Temporally selective contextual encoding in the dentate gyrus of the hippocampus.

A recent model of the hippocampus predicts that the unique properties of the dentate gyrus allow for temporal separation of events. This temporal separation is accomplished in part through the continual generation of new neurons, which, due to a transient window of hyperexcitability, could allow for preferential encoding of information present during their development. Here we obtain in vivo electrophysiological recordings and identify a cell population exhibiting activity that is selective to single contexts when rats experience a long temporal separation between context exposures during training. This selectivity is attenuated as the temporal separation between context exposures is shortened and is further attenuated when neurogenesis is reduced. Our data reveal the existence of a temporal orthogonalizing neuronal code within the dentate gyrus, a hallmark feature of episodic memory.

The role of visual cortex acetylcholine in learning to discriminate temporally modulated visual stimuli.

Cholinergic neurons in the basal forebrain innervate discrete regions of the cortical mantle, bestowing the cholinergic system with the potential to dynamically modulate sub-regions of the cortex according to behavioral demands. Cortical cholinergic activity has been shown to facilitate learning and modulate attention. Experiments addressing these issues have primarily focused on widespread cholinergic depletions, extending to areas involved in general cognitive processes and sleep cycle regulation, making a definitive interpretation of the behavioral role of cholinergic projections difficult. Furthermore, a review of the electrophysiological literature suggests that cholinergic modulation is particularly important in representing the fine temporal details of stimuli, an issue rarely addressed in behavioral experimentation. The goal of this work is to understand the role of cholinergic projections, specific to the sensory cortices, in learning to discriminate fine differences in the temporal structure of stimuli. A novel visual Go/No-Go task was developed to assess the ability of rats to learn to discriminate fine differences in the temporal structure of visual stimuli (lights flashing at various frequencies). The cholinergic contribution to this task was examined by selective reduction of acetylcholine projections to visual cortex (VCx) (using 192 IgG-saporin), either before or after discrimination training. We find that in the face of compromised cholinergic input to the VCx, the rats' ability to learn to perform fine discriminations is impaired, whereas their ability to perform previously learned discriminations remains unaffected. These results suggest that acetylcholine serves the role of facilitating plastic changes in the sensory cortices that are necessary for an animal to refine its sensitivity to the temporal characteristics of relevant stimuli.

Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats.

Despite abundant evidence of behavioral and electrophysiological dysfunction of the rodent hippocampal formation with aging, the structural basis of age-related cognitive decline remains unclear. Recently, unbiased stereological studies of the mammalian hippocampus have found little evidence to support the dogma that cellular loss accompanies hippocampal aging, thereby supporting an alternative hypothesis that aging is marked by widespread conservation of neuronal number. However, to date, the effects of aging have not been reported in another key component of memory systems in the rodent brain, the entorhinal cortex. In the present study, we stereologically estimated total neuronal number and size (cross-sectional area and cell volume) in the subdivisions and cellular layers of the rat entorhinal cortex, using the optical fractionator and nucleator, respectively. Comparisons were made among Fischer 344 rats that were young, aged-impaired, and aged-unimpaired (based on functional analysis in the Morris water maze). No significant differences in cell number or size were observed in any of the entorhinal subdivisions or laminae examined in each group. Thus, aging is associated with widespread conservation of neuronal number, despite varying degrees of cognitive decline, in all memory-related systems examined to date. These data suggest that mechanisms of age-related cognitive decline are to be found in parameters other than neuronal number or size in the cortex of the mammalian brain.

A neural circuit analysis of visual recognition memory: role of perirhinal, medial, and lateral entorhinal cortex.

Using a continuous recognition memory procedure for visual object information, we sequentially presented rats with eight novel objects and four repeated objects (chosen from the 8). These were selected from 120 different three-dimensional objects of varying sizes, shapes, textures, and degree of brightness. Repeated objects had lags ranging from 0 to 4 (from 0 to 4 different objects between the first and repeated presentation). An object was presented on one side of a long table divided in half by an opaque Plexiglas guillotine door, and the latency between opening the door and the rat moving the object was measured. The first presentation of an object resulted in reinforcement, but repeated presentations did not result in a reinforcement. After completion of acquisition training (significantly longer latencies for repeated presentation compared with the first presentation of an object), rats received lesions of the perirhinal, medial, or lateral entorhinal cortex or served as sham operated controls. On the basis of postsurgery testing and additional tests, the results indicated that rats with perirhinal cortex lesions had a sustained impairment in performing the task. There were no sustained deficits with medial or lateral entorhinal cortex lesions. The data suggest that recognition memory for visual object information is mediated primarily by the perirhinal cortex but not by the medial or lateral entorhinal cortex.

Changes in functional connectivity in orbitofrontal cortex and basolateral amygdala during learning and reversal training.

Interconnections between orbitofrontal cortex (OFC) and basolateral amygdala (ABL) are critical for encoding and using associative information about the motivational significance of stimuli. Previously, we reported that neurons in OFC and ABL fired selectively to cues during odor discrimination learning and reversal training. Here we conducted an analysis of correlated firing in the cell pairs recorded in the previous study. Correlated firing during the intertrial intervals was compared across task phases during different phases of acquisition and reversal learning. Changes in correlated activity during initial learning and subsequent accurate performance on the discrimination problems closely resembled the changes in odor selectivity in OFC and ABL reported earlier. Increased correlated firing was most pronounced in OFC during accurate go, no-go performance in the postcriterion phase of performance, whereas correlated firing in ABL increased primarily during an earlier phase of learning. In contrast, findings during subsequent reversal training diverged from our earlier report in which odor selectivity diminished in OFC and reversed in ABL. When the reinforcement contingencies of the odors were reversed after the rat had learned the original associations, correlated firing further increased significantly in OFC but remained stable in ABL. This evidence that associative encoding increments with reversal learning in OFC suggests that the original associations, although not expressed as stimulus driven activity, may be maintained within the network as new associations are acquired.

A comparison of the effects of bilateral and unilateral infusions of muscimol into the basal forebrain on cued detection of visual targets in rats.

This study investigated the role of the basal forebrain cholinergic system (BFCS) in rats' performance of a visuospatial attention task. Muscimol was infused bilaterally and unilaterally into the BFCS to inhibit cholinergic projections to the cortex. Muscimol slowed responding without significantly affecting side-bias. Bilateral infusions increased accuracy for all targets, whereas unilateral infusions reduced accuracy for targets contralateral to the infusion and increased accuracy for targets ipsilateral to the infusion. After a low unilateral dose of muscimol, invalid cues impaired detection of contralateral targets and spared detection of ipsilateral targets. A high unilateral dose of muscimol impaired detection of contralateral targets independently of cueing. These results suggest that interhemispheric imbalance in cortical activity by pharmacological manipulation of the BFCS can impair the detection of lateralized visual stimuli.

Selective removal of cholinergic neurons in the basal forebrain alters cued target detection.

A spatial orienting task was used to assess attention in rats with selective cholinergic lesions of the basal forebrain. The task required each rat to press a lever in response to a visual target that could occur in one of two locations. A target could be preceded by a cue that either accurately predicted the location of the target (valid) or appeared in the location opposite the target (invalid). Target detection was facilitated by valid cues and degraded by invalid cues in control rats. Performance of rats with lesions was equivalent to that of control rats for valid cues, but reflected an increased cost of invalid cueing. These data support a modulatory role for the basal forebrain cholinergic system in visuospatial attention.

Cognitive functions of the basal forebrain.

Studies of the function of the basal forebrain have focused on cholinergic neurons that project to cortical and limbic structures critical for various cognitive abilities. Recent experiments suggest that these neurons serve a modulatory function in cognition, by optimizing cortical information processing and influencing attention.

Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning.

Orbitofrontal cortex (OFC) is part of a network of structures involved in adaptive behavior and decision making. Interconnections between OFC and basolateral amygdala (ABL) may be critical for encoding the motivational significance of stimuli used to guide behavior. Indeed, much research indicates that neurons in OFC and ABL fire selectively to cues based on their associative significance. In the current study recordings were made in each region within a behavioral paradigm that allowed comparison of the development of associative encoding over the course of learning. In each recording session, rats were presented with novel odors that were informative about the outcome of making a response and had to learn to withhold a response after sampling an odor that signaled a negative outcome. In some cases, reversal training was performed in the same session as the initial learning. Ninety-six of the 328 neurons recorded in OFC and 60 of the 229 neurons recorded in ABL exhibited selective activity during evaluation of the odor cues after learning had occurred. A substantial proportion of those neurons in ABL developed selective activity very early in training, and many reversed selectivity rapidly after reversal. In contrast, those neurons in OFC rarely exhibited selective activity during odor evaluation before the rats reached the criterion for learning, and far fewer reversed selectivity after reversal. The findings support a model in which ABL encodes the motivational significance of cues and OFC uses this information in the selection and execution of an appropriate behavioral strategy.

