Functional reorganization of a prefrontal cortical network mediating consolidation of trace eyeblink conditioning.

The medial prefrontal cortex (mPFC) has been studied for its role in various cognitive functions, but the roles of its subregions remain unclear. We performed tetrode recordings simultaneously from prelimbic (PL) and rostral (rACC) and caudal (cACC) anterior cingulate subregions of the rabbit mPFC to understand their interactions during learning and tests of remote memory retention for whisker-signaled trace eyeblink conditioning. cACC neurons exhibited an innate response to the conditioning stimulus (CS) that rapidly decreased across sessions, suggesting an attentional role for facilitating CS-US associations. rACC neurons from conditioned rabbits exhibited robust responses to the CS that decreased within each session, possibly evaluating its emotional salience. PL neurons exhibited robust persistent activity during the trace interval during tests of remote memory retention, suggesting its involvement in retrieval and execution of a consolidated response. Mechanistically, conditioning was associated with a greater percentage of persistently responsive neurons than neurons from pseudoconditioned control rabbits, and responses differed significantly between trials with and without conditioned responses. Collectively, these responses reflect a functional reorganization of neural activity within the prefrontal network from an attentional mode to one that orchestrates the retrieval and execution of the learned response.

Hippocampal lesion effects on occasion setting by contextual and discrete stimuli.

Three experiments examined the role of the dorsal hippocampus (dHIPP) in occasion setting with diffuse contextual and discrete light stimuli serving as occasion setters in classical fear conditioning with rats. Both sham-operated and dHIPP-lesioned animals readily learned a L→T+, T- serial feature-positive discrimination in which a light (L) "set the occasion" for reinforcement of a tone (T+). dHIPP-lesioned animals were deficient, however, in acquiring a similar discrimination in which different contexts (A and B) served as occasion setters, i.e., A(T+) and B(T-). The lesioned animals also failed to discriminate between a context in which a tone had been partially reinforced and a context in which no conditioning had taken place, whereas sham-operated animals froze more to the tone in the conditioned context than in the novel context. Collectively, the data indicate that the dorsal hippocampus is important in processing information about the signaling value of contextual, but not discrete, stimuli.

Stress impairs optimal behavior in a water foraging choice task in rats.

Stress is a biologically significant social-environmental factor that plays a pervasive role in influencing human and animal behaviors. While stress effects on various types of memory are well characterized, its effects on other cognitive functions are relatively unknown. Here, we investigated the effects of acute, uncontrollable stress on subsequent decision-making performance in rats, using a computer vision-based water foraging choice task. Experiencing stress significantly impaired the animals' ability to progressively bias (but not maintain) their responses toward the larger reward when transitioning from equal to unequal reward quantities. Temporary inactivation of the amygdala during stress, however, blocked impairing effects on decision making.

Dissociating space and trace in dorsal and ventral hippocampus.

Emerging evidence suggests that the hippocampus can be anatomically and functionally dissociated along its septotemporal axis into dorsal and ventral subregions. With respect to function, we have recently demonstrated that pre-training excitotoxic lesions of ventral, but not dorsal, hippocampus impair the acquisition of trace fear conditioning, whereas post-training lesions of either dorsal or ventral hippocampus impair the subsequent expression of trace fear conditioning (Yoon and Otto (2007) Neurobiol Learn Mem 87:464-475). In addition to trace fear conditioning, dorsal and ventral hippocampus appear to be differentially involved in a number of spatial memory tasks. The present study examined the effects of temporary inactivation of dorsal or ventral hippocampus on the acquisition and expression of trace fear conditioning and on performance of a spatial delayed reinforced alternation task. The findings demonstrate a double dissociation of dorsal and ventral hippocampal function: inactivation of ventral, but not dorsal, hippocampus attenuated the acquisition and expression of trace fear conditioning, whereas inactivation of dorsal, but not ventral, hippocampus dramatically impaired performance in the delayed reinforced alternation task. These data further support the notion that dorsal and ventral hippocampus contribute differentially to performance in a variety of paradigms.

Prefrontal cortex and hippocampus subserve different components of working memory in rats.

Both the medial prefrontal cortex (mPFC) and hippocampus are implicated in working memory tasks in rodents. Specifically, it has been hypothesized that the mPFC is primarily engaged in the temporary storage and processing of information lasting from a subsecond to several seconds, while the hippocampal function becomes more critical as the working memory demand extends into longer temporal scales. Although these structures may be engaged in a temporally separable manner, the extent of their contributions in the "informational content" of working memory remains unclear. To investigate this issue, the mPFC and dorsal hippocampus (dHPC) were temporarily inactivated via targeted infusions of the GABA(A) receptor agonist muscimol in rats prior to their performance on a delayed alternation task (DAT), employing an automated figure-eight maze that required the animals to make alternating arm choice responses after 3-, 30-, and 60-sec delays for water reward. We report that inactivation of either the mPFC or dHPC significantly reduced DAT at all delay intervals tested. However, there were key qualitative differences in the behavioral effects. Specifically, mPFC inactivation selectively impaired working memory (i.e., arm choice accuracy) without altering reference memory (i.e., the maze task rule) and arm choice response latencies. In contrast, dHPC inactivation increased both reference memory errors and arm choice response latencies. Moreover, dHPC, but not mPFC, inactivation increased the incidence of successive working memory errors. These results suggest that while both the mPFC and hippocampus are necessarily involved in DAT, they seem to process different informational components associated with the memory task.

Differential contributions of dorsal vs. ventral hippocampus to auditory trace fear conditioning.

The effect of excitotoxic lesions of dorsal vs. ventral hippocampus on the acquisition and expression of auditory trace fear conditioning was examined in two studies. In Experiment 1, animals received excitotoxic lesions of either the dorsal or ventral hippocampus or sham surgeries one week prior to conditioning, and were tested 24 h later. In Experiment 2, animals received excitotoxic lesions of either the dorsal or ventral hippocampus or sham surgeries 24 h after training, and were tested one week after surgery. Both pre- and post-training lesions of ventral hippocampus impaired the acