Use of immediate-early gene expression to map relationships between limbic structures supporting memory

This thesis explores the influence of brain regions within the "extended hippocampal memory system" on the activity of the retrosplenial cortex in the rat. One of the first goals was to use lesion studies to improve the understanding of the vulnerability of the retrosplenial cortex, especially in the context of diencephalic and temporal lobe amnesia. The second was to assess what are the brain areas within the temporal lobe involved in object recognition and how they interact. These two objectives were made possible by visualising immediate-early gene expression. By combining this technique with lesions, distal effects of different lesions (hippocampus, mammillothalamic tract and fornix) on the activity of the retrosplenial cortex were measured. For object recognition, the immediate-early gene imaging enabled the assessment of normal brain activity in rats associated with behavioural discrimination of novelty. The lesion studies provide information about the specific and common vulnerability of the retrosplenial cortex, as all three distal lesions resulted in a decrease of immediate-early gene activity in the retrosplenial cortex. In addition, these findings unify diencephalic amnesia with temporal amnesia, and emphasize the need to study networks or systems instead of individual structure. The immediate-early gene/object recognition experiment implicated the caudal part of the perirhinal cortex (and Te2) and of the hippocampus in object recognition, and highlighted the importance of mapping brain region relationships within a connected system. Taken together, these experiments provide clear support for the concept of an extended hippocampal memory system, but also show how this system may interact with other structures involved in different forms of memory. The findings underlie the potential afforded by use of immediate-early gene expression techniques in animal studies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Anterior thalamic nuclei lesions in rats disrupt markers of neural plasticity in distal limbic brain regions

AbstractIn two related experiments, neurotoxic lesions were placed in the anterior thalamic nuclei of adult rats. The rats were then trained on behavioral tasks, immediately followed by the immunohistochemical measurement of molecules linked to neural plasticity. These measurements were made in limbic sites including the retrosplenial cortex, the hippocampal formation, and parahippocampal areas. In Experiment 1, rats with unilateral anterior thalamic lesions explored either novel or familiar objects prior to analysis of the immediate-early gene zif268. The lesions reduced zif268 activity in the granular retrosplenial cortex and postsubiculum. Exploring novel objects resulted in local changes of hippocampal zif268, but this change was not moderated by anterior thalamic lesions. In Experiment 2, rats that had received either bilateral anterior thalamic lesions or control surgeries were exposed to novel room cues while running in the arms of a radial maze. In addition to zif268, measurements of c-AMP response element binding protein (CREB), phosphorylated CREB (pCREB), and growth associated protein43 (GAP-43) were made. As before, anterior thalamic lesions reduced zif268 in retrosplenial cortex and postsubiculum, but there were also reductions of pCREB in granular retrosplenial cortex. Again, the hippocampus did not show lesion-induced changes in zif268, but there were differential effects on CREB and pCREB consistent with reduced levels of hippocampal CREB phosphorylation following anterior thalamic damage. No changes in GAP-43 were detected. The results not only point to changes in several limbic sites (retrosplenial cortex and hippocampus) following anterior thalamic damage, but also indicate that these changes include decreased levels of pCREB. As pCREB is required for neuronal plasticity, partly because of its regulation of immediate early-gene expression, the present findings reinforce the concept of an ‘extended hippocampal system’ in which hippocampal function is dependent on distal sites such as the anterior thalamic nuclei

Use of immediate-early gene expression to map relationships between limbic structures supporting memory

This thesis explores the influence of brain regions within the 'extended hippocampal memory system' on the activity of the retrosplenial cortex in the rat. One of the first goals was to use lesion studies to improve the understanding of the vulnerability of the retrosplenial cortex, especially in the context of diencephalic and temporal lobe amnesia. The second was to assess what are the brain areas within the temporal lobe involved in object recognition and how they interact. These two objectives were made possible by visualising immediate-early gene expression. By combining this technique with lesions, distal effects of different lesions (hippocampus, mammillothalamic tract and fornix) on the activity of the retrosplenial cortex were measured. For object recognition, the immediate-early gene imaging enabled the assessment of normal brain activity in rats associated with behavioural discrimination of novelty. The lesion studies provide information about the specific and common vulnerability of the retrosplenial cortex, as all three distal lesions resulted in a decrease of immediate-early gene activity in the retrosplenial cortex. In addition, these findings unify diencephalic amnesia with temporal amnesia, and emphasize the need to study networks or systems instead of individual structure. The immediate-early gene/object recognition experiment implicated the caudal part of the perirhinal cortex (and Te2) and of the hippocampus in object recognition, and highlighted the importance of mapping brain region relationships within a connected system. Taken together, these experiments provide clear support for the concept of an extended hippocampal memory system, but also show how this system may interact with other structures involved in different forms of memory. The findings underlie the potential afforded by use of immediate-early gene expression techniques in animal studies

