Unpredictable mealtimes rather than social jetlag affects acquisition and retention of hippocampal dependent memory.

Some degree of circadian rhythm disruption is hard to avoid in today's society. Along, with many other deleterious effects, circadian rhythm disruption impairs memory. One way to study this is to expose rats to daylengths that are outside the range of entrainment. As a result, circadian processes and behaviors occur during phases of the light dark cycle in which they typically would not. Even brief exposures to these day lengths can impair hippocampal dependent memory. In a recent report, we created an unentrainable light dark cycle that was intended to resemble aspects of social jetlag. As predictable mealtime impacts circadian entrainment, in that report, we also created an unpredictable meal schedule with the idea that failure to entrain to a meal might afford a disadvantage in some instances. Both of these manipulations impaired retention in a spatial water plus-maze task. Using the same manipulations, the present study investigated their effects on acquisition in distributed and massed spatial water plus-maze paradigms. As in other reports with unentrainable daylengths, acquisition was not affected by our lighting manipulation. Conversely, in accordance with our past report, unpredictable mealtimes had a harmful effect on hippocampal dependent memory. Notably, impaired acquisition in the distributed version, and impaired retention in the massed version. In tandem, these data suggest that failure to consolidate or retrieve the information is the likely culprit. The unpredictable mealtime manipulation offers a unique opportunity to study the effects of circadian entrainment on memory.

Lesions to the lateral mammillary nuclei disrupt spatial learning in rats.

The head direction (HD) signal is thought to originate in the reciprocal connections between the dorsal tegmental nuclei (DTN) and the lateral mammillary nuclei (LMN) and lesions to these structures disrupt the HD signal in downstream structures. Lesions to the DTN also disrupt performance on spatial tasks where directional heading is thought to be important. In Experiment 1, rats with bilateral electrolytic lesions of the LMN and sham controls were trained on 2 tasks previously shown to be sensitive to DTN damage. Rats were first trained on either a direction or rotation problem in a water T maze. LMN-lesioned rats were impaired relative to sham controls, on both the first block of 8 trials and on the total number of trials taken to reach criterion. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in a food cup at the center of the table, and return to the home cage. Again, LMN-lesioned rats were impaired relative to sham rats, making more errors on the return component of the foraging trip. In Experiment 2, rats with electrolytic LMN lesions were also impaired on a dry land version of the direction and rotation problems and had difficulty discriminating between reinforced and nonreinforced locations on a 12-arm maze. These results build on previous behavioral and cell-recording studies and demonstrate the importance of the direction system to spatial learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Consistent meal times improve performance on a daily time-place learning task.

The ability of an animal to learn the spatiotemporal variability of stimuli is known as time-place learning (TPL). The present study investigated the role of the food-entrainable oscillator (FEO) in TPL. Rats were trained in an operant conditioning chamber which contained two levers that distributed a food reward, such that one lever provided food rewards in morning sessions, while the other lever provided food rewards in afternoon sessions. We expected that having access to the FEO would provide rats with more accurate depictions of time of day, leading to better performance. Rats received either one meal per day (1M group), which permitted FEO access, or many meals per day (MM group), which prevented FEO access. As predicted, 1M rats had a significantly higher percentage of correct first presses than MM rats. Once rats successfully learned the task, probe tests were conducted to determine the timing strategy used. Of the 10 rats that successfully learned the time-place discrimination, six used a circadian timing strategy. Future research should determine whether the advantage in learning seen in the rats having access to the FEO is specific to the daily TPL task used in this study, or to learning and memory tasks more generally.

Locus Coeruleus Optogenetic Light Activation Induces Long-Term Potentiation of Perforant Path Population Spike Amplitude in Rat Dentate Gyrus.

Norepinephrine (NE) in dentate gyrus (DG) produces NE-dependent long-term potentiation (NE-LTP) of the perforant path-evoked potential population spike both in vitro and in vivo. Chemical activators infused near locus coeruleus (LC), the source of DG NE, produce a NE-LTP that is associative, i.e., requires concurrent pairing with perforant path (PP) input. Here, we ask if LC optogenetic stimulation that allows us to activate only LC neurons can induce NE-LTP in DG. We use an adeno-associated viral vector containing a depolarizing channel (AAV8-Ef1a-DIO-eChR2(h134r)-EYFP-WPRE) infused stereotaxically into the LC of TH:Cre rats to produce light-sensitive LC neurons. A co-localization of ~62% in LC neurons was observed for these channels. Under urethane anesthesia, we demonstrated that 5-10 s 10 Hz trains of 30 ms light pulses in LC reliably activated neurons near an LC optoprobe. Ten minutes of the same train paired with 0.1 Hz PP electrical stimulation produced a delayed NE-LTP of population spike amplitude, but not EPSP slope. A leftward shift in the population spike input/output curve at the end of the experiment was also consistent with long-term population spike potentiation. LC neuron activity during the 10 min light train was unexpectedly transient. Increased LC neuronal firing was seen only for the first 2 min of the light train. NE-LTP was more delayed and less robust than reported with LC chemo-activation. Previous estimates of LC axonal conduction times suggest acute release of NE occurs 40-70 ms after an LC neuron action potential. We used single LC light pulses to examine acute effects of NE release and found potentiated population spike amplitude when a light pulse in LC occurred 40-50 ms, but not 20-30 ms, prior to a PP pulse, consistent with conduction estimates. These effects of LC optogenetic activation reinforce evidence for a continuum of NE potentiation effects in DG. The single pulse effects mirror an earlier report using LC electrical stimulation. These acute effects support an attentional role of LC activation. The LTP of PP responses induced by optogenetic LC activation is consistent with the role of LC in long-term learning and memory.

Rats in a levered T-maze task show evidence of time-place discriminations in two different measures.

It is difficult for rats to learn to go to an arm of a T-maze to receive food that is dependent on the time of day, unless the amount of food in each daily session is different. In the same task, rats show evidence of time-place discriminations if they are required to press levers in the arms of the T-maze, but learning is only evident when the first lever press is considered, and not the first arm visited. These data suggest that rats struggle to use time as a discriminative stimulus unless the rewards/events differ in some dimension, or unless the goal locations can be visited prior to making a response. If both of these conditions are met in the same task, it might be possible to compare time-place learning in two different measures that essentially indicate performance before and after entering the arms of the T-maze. In the present study, we investigated time-place learning in rats with a levered T-maze task in which the amounts of food varied depending on the time of day. The first arm choices and first lever presses both indicated that the rats had acquired time-place discriminations, and both of these measures became significantly different from chance during the same block. However, there were subtle differences between the two measures, which suggest that time-place discrimination is aided by visiting the goal locations.

Mice use start point orientation to solve spatial problems in a water T-maze.

Behavioral work has demonstrated that rats solve many spatial problems using a conditional strategy based on orientation at the start point. The present study assessed whether mice use a similar strategy and whether the strategy would be affected by the poorer directional sensitivity of mice. In Experiment 1, mice were trained on a response, a direction or one of two place problems to locate a hidden platform in a water T-maze located in two positions. In the response task, mice made a right (or left) turn from two different start points located 180° apart. In the direction task, the maze was shifted (to the left or right) and the start points rotated by 180° across trials, but the platform was in a constant direction relative to room cues. In the translation place task, the mice were trained to locate the platform in a fixed location relative to extra-maze cues when the maze was shifted across trials, but the orientation of the start arm did not change. In the rotation place task, the mice were trained to locate the platform in a fixed location when the maze was shifted and the start points rotated by 90° across trials. As previously reported with rats, mice had difficulty solving the translation place problem compared with the other three problems. Unlike rats, mice learned the direction problem in significantly fewer trials than the rotation problem. This difference between acquisition of the direction and rotation problems was replicated in Experiment 2. The difficulty mice have in discriminating start point orientations that are 90° apart as opposed to 180° apart can be attributed to the broader firing ranges of HD cells in mice compared with rats.

The effects of lesions to the postsubiculum or the anterior dorsal nucleus of the thalamus on spatial learning in rats.

To investigate the role of the head direction (HD) cell circuit in spatial navigation, rats with bilateral, neurotoxic lesions to the postsubiculum (PoS; Experiment 1) or the anterior dorsal nucleus of the thalamus (ADN; Experiment 2) were compared to sham controls on 2 tasks that could be solved using directional heading. Rats were first trained on a direction problem in a water T maze where they learned to travel either east or west from 2 locations in the experimental room. ADN lesioned rats were impaired relative to sham controls on the first block of 8 trials, but not on the total trials taken to reach criterion. This transient deficit was not observed in rats with lesions to the PoS. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in the center of the table, and return to the home cage. Both PoS and ADN lesioned rats showed impairments on this task relative to sham rats, making more errors on the return component of the foraging trip. The spatial deficits produced by lesions to the PoS and the ADN, downstream structures in the HD cell circuit, are not as severe as those observed in earlier studies in rats with lesions to the dorsal tegmental nucleus.

In a daily time-place learning task, time is only used as a discriminative stimulus if each daily session is associated with a distinct spatial location.

It is difficult for rats to acquire daily time-place (TP) learning tasks. One theory suggests that rats do not use time of day as a stimulus signaling a specific response. In the present study, we tested rats' ability to use time of day as a discriminative stimulus. A fixed-interval procedure was used in which one lever provided reinforcement on a FI-5-s schedule in morning sessions, and the same lever provided reinforcement on a FI-30-s schedule in afternoon sessions. Because only one place was used in this paradigm, the rats could only use time of day to acquire the task. Mean responses during the first 5 s of the first trial in each session indicated that the rats did not discriminate between the two sessions. In Phase II, a different lever location was used for each of the two daily sessions, which meant that both spatial and temporal information could be used to acquire the task. The rats readily acquired the task in this phase, and probe trials indicated that the rats were using a combination of spatial and temporal information to discriminate between the two different trial types. When the spatial cue was removed in Phase III, rats no longer discriminated the two sessions, suggesting that time can only be used as a discriminative stimulus when each daily session is associated with a distinct spatial location.

Hippocampal spatial mapping and the acquisition of competing responses.

Response reversal learning is facilitated in many species, including humans, when competing responses occur in separate contexts. This suggests hippocampal maps may facilitate the acquisition of competing responses and is consistent with the hypothesis that contextual encoding permits rapid acquisition of new behaviors in similar environments. To test this hypothesis, the pattern of Arc expression was examined after rats completed a series of left/right response reversals in a T-maze. This reversal training occurred in the same room, two different rooms, or within a single room but with the maze enclosed in wall-length curtains of different configurations (i.e., black/white square or circle). Across CA1 and CA3, successive T-maze exposures in the same room recruited the same cells to repeatedly transcribe Arc, while a unique population of cells transcribed Arc in response to each of two different rooms as well as to the two unique curtain configurations in the same room. The interference from original learning that was evident on the first reversal in animals without a context switch was absent in groups that experienced changes in room or curtain configuration. However, only the use of unique rooms, and not changes in the curtained enclosure, facilitated learning across response reversals relative to the groups exposed to only one room. Thus, separate hippocampal maps appear to provide protection from the original learning interference but do not support improved reversals over trials. The present data suggest changes in heading direction input, rather than remapping, are the source of facilitation of reversal learning.

The effects of bilateral lesions to the dorsal tegmental nucleus on spatial learning in rats.

The head-direction (HD) signal is believed to originate in the dorsal tegmental nucleus (DTN) and lesions to this structure have been shown to disrupt HD cell firing in other areas along the HD cell circuit. To investigate the role of the DTN in spatial navigation, rats with bilateral, electrolytic (Experiment 1), or neurotoxic (Experiment 2) lesions to the DTN were compared with sham controls on two tasks that differed in difficulty and could be solved using directional heading. Rats were first trained on a direction problem in a water T maze where they learned to travel either east or west from two locations in the experimental room. DTN-lesioned rats were impaired relative to sham controls, both early in training, on the first block of eight trials, and on the total trials taken to reach criterion. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in the center of the table and return to the home cage. Again, DTN-lesioned rats were impaired relative to sham rats, making more errors on the return component of the foraging trip. These data extend previous cell-recording studies and behavioral tests in which rats with electrolytic DTN lesions were used, and they demonstrate the importance of the direction system to spatial learning.

Aversive, appetitive and flavour avoidance responses in the presence of contextual cues.

Appetitive, aversive and avoidance responses to a flavoured solution in distinct contexts were examined. Rats placed in either a white or black box were given access to saccharin. Consumption was followed by an injection of a toxin in one but not the other box. Rats showed more aversive responses in anticipation of and during the presentation of saccharin in the box paired with the toxin than in the box paired with vehicle. The reverse was true for appetitive responses. The acquisition of conditioned avoidance paralleled the acquisition of aversive and appetitive responses. These findings demonstrate that the toxin does not have to overlap exposure to contextual cues to produce conditioned aversive responses, that the aversive and appetitive responses to a flavour can be modulated by visually distinct environments that predict the toxin, and that conditioned avoidance and conditioned aversions develop simultaneously during acquisition. Thus, environmental cues can modulate anticipatory nausea and may prove helpful in the control of nausea in clinical settings.

Rats' orientation is more important than start point location for successful place learning.

Rats were trained to locate food on a plus maze that was moved between 2 locations. The food was in a fixed location relative to room cues but the maze, and the animals' start point, were either translated (shifted to the left or right) or rotated (by 90 degrees or 45 degrees ) across trials. Rats started from the same or different places solved the problem if they headed in a direction different from the start point. Rats started from different places were impaired if they headed in the same direction, suggesting that orientation is more important than start point for successful performance. The same pattern of results was obtained when rats were trained inside a curtained enclosure, suggesting that orientation is not derived solely from a view of distal visual cues while on the maze. It appears that rats use their heading, or direction of movement, to guide their responses at a choice point.

The contribution of spatial cues to memory: direction, but not cue, changes support response reversal learning.

In four experiments, rats were trained on a response problem followed by three reversals. Rats that changed rooms between acquisition and reversals learned the reversals in fewer trials than rats that remained in the same room, even when distal visual cues were limited. Changes in orientation, even in the same room, also facilitated response reversal learning. The advantage observed with changes in orientation across reversals does not appear to be due to differences in local views or to different start positions. Direction changes, but not cue changes, may support response reversal learning by taking advantage of the natural interaction between responses and direction when one map is used.

CA1 ischemic injury does not affect the ability of Mongolian gerbils to solve response, direction, or place problems.

Open field and T-maze paradigms are used to test the effects of hippocampal lesions on spatial memory in rodents. Place cells in the dorsal CA1 region of the hippocampus are known to be responsible for the formation of global place maps, while CA3 neurons respond to changes in local contexts. It is proposed here that when dorsal CA1 is selectively destroyed, gerbils will be unable to solve direction and place problems while context-dependent representations of relative maze positions should be spared since CA3 cells are left intact. Twenty female Mongolian gerbils were subjected to 5 min of forebrain ischemia, and, along with 20 controls, were subsequently tested on a response, direction or one of two types of open field place problems. Locomotion in a circular open field was recorded as a measure of hyperactivity. Gerbils with damage restricted to dorsal CA1 were hyperactive compared to controls, but were not impaired on place, direction, or response tasks. Because gerbils solved these tasks in the absence of dorsal CA1, maze tasks which have traditionally been labeled "place" or "direction" tasks may actually be testing the animal's ability to discriminate between two relative contexts, without the need for a global place map. Our findings support recent reports that different hippocampal subfields control different aspects of spatial learning and memory. Specifically, the context-dependent representations in CA3 appear to support the learning of the "place" and, likely, "direction" solutions in current and previous open field and T-maze tasks.

