Experiment 2a may berelated to the fact that these animals required fewer choices to retrieve the fourpellets and hence did not exceed their reduced working memory capacity.A final possibility that must be considered is that the lidocaine-induceddeficit in test phase performance may not only produce an inability to retrievepreviously acquired information but also an inability to select information that isrelevant to the current situation. During the training phase the animal is facedwith 4 open arms rather than 8 during the test phase. Hence in the latter casethere is a greater number of non-baited arms that must be avoided. As thebehavior of the lidocaine-treated animals was random during the test phase, itsuggests that these animals were incapable of directing their responding to thecorrect subset of baited arms. The failure to observe similar impairments duringthe training phase of Experiment 2a may be related to the fact that the blockadeof four arms provided proximal cues indicating which arms were to be attendedto. Purves (1993) proposes that the NN.Acc. is part of a general spatialprocessing system and that this system is distinct from that used to processproximal cues\". As no such proximal cues were available during the test phase,83the animals had to use previously acquired knowledge about the spatial locationof arms which previously contained food to direct their responding to the correctsubset of newly baited arms. Therefore, the transient N.Acc. lesions may haveimpaired the process through which the specific information regarding thelocation of the correct subset of baited arms, comes to influence responding in acomplex spatial environment. According to this interpretation, the N.Acc. isinvolved in the process through which relevant information influences currentmodes of behavior.This interpretation is in accordance with clinical literature suggesting that aninherited or acquired deviation in ventral straital circuitry, might result in a gravedisturbance in cognitive or emotional filtering processes\" (Swerdlow & Koob1987 pg 203). Furthermore, without the inhibitory influence of the N.Acc. on itsefferent connections \"appropriate filtering and amplification of cortical informationcannot occur at the level of the N.Acc, and irrelevant and relevant cognitive oremotional activity are not segregated\" (Swerlow & Koob 1987, pg 204). WhileSwerdlow & Koob suggest that these effects are due to excessive DA activity inthe N.Acc. which inhibits GABAergic output neurons to the ventral pallidum,lidocaine may have the same effect, in that it also inhibits N.Acc. output neurons.Hence transient lidocaine-induced lesions of the N.Acc. could block the flow oflimbic input and cause ungated activity in the efferents of this structure.Swerdlow & Koob's theory is quite similar to that of Margulies (1985) who hashypothesized that while the hippocampus may detect noteworthy or salientenvironment cues, the N.Acc is involved in \" the integration of new noteworthyevents into ongoing thought or behavior\" (pg 254). Taken together theseclinically based theories suggest that the N.Acc. modulates the flow of limbicinput, allowing only some types information to influence behavior.84These clinical theories are supported by electrophysiological datademonstrating such a modulatory role for the N.Acc. Stimulation of the fornixcauses excitatory post synaptic potential (EPSP)/ inhibitory post synapticpotential (IPSP) sequences in N.Acc. cells (Pennartz & Katai 1991). It ishypothesized that the IPSP sequences in the N.Acc. limit the impact ofhippocampal input. DA in the N.Acc. also modulates the effects of hippocampalinput by inhibiting both the elicited EPSP and IPSP (Pennartz et al. 1992).However the magnitude of this modulation is dependent on the frequency ofhippocampal stimulation. If 6 Hz stimulation is delivered to the fornix, there isvery little signal modulation by DA in the N.Acc., while the effects of 0.5Hzstimulation are greatly reduced (DeFrance et al. 1985). This is a noteworthyfinding as the hippocaMpus fires at 6 Hz when an animal is actively exploring itsenvironment (Bland & Vanderwolf 1972). Furthermore tetanic stimulation in the6 Hz range is effective in inducing long-term potentiation ( a synaptic model oflearning and memory) in the hippocampus (Bliss & Lynch 1988). This suggeststhat information processed by the hippocampus during exploration or learningmay be selectively enhanced by the N.Acc. relative to information processed bythe hippocampus at other times.As well as playing a role in modulating limbic input, the N.Acc. may also becrucial to the process through which this input comes to influence behavior.Various manipulations of the pathway from the hippocampus, through the N.Accto the ventral pallidum and MLR can selectively enhance or inhibit locomotion(for review see Mogenson & Yang 1991). Furthermore, enhanced locomotiondue to hippocampal lesions can be blocked by inhibition of DA activity in theN.Acc. (Mittleman, LeDuc & Whishaw, in press). In the present series ofexperiments, the transient N.Acc. lesions may have impaired the ability of thisstructure to allow information, processed by limbic structures, regarding the85location of previously visited arms of the maze, to guide the animals' ongoingresponding.Given the role of the hippocampal formation in spatial navigation and inspatial win-shift behavior, the discussion thus far has emphasized that thehippocampus is critical to the role played by the N.Acc. in guiding behavior.However, it is also possible that the transient N.Acc. lesions altered the effectsthat input from the frontal cortex has on behavioral output. The N.Acc. receivesa direct projection as well as an indirect projection, through the subiculum, fromthe medial prefrontal cortex (Alexander, Crutcher & Delong 1990; Groenewegenet al. 1987; Groenewegen et al. 1991; Heimer et al. 1991; McGeorge & Faull1989). Damage to the prefrontal cortex in humans, causes memory deficits onspatial and non-spatial conditional learning tasks, memory for temporal orderand in planning (Joyce & Robbins 1991; Milner 1982; Milner & Petrides 1984;Milner, Petrides & Smith 1985; Petrides 1989; Shallice 1981). In rats, lesions ofthe frontal cortex can cause impairments on various spatial learning tasks,delayed response learning, response flexibility, delayed alternation behavior,foraging on an 8-arm maze and tasks requiring memory for frequency ofstimulus presentation (Divac 1971; Kesner 1990; Kesner & Holbrook 1987;Kesner, Farnsworth & DiMattia 1989; Kolb 1984; Kolb, Pittman, Sutherland &Whishaw 1982; Kolb, Sutherland & Whishaw 1983; Winocour 1991). It is clearthat many of these processes are necessary for optimal performance on thespatial win-shift task, and hence the role of the frontal-N.Acc. pathway may be ofutmost importance in this regard.Robbins (1990 & 1991) suggests that the frontal cortex mediates thegeneration of plans based on previously acquired and currently availableinformation, while the N.Acc. translates this information into a sequences ofresponses. Therefore, these two areas act to guide purposive, or goal-oriented86behaviors. One effect of transient N.Acc. lesions may be to disrupt thiscoordinated activity and thereby cause a shift to random responding. Therefore,an alternative explanation for the random performance of lidocaine-treatedanimals in the present study may be that they are unable to translate theresponse strategies generated by the frontal cortex into the proper sequences ofresponses. 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Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use."@en ; ns0:scholarLevel "Graduate"@en ; dcterms:title "Selective memory impairments produced by transient lidocaine-induced lesions of the nucleus accumbens"@en ; dcterms:type "Text"@en ; ns0:identifierURI "http://hdl.handle.net/2429/1446"@en .