Lesions of the Rat Perirhinal Cortex Spare the Acquisition of a Complex Configural Visual Discrimination Yet Impair Object Recognition

Rats with perirhinal cortex lesions were sequentially trained in a rectangular water tank on a series of 3 visual discriminations, each between mirror-imaged stimuli. When these same discriminations were tested concurrently, the rats were forced to use a configural strategy to solve the problems effectively. There was no evidence that lesions of the perirhinal cortex disrupted the ability to learn the concurrent configural discrimination task, which required the rats to learn the precise combination of stimulus identity with stimulus placement (“structural” learning). The same rats with perirhinal cortex lesions were also unimpaired on a test of spatial working memory (reinforced T maze alternation), although they were markedly impaired on a new test of spontaneous object recognition. For the recognition test, rats received multiple trials within a single session in which on every trial, they were allowed to explore 2 objects, 1 familiar, the other novel. On the basis of their differential exploration times, rats with perirhinal cortex lesions showed very poor discrimination of the novel objects, thereby confirming the effectiveness of the surgery. The discovery that bilateral lesions of the perirhinal cortex can leave configural (structural) learning seemingly unaffected points to a need to refine those models of perirhinal cortex function that emphasize its role in representing conjunctions of stimulus features

Perirhinal cortex lesions in rats: Novelty detection and sensitivity to interference

Rats with perirhinal cortex lesions received multiple object recognition trials within a continuous session to examine whether they show false memories. Experiment 1 focused on exploration patterns during the first object recognition test postsurgery, in which each trial contained 1 novel and 1 familiar object. The perirhinal cortex lesions reduced time spent exploring novel objects, but did not affect overall time spent exploring the test objects (novel plus familiar). Replications with subsequent cohorts of rats (Experiments 2, 3, 4.1) repeated this pattern of results. When all recognition memory data were combined (Experiments 1–4), giving totals of 44 perirhinal lesion rats and 40 surgical sham controls, the perirhinal cortex lesions caused a marginal reduction in total exploration time. That decrease in time with novel objects was often compensated by increased exploration of familiar objects. Experiment 4 also assessed the impact of proactive interference on recognition memory. Evidence emerged that prior object experience could additionally impair recognition performance in rats with perirhinal cortex lesions. Experiment 5 examined exploration levels when rats were just given pairs of novel objects to explore. Despite their perirhinal cortex lesions, exploration levels were comparable with those of control rats. While the results of Experiment 4 support the notion that perirhinal lesions can increase sensitivity to proactive interference, the overall findings question whether rats lacking a perirhinal cortex typically behave as if novel objects are familiar, that is, show false recognition. Rather, the rats retain a signal of novelty but struggle to discriminate the identity of that signal

Association rules for rat spatial learning: the importance of the hippocampus for binding item identity with item location

Three cohorts of rats with extensive hippocampal lesions received multiple tests to examine the relationships between particular forms of associative learning and an influential account of hippocampal function (the cognitive map hypothesis). Hippocampal lesions spared both the ability to discriminate two different digging media and to discriminate two different room locations in a go/no-go task when each location was approached from a single direction. Hippocampal lesions had, however, differential effects on a more complex task (biconditional discrimination) where the correct response was signaled by the presence or absence of specific cues. For all biconditional tasks, digging in one medium (A) was rewarded in the presence of cue C, while digging in medium B was rewarded in the presences of cue D. Such biconditional tasks are “configural” as no individual cue or element predicts the solution (AC+, AD−, BD+, and BC−). When proximal context cues signaled the correct digging choice, biconditional learning was seemingly unaffected by hippocampal lesions. Severe deficits occurred, however, when the correct digging choice was signaled by distal room cues. Also, impaired was the ability to discriminate two locations when each location was approached from two directions. A task demand that predicted those tasks impaired by hippocampal damage was the need to combine specific cues with their relative spatial positions (“structural learning”). This ability makes it possible to distinguish the same cues set in different spatial arrays. Thus, the hippocampus appears necessary for configural discriminations involving structure, discriminations that potentially underlie the creation of cognitive maps

Finding and not finding rat perirhinal neuronal responses to novelty:Rat perirhinal neuronal responses to novelty

There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in “paired viewing” experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had “object fields”); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition‐related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc

An associative analysis of object memory

Different aspects of recognition memory in rodents are commonly assessed using variants of the spontaneous object recognition procedure in which animals explore objects that differ in terms of their novelty, recency, or where they have previously been presented. The present article describes three standard variants of this procedure, and outlines a theory of associative learning, SOP [1] which can offer an explanation of performance on all three types of task. The implications of this for theoretical interpretations of recognition memory and the procedures used to explore it are discussed

The novel object recognition memory: neurobiology, test procedure, and its modifications

Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology