Representation In Rats Research Articles

Unique Transcriptomic Cell Types of the Granular Retrosplenial Cortex are Preserved Across Mice and Rats Despite Dramatic Changes in Key Marker Genes.

The granular retrosplenial cortex (RSG) supports key functions ranging from memory consolidation to spatial navigation. The mouse RSG contains several cell types that are remarkably distinct from those found in other cortical regions. This includes the physiologically and transcriptomically unique low rheobase neuron that is the dominant cell-type in RSG layers 2/3 (L2/3 LR), as well as the similarly exclusive pyramidal cells that comprise much of RSG layer 5a (L5a RSG). While the functions of the RSG are extensively studied in both mice and rats, it remains unknown if the transcriptomically unique cell types of the mouse RSG are evolutionarily conserved in rats. Here, we show that mouse and rat RSG not only contain the same cell types, but key subtypes including the L2/3 LR and L5a RSG neurons are amplified in their representations in rats compared to mice. This preservation of cell types in male and female rats happens despite dramatic changes in key cell-type-specific marker genes, with the Scnn1a expression that selectively tags mouse L5a RSG neurons completely absent in rats. Important for Cre-driver line development, we identify alternative, cross-species genes that can be used to selectively target the cell types of the RSG in both mice and rats. Our results show that the unique cell types of the RSG are evolutionarily conserved across millions of years of evolution between mice and rats, but also emphasize stark species-specific differences in marker genes that need to be considered when making cell-type-specific transgenic lines of mice versus rats.

Time is just a memory.

Experience unfolds continuously in time, but we remember discrete sequences of events. In this issue of Nature Neuroscience, Montchal et al. describe brain activity patterns that predict how well people remember precisely when recent events occurred. Converging evidence suggests that homologous neural machinery structures temporal representations in rats and people.

Motor cortex somatotopic presentation after restriction of neck movement in rats.

[Purpose] In this study, we aimed to investigate the effects of neck movement restriction on somatotopic mapping of the motor cortex. We restricted cervical extension for two weeks and investigated the effects on motor cortex somatic representation in rats. [Subjects and Methods] We placed six Wistar rats into each of three groups: (i) the experimental group, in which cervical extension was restricted; (ii) the sham group, in which cervical movement was not restricted, but a splint was placed in the shoulder girdle; and (iii) the control group. After cervical immobilization for two weeks, we evaluated the motor cortex somatic representation using intra-cortical micro-stimulation. [Results] In the experimental group, the areas of the cervical and vibrissal domains of the motor cortex decreased by approximately 50%, and the forelimb domain showed slight reduction. In addition, a trunk domain formed at the locus of the vibrissal area. There were no differences between the sham and control groups. [Conclusion] Restriction of cervical extension for two weeks resulted in changes in motor cortex somatic representation. Reversible changes occurred in cortical areas that controlled the neck and parts of the body involved in cervical movement.

Ellagic acid: Insights into its neuroprotective and cognitive enhancement effects in sporadic Alzheimer's disease

Sporadic Alzheimer's disease (SAD), an age-associated dementia, is described as neuronal loss and marked cognitive impairment. Ellagic acid (EA) is a phenolic phytoconstituent obtained from grains and fruits, having evident antioxidant effects and known to modulate several endogenous molecular signals in humans in a beneficial way. The current study evaluated the safety profile of EA in the SH-SY5Y human neuroblastoma cell line, performing anti-oxidative effect by DPPH assay, and evaluating anti-AchE (acetylcholinesterase) effect against AchE enzyme from Electrophorus electricus. The observations were further confirmed by in vivo therapeutic effects in streptozotocin (STZ)-induced SAD rats in the context of altered biochemical and behavioral features. Treatment with EA (50 mg/kg, p.o.) for 30 days revealed reduction in STZ (3 mg/kg i.c.v.) prompted SAD and associated biochemical abnormalities in experimental rats which included diminished oxidative stress profile, pro-inflammatory markers i.e. GFAP and CRP; AchE level, and amyloid-β plaque level. Moreover, an elevated level of synaptophysin indicated improved synaptic connectivity, and intact neural architecture showed neuroprotection in the EA group. Furthermore, the behavioral investigation by maze paradigms revealed reduced locomotor behavior, irregular spontaneous alternation, declination in memory score and increased memory errors in SAD rats. EA treatment normalized these SAD-associated abnormal behavioral representations in rats. Hence our findings suggest neuroprotective effects of EA and improvement in cognitive behavior in SAD rats.

Imagine that! Cue-evoked representations guide rat behavior during ambiguous situations.

Mental imagery involves the perceptual-like experience of an event that is not physically present, or detected by the senses. Fast and Blaisdell (2011) reported that rats use the representation of an associatively retrieved event to guide behavior in ambiguous situations. Rats were reinforced for lever-pressing during 1 of 2 lights but not both lights. They were then tested with 1 light illuminated while the second light was either covered by an opaque shield (ambiguous) or uncovered and unlit (explicitly absent). Rats lever-pressed less when the second light was covered compared with unlit, suggesting that a representation of the ambiguously absent light guided their behavior. However, Dwyer and Burgess (2011) offered an alternative mechanism in which the explicit absence of a cue gains associative value during training. Covering the light at test could effectively remove these associative properties, resulting in a generalization decrement of behavior. The current experiments were designed to test contrasting predictions made by these 2 accounts. Experiment 1 empirically established that generalization decrement can occur when an element of a compound cue is presented alone at test, but this decrement is attenuated, rather than enhanced, when the absent element is covered. Experiment 2 utilized a conditioned inhibition procedure to demonstrate that rat behavior during cue ambiguity is driven by an associatively retrieved representation rather than by generalization decrement. Collectively, the results argue against a purely nonrepresentational associative account of behavior and support a role for associatively retrieved representations in rats.

Transformation-Tolerant Object Recognition in Rats Revealed by Visual Priming

Successful use of rodents as models for studying object vision crucially depends on the ability of their visual system to construct representations of visual objects that tolerate (i.e., remain relatively unchanged with respect to) the tremendous changes in object appearance produced, for instance, by size and viewpoint variation. Whether this is the case is still controversial, despite some recent demonstration of transformation-tolerant object recognition in rats. In fact, it remains unknown to what extent such a tolerant recognition has a spontaneous, perceptual basis, or, alternatively, mainly reflects learning of arbitrary associative relations among trained object appearances. In this study, we addressed this question by training rats to categorize a continuum of morph objects resulting from blending two object prototypes. The resulting psychometric curve (reporting the proportion of responses to one prototype along the morph line) served as a reference when, in a second phase of the experiment, either prototype was briefly presented as a prime, immediately before a test morph object. The resulting shift of the psychometric curve showed that recognition became biased toward the identity of the prime. Critically, this bias was observed also when the primes were transformed along a variety of dimensions (i.e., size, position, viewpoint, and their combination) that the animals had never experienced before. These results indicate that rats spontaneously perceive different views/appearances of an object as similar (i.e., as instances of the same object) and argue for the existence of neuronal substrates underlying formation of transformation-tolerant object representations in rats.

Unique Contributions of Distinct Cholinergic Projections to Motor Cortical Plasticity and Learning

The cholinergic basal forebrain projects throughout the neocortex, exerting a critical role in modulating plasticity associated with normal learning. Cholinergic modulation of cortical plasticity could arise from 3 distinct mechanisms by 1) "direct" modulation via cholinergic inputs to regions undergoing plasticity, 2) "indirect" modulation via cholinergic projections to anterior, prefrontal attentional systems, or 3) modulating more global aspects of processing via distributed inputs throughout the cortex. To segregate these potential mechanisms, we investigated cholinergic-dependent reorganization of cortical motor representations in rats undergoing skilled motor learning. Behavioral and electrophysiological consequences of depleting cholinergic inputs to either motor cortex, prefrontal cortex, or globally, were compared. We find that local depletion of cholinergic afferents to motor cortex significantly disrupts map plasticity and skilled motor behavior, whereas prefrontal cholinergic depletion has no effect on these measures. Global cholinergic depletion perturbs map plasticity comparable with motor cortex depletions but results in significantly greater impairments in skilled motor acquisition. These findings indicate that local cholinergic activation within motor cortex, as opposed to indirect regulation of prefrontal systems, modulate cortical map plasticity and motor learning. More globally acting cholinergic mechanisms provide additional support for the acquisition of skilled motor behaviors, beyond those associated with cortical map reorganization.

Responses of infragranular neurons in the rat primary somatosensory cortex to forepaw and hindpaw tactile stimuli

Infragranular layers constitute the main output of the primary somatosensory cortex and represent an important stage of cortico-cortical and cortico-subcortical integration. We have previously used chronic multiple single-unit recordings to study the spatiotemporal structure of tactile responses of infragranular neurons within the forepaw cortical representation in rats [Tutunculer B, Foffani G, Himes BT, Moxon KA (2006) Structure of the excitatory receptive fields of infragranular forelimb neurons in the rat primary somatosensory cortex responding to touch. Cereb Cortex 16:791–810]. Here we extend our understanding of this structure by studying the overlap between the forepaw and hindpaw cortical representations. We recorded 204 responsive neurons in chronic experiments from eight anesthetized rats. Overall, only 23% of neurons responded exclusively to one paw, 52% of neurons responded to two paws, 19% of neurons responded to three paws, and 5% of neurons responded to all four paws. Quantitative measures of response magnitudes and latencies revealed the following main results. (1) The responses of forepaw neurons overall displayed greater magnitudes and shorter latencies than the responses of hindpaw neurons. (2) The responses to ipsilateral stimuli displayed smaller magnitudes, and longer—and more variable—latencies than the responses to contralateral stimuli. (3) The responses of forepaw neurons to hindpaw stimuli displayed smaller magnitudes and longer latencies than the responses to forepaw stimuli, whereas the responses of hindpaw neurons to forepaw stimuli displayed smaller magnitudes but similar latencies compared with the responses to hindpaw stimuli. These results show that the spatiotemporal structure of tactile responses of infragranular neurons extends across all four paws, and provide the basic architecture for studying physiological integration and pathophysiological reorganization of tactile information in the infragranular layers of the rat primary somatosensory cortex.

The extended hippocampal‐diencephalic memory system: Enriched housing promotes recovery of the flexible use of spatial representations after anterior thalamic lesions

The anterior thalamic (AT) nuclei constitute an important component of an extended hippocampal-diencephalic system, and severe persisting memory deficits are normally found after AT damage. This study examined whether postoperative enrichment promotes the recovery of the flexible use of spatial representations in rats with AT lesions. After training to swim from a single constant start position to a submerged platform in a Morris water maze, rats with AT lesions that were housed in standard cages (AT-Std) performed poorly when required to swim to the platform from novel start positions during probe trials. By contrast, rats with AT lesions but housed in enriched environments (AT-Enr), like sham-lesion rats, showed relatively little disruption when tested with novel start positions. AT-Std rats also initially showed impaired acquisition of the task, whereas AT-Enr rats learned at a similar rate to that of the Sham-Std group. Beneficial effects of enrichment were replicated in the subsequent standard water maze procedure that used varying start positions throughout training to acquire a new platform location. Although it is clear that AT damage can severely disrupt episodic-like memory processes, and appear to be a core part of the interlinked neural systems subserving episodic memory, the current findings strongly encourage study on the adaptive response of the brain to thalamic lesions and prospects for the development of rehabilitation programs in cases of anterograde amnesia associated with diencephalic injury.

Unstable CA1 place cell representation in rats with entorhinal cortex lesions

Recent studies emphasize the importance of the entorhinal cortex in spatial representation and navigation. Furthermore, evidence is accumulating to show that spatial processing depends on interactions between the entorhinal cortex and the hippocampus. To investigate these interactions, we examined the effects of entorhinal cortex lesions on the activity of hippocampal CA1 place cells. Rats received bilateral radiofrequency lesions of the entorhinal cortex or sham lesions before place cell recording. Place cells were recorded as the rats performed a pellet-chasing task in a cylinder containing three cue-objects. Entorhinal cortex lesions did not abolish place cell spatial firing but reduced noticeably discharge rate and field size. Most importantly, the lesions affected firing field stability when cells were recorded both in constant conditions and following cue manipulations (object rotation, object removal). These findings indicate that the entorhinal cortex is necessary for the stability of hippocampal representations across exposures to a familiar environment. Consistent with the recent discovery of grid cells in the medial entorhinal cortex, our results suggest that the entorhinal cortex contributes to providing a spatial framework that would enable the hippocampus to maintain stable environment-specific representations.

Definition of a new maze paradigm for the study of spatial behavior in rats

The present work defines a simple behavioral paradigm to evaluate spatial representation in rats. In two experimental conditions differing in the richness of distal visual cues, rats learned to locate a food goal in a cross maze from various starting points. We conducted different challenges consisting of (i) reaching the same goal from a modified arrangement of the maze arms (geometric challenge), (ii) reaching the goal within a 90° rotated maze, herein checking the use of a place strategy, and (iii) investigating the effect of central cholinergic blockade over the retention of the task. Results showed that rats needed 12–30 trials to learn a place response, depending upon the richness of the visual environment. The maze rotation did not produce any impairment whereas the geometric challenge affected the performance specifically under the visually richer environment. Scopolamine injection (i.p.) produced a significant impairment in place recognition. Our present work shows that this maze procedure constitutes a useful paradigm to assess learning and processing of a place representation by rats. Similarly to what has been shown in other popular maze paradigms, our results show that rats mostly rely on distal extra-maze cues to solve the task, but also compute intra-maze information.

Integration and representation in rats' serial pattern learning in the T-maze.

Rats were exposed to three-trial series consisting of reinforced (R) trials and one nonreinforced (N) trial in a fixed order, RRN and RNR (Experiments 1 and 2) or NRR and RRN (Experiment 3), on extended visually distinct runways in a T-maze. When initially presented with the same sequence on each series in a session (separate presentations) with the same runway on all trials within a series (Experiments 1 and 3), all the rats developed slower running speeds on N than on R trials. When a runway was sometimes changed between the first and next two trials during separate presentations training (Experiment 2) or both sequences were later intermixed within each session in each experiment, only rats exposed to each sequence on a specific runway maintained these serial running patterns. Rats displayed serial running patterns on a test RNN sequence similar to that on the RNR sequence (Experiment 2), as would be predicted by an intertrial association model of serial pattern learning (Capaldi & Molina, 1979), but responded on test RRR and NRN sequences (Experiment 3) as would be predicted by an ordinal-trial-tag/intratrial association model (Burns, Wiley, & Payne, 1986). Results from test series of free-choice trials in Experiments 1 and 2 failed to support a prediction of the intratrial association model that these rats would integrate RRN and RNR sequences. Rather than always selecting a baited runway on both the second and the third free-choice trials, the rats only selected a baited runway on the third trial on the basis of their choice on the second trial, as would be predicted by the intertrial association model. Only after experiencing all possible outcome sequences during forced-choice training in Experiment 3 did these rats predominantly select a baited runway on every free-choice trial.

Lesions of the Basolateral Amygdala Disrupt Selective Aspects of Reinforcer Representation in Rats

The amygdala is known to play a role in learning about motivationally significant events. We investigated this role further by examining the effects of excitotoxic lesions of the basolateral amygdala on the ability of rats to use instrumental outcomes to direct responding (the differential outcomes effect) and on the ability of Pavlovian cues to modulate instrumental performance based on shared outcomes (reinforcer-selective Pavlovian-to-instrumental transfer). We found that basolateral amygdala (BLA) lesions did not affect the ability of rats to learn a basic instrumental conditional discrimination, but did disrupt the ability of differential outcomes to facilitate acquisition. In Pavlovian-to-instrumental transfer, BLA lesions did not disrupt the basic enhancement of instrumental performance but did abolish the reinforcer specificity of that enhancement. These results suggest that the BLA is involved in the representation of the sensory aspects of motivationally significant events.

Spatial learning by rats across visually disconnected environments

Experiments were designed in which some properties of spatial representations in rats could be examined. Adult subjects were trained to escape through a hole at a fixed position in a large circular arena (see Schenk, 1989). The experiments were conducted in the dark, with a limited number of controlled visual light cues, in order to assess the minimal cue requirement for place learning. Three light cues identical in shape, height, and distance from the table were used. Depending on the condition, they were either permanently on or alternatively on or off, contingent on the position of the rat in the field. Two questions were asked: (1) How many identical visual cues were necessary for spatial discrimination in the dark, and (2) could rats integrate the relative positions of separate cues, under conditions in which the rat was never allowed to perceive all three cues simultaneously. The results suggest that rats are able to achieve a place discrimination task even if the three cues necessary for efficient orientation can never be seen simultaneously. A dissociation between the discrimination of the spatial position of the goal and the capacity to reach it by a direct path suggests that, with a reduced number of cues, prolonged locomotion might be required for accurate orientation in the environment.

Object-goal positioning influences spatial representation in rats

Three tests investigated how the geometric relation between object/landmarks and goals influenced spatial choice behavior in rats. Two groups searched for hidden food in an object-filled circular arena containing 24 small poles. For the “Proximal” group, four distinct objects in a square configuration were placed close to four baited poles. For the “Distal” group, the identical configuration of objects was rotated 45° relative to the poles containing the hidden food. The Proximal group learned to locate the baited poles more quickly than the Distal group. Tests with removed and rearranged landmarks indicated that the two groups learned to use the objects differently. The results suggested that close proximity of objects to goals encouraged their use as beacons, while greater distance of objects from goals resulted in the global encoding of the geometric properties of the arena and the use of the objects as landmarks.

Blockade of GABAergic inhibition reveals reordered cortical somatotopic maps in rats that sustained neonatal forelimb removal.

A previous study from this laboratory demonstrated that forelimb removal at birth results in invasion of the cuneate nucleus (CN) by sciatic nerve axons and the development of CN cells including thalamic projection neurons with receptive fields that include both the forelimb stump and the hindlimb. However, recordings from unit clusters in lamina IV of the primary somatosensory cortex (SI) of these animals revealed the presence of only a very few sites in the forelimb stump representation where responses to hindlimb stimulation could also be recorded. In the present study we tested the possibility that input from the hindlimb was suppressed in lamina IV of the cortical stump representation via GABAergic inhibitory mechanisms by mapping this cortical region, applying the gamma-aminobutyric acid-A (GABA(A)) and GABA(B) receptor antagonists bicuculline and phaclofen (50 microM each), and then remapping the same sites. In six neonatally manipulated rats, 15 of 242 sites (6.2%) in the stump representation responded to hindlimb stimulation before GABA receptor blockade and 107 (44.2%) of the same sites responded to stimulation of the hindlimb during blockade (P < 0.05). In six normal adult rats, 7 of 264 sites (2.7%) in the forelimb representation responded to hindlimb stimulation before the application of bicuculline and phaclofen. During GABA receptor blockage, 31 of these sites (11.7%) responded to such stimulation (P < 0.02 vs. the untreated normal cortex and P < 0.01 vs. the neonatally manipulated rats treated with GABA blockers). To specifically test the role of GABA(A) versus GABA(B) receptors in the inhibition of hindlimb input to the SI stump representation in rats that sustained neonatal forelimb removal, either bicuculline or phaclofen alone was applied to SI in nine neonatally manipulated animals. In four rats treated with bicuculline, 12 of 184 sites (6.5%) in the stump representation responded to hindlimb stimulation before treatment and 61 of 184 sites (33.2%) responded to such stimulation during application (P < 0.01). In animals (n = 5) treated with phaclofen, 18 of 251 sites (7.2%) responded to hindlimb stimulation before treatment and 64 of these sites (25.5%) responded to such stimulation during application (P < 0.05). There was no significant difference between the results obtained with bicuculline alone, phaclofen alone, or the two GABA blockers delivered together (P > 0.05). These results indicate that hindlimb input to the portion of SI representing the forelimb stump is functionally suppressed in rats that have sustained neonatal forelimb removal and that GABAergic inhibition, mediated by both GABA(A) and GABA(B) receptors, is involved in this process.