Effects of unilateral removal of basal forebrain cholinergic neurons on cued target detection in rats.

Corticopetal cholinergic neurons in the basal forebrain (BF) were removed unilaterally from rats by infusing the cholinergic immunotoxin 192 IgG-saporin into the substantia innominata. After 2 weeks, the rats with right-hemisphere infusions showed signs of visuospatial neglect for targets in the left visual field in a cued visual target detection task based upon human covert orienting procedures. No behavioral effects were evident 4-6 weeks post-infusion. Ten to 22 weeks post-infusion all rats responded more quickly and less accurately to targets in the visual field contralateral to the infusion than to targets ipsilateral to the infusion: further, accuracy for contralateral targets decreased with increasing time between trial initiation and target presentation (target delay), whereas accuracy for ipsilateral targets increased with target delay. Cues did not affect responding to targets in the contralateral visual field more than to targets in the ipsilateral field. The changes in performance could not be attributed to sensory or mnemonic impairment or to response bias. The temporal characteristics of response accuracy and latency suggest the competitive interaction of two time-dependent processes: an attentional process which relies upon cholinergic input from the BF, and a response preparation process which is normally inhibited by the attentional process. These results suggest a role for corticopetal cholinergic pathways in maintaining attention to salient stimuli by inhibiting subcortical motor circuits.

Orbitofrontal cortex and basolateral amygdala encode expected outcomes during learning.

Reciprocal connections between the orbitofrontal cortex and the basolateral nucleus of the amygdala may provide a critical circuit for the learning that underlies goal-directed behavior. We examined neural activity in rat orbitofrontal cortex and basolateral amygdala during instrumental learning in an olfactory discrimination task. Neurons in both regions fired selectively during the anticipation of rewarding or aversive outcomes. This selective activity emerged early in training, before the rats had learned reliably to avoid the aversive outcome. The results support the concept that the basolateral amygdala and orbitofrontal cortex cooperate to encode information that may be used to guide goal-directed behavior.

Memory for temporal order of new and familiar spatial location sequences: role of the medial prefrontal cortex.

Rats with medial prefrontal cortex or sham control lesions were tested on an eight-arm radial maze task to examine memory for the temporal order of a variable and a constant sequence of spatial locations as a function of temporal distance. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected or fixed for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal distance (0, 2, 4, or 6) or the number of arms that occurred between the two test arms in the study phase. For the variable sequences based on new information, control rats showed an increasing temporal distance function. Relative to control rats, medial prefrontal cortex-lesioned rats displayed a temporal order memory deficit across all distances. For the constant sequence based on familiar information, control rats performed well across all distances. Relative to controls, the medial prefrontal cortex-lesioned rats displayed a performance deficit. The results support the idea that the medial prefrontal cortex contributes to mnemonic operations associated with temporal order for new and familiar spatial location information.

The amygdala and emotion.

The amygdala complex has long been known as part of the neural circuitry critical for emotion. Beyond its role in emotional reactivity, studies of animal models and patients with amygdala damage demonstrate its importance in emotional learning, whereby cues acquire significance through association with rewarding or aversive events. Although its function in associative learning has become well established, other recent research has advanced the concept that the amygdala regulates additional cognitive processes, such as memory or attention. For example, a correspondence in the function of the amygdala has recently been shown in the modulation of memory in humans and laboratory animals. The use of animal models has progressively defined the circuitry for these functions within the amygdala and its interconnections with other brain systems, including pathways through which the amygdala modulates memory and regulates attention. These various lines of research are progressively advancing our understanding of the amygdala's role in providing linkages between affect and cognition.

Basal forebrain cholinergic lesions disrupt increments but not decrements in conditioned stimulus processing.