Where am I? Distal cues use requires sensitivity to start location change in the rat.

Place learning is impaired when a single plus maze is moved between adjacent locations 33-120 cm apart. This maze translation creates distinct start locations but maintains a single goal location with respect to distal cues. Hippocampal cell recording data suggest the majority of place fields are tied to apparatus boundaries, not to distal cues, when an apparatus is moved these distances to the left or right. Thus, rats may fail to appreciate the existence of multiple start locations with respect to distal cues when the maze is moved in this way and their start location on the surface is constant. Performance on the single plus maze problem was improved when texture cues were correlated with different start locations. Place learning was supported when multiple start locations were provided on a single large surface (double plus maze), even though rats did not explore the entire surface. Place learning was also supported when random extensions were added to a double plus maze such that start locations, relative to surface boundaries, were not informative as to goal location. This outcome suggests sensitivity to multiple start locations is required for distal cue use in translational place problems.

Location serves as a conditional cue when harp seals (Pagophilus groenlandicus) solve object discrimination reversal problems.

We examined the capacity of harp seals (Pagophilus groenlandicus) to use spatial context (i.e., their tank) as a conditional cue to solve a two-choice visual discrimination reversal task. Seals were trained to touch one of two 3D objects. Two of four seals experienced a context shift that coincided with each of five reversals in the reward value of the two stimuli (i.e., a reversal of S+ and S-); these seals solved the six discriminations in significantly fewer trials than did seals that did not experience a context shift with the contingency reversal. Thus, harp seals use contextual cues when encoding information. The findings are discussed in terms of harp seals' adaptations to the pack-ice environment, the constraints of the learning tasks, and the nature of the subjects that were raised in captivity.

The effects of hippocampal lesions on response, direction, and place learning in rats.

Rats with hippocampal or sham lesions were trained to find food on a T maze located at 2 positions. Response rats were required to make a right or left turn. Direction rats were required to go in a consistent direction (east or west). Place rats were required to go to a consistent location, relative to room cues. One place group had distinguishable start points at the 2 maze positions, whereas another place group had start points facing the same side of the room. Controls took longer to solve a place problem than the response and direction problems when the start points were not distinguishable. Rats with hippocampal lesions were not different than controls on the response problem but were impaired on the direction and place problems.

Perirhinal cortex lesions impair context aversion learning.

Rats with perirhinal cortex lesions were compared with sham controls on a conditional discrimination in which saccharin was paired with LiCl in context 1, but paired with saline in context 2. Perirhinal-lesioned rats were slightly slower to acquire the discrimination but reached control levels by the end of acquisition. Both groups showed transfer to familiar tap water, consuming less in context 1 than in context 2. Unlike sham rats, perirhinal rats failed to show an aversion to context 1 on a place choice test. These data provide neuroanatomical support for the postulated difference between Pavlovian conditioning and conditional learning.

An analysis of response, direction, and place learning in an open field and T maze.

Rats were trained to locate food in a response, direction, or place problem on an open field located at 2 positions. In Experiment 1, both the response and direction groups solved the problem. The place group failed to solve the task in approximately 300 trials. Experiment 2 demonstrated that rats need distinguishable start points to solve a place problem when neither a response nor a direction solution is available. Findings from Experiment 3 suggest that a combination of path traveled and distinct cues help to differentiate start points. Experiment 4 replicated the findings using a T maze. These results suggest "place" solutions are difficult for rats. The data are discussed with respect to conditional learning and modern spatial mapping theory.