Effects of parietal cortex lesions on spatial problem solving in the rat

The Maier 3-table task was used to examine spatial representations in rats with lesions of the parietal cortex. Some animals had anteriorly placed lesions, some posteriorly placed in cortical areas, sometimes regarded as ‘parietal’ in earlier studies. After 5 days of familiarization, animals were given 18 days of testing on the standard Maier task. Both parietal groups were initially impaired, but reached the same level of performance as controls by the end of the test period. Learning occurred both within and between sessions for the anterior group, but only between sessions for the posterior group. There was no major functional differentiation apparent on this task between the two ‘parietal’ areas. Rate of exploration increased in both parietal groups across test sessions as task performance improved. It is argued that the change in exploratory activity across sessions in parietal groups may reflect the adoption of a compensatory strategy which improved performance, but that improvement could also have been due to neural changes, as structures, such as the frontal cortex or hippocampus, assume some functions normally mediated by the parietal area.

Place and position learning in honeybees (Apis mellifera).

Foraging honeybees (Apis mellifera) were trained individually to choose between 2 identical targets set close together on a large table in a heterogeneous surround. Discrimination was facilitated by the introduction of a small object that was nearer to 1 target than the other. It was also facilitated by the introduction of a longer object or a curved shield that was not differentially placed with respect to the targets but designed to encourage a fixed orientation to them. results support a distinction between place learning and position learning in honeybees. When a honeybee is trained to choose between two targets that differ in some integral property, such as color, the locations of the targets must be interchanged to demonstrate discrimination of color apart from location. Discrimination of location, which may be evident in a preference displayed at the outset of training or established by differential reinforcement (Couvillon, Klosterhalfen, & Bitterman, 1983; Klosterhalfen, Fischer, & Bitterman, 1978), is interesting because location is not an integral property of a target but may be given in relation either to its surround (place learning) or to the orientation of the animal (position learning). Place and position learning were first clearly distinguished in some early experiments with rats (Blodgett & McCutchan, 1947; Tolman, Ritchie, & Kalish, 1946). Trained on an elevated T maze whose situation in a visually heterogeneous environment is changed from trial to trial, rats can learn readily to go always to a fixed place, whether a left or a right turn at the choice point is required to take them there on any given trial. They also can learn—more readily in a homogeneous environment than in a heterogeneous one (Restle, 1957)—to turn always to the left or always to the right at the choice point, although the same turn takes them to different places on different trials. Learning always to turn left or right at a choice point has traditionally been characterized as response learning rather than position learning on the assumption that the motor system is uniquely involved. That assumption is clearly expressed by Leonard and McNaughton (1990) in a recent essay on the neurobiology of spatial representation in rats: The response strategy, they wrote, employs a specific sequence of motor acts, largely independently of the distribution of sensory cues, to attain a goal of navigation (p. 375). Our own preference is for the more neutral term, position learning, because persuasive evidence for the motor interpretation is