Magnocellular neurons in the basal forebrain provide the major cholinergic innervation of cortex. Recent research suggests that this cholinergic system plays an important role in the regulation of attentional processes. The present study examined the ability of rats with selective immunotoxic lesions of these neurons (made with 192 IgG-saporin) to modulate attention within an associative learning framework. Each rat was exposed to conditioned stimuli (CS) that were either consistent or inconsistent predictors of subsequent cues. Intact control rats showed increased CS associability when that cue was an inconsistent predictor of a subsequent cue, whereas lesioned rats were impaired in increasing attention to the CS when its established relation to another cue was modified. In a separate experiment designed to test latent inhibition, it was shown that removal of the corticopetal cholinergic neurons spared a decrement in associability that occurs when rats are extensively preexposed to a CS prior to conditioning. These data indicate that the cholinergic innervation of cortex is critical for incrementing, but not for decrementing attentional processing. The specific behavioral tests used to assess the role of the basal forebrain cholinergic system in the present study were previously used to identify a role for the amygdala central nucleus in attention (Holland and Gallagher, 1993b). Those studies, together with the results in this report, indicate that regulation of attentional processes during associative learning may be mediated by projections from the amygdala to the basal forebrain cholinergic system.

Spatial learning in male and female Long-Evans rats.

Male and female Long-Evans rats were tested in the Morris water maze at 6 months of age. A place training procedure, in which rats learned the position of a camouflaged platform, was followed by cue training, in which rats escaped to a visible platform. No sex difference was found in place learning ability. Search accuracy on probe trials, when the platform was unavailable, was also equivalent for the male and female groups. These results contrast with previous studies of rodents at younger ages, which have reported a male advantage in spatial learning. It is suggested that the age at which rats are assessed may be an important factor, possibly reflecting a different course in the relatively protracted maturation of the hippocampus in male and female rats. The results of this investigation are also discussed with reference to studies of sex differences for spatial abilities in humans.

Memory for spatial location as a function of temporal lag in rats: role of hippocampus and medial prefrontal cortex.

Rats with medial prefrontal cortex, hippocampus, or cortical control lesions were tested on an eight-arm radial maze task, in order to examine memory for the temporal order of spatial locations as a function of temporal lag. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal lag (0-6) or the number of arms that occurred between the two test arms in the study phase. The control rats performed at chance at a temporal lag of zero, but their performance was above chance for the remaining lags, improving after the temporal lag exceeded zero. The hippocampal-lesioned rats showed a marked deficit, performing at chance for all lags, with some savings for those items occurring at the end of the list. The medial prefrontal cortex-lesioned rats showed a less severe deficit. The results of these data support the notion that both the hippocampus and the medial prefrontal cortex play significant roles in memory for the temporal order of spatial locations.

Continuous recognition of spatial and nonspatial stimuli in hippocampal-lesioned rats.

The present experiments compared the performance of hippocampal-lesioned rats to control rats on a spatial continuous recognition task and an analogous nonspatial task with similar processing demands. Daily sessions for Experiment 1 involved sequential presentation of individual arms on a 12-arm radial maze. Each arm contained a Froot Loop reinforcement the first time it was presented, and latency to traverse the arm was measured. A subset of the arms were repeated, but did not contain reinforcement. Repeated arms were presented with lags ranging from 0 to 6 (0 to 6 different arm presentations occurred between the first and the repeated presentation). Difference scores were computed by subtracting the latency on first presentations from the latency on repeated presentations, and these scores were high in all rats prior to surgery, with a decreasing function across lag. There were no differences in performance following cortical control or sham surgery. However, there was a total deficit in performance following large electrolytic lesions of the hippocampus. The second experiment employed the same continuous recognition memory procedure, but used three-dimensional visual objects (toys, junk items, etc., in various shapes, sizes, and textures) as stimuli on a flat runway. As in Experiment 1, the stimuli were presented successively and latency to run to and move the object was measured. Objects were repeated with lags ranging from 0 to 4. Performance on this task following surgery did not differ from performance prior to surgery for either the control group or the hippocampal lesion group. These results provide support for Kesner's attribute model of hippocampal function in that the hippocampus is assumed to mediate data-based memory for spatial locations, but not three-dimensional visual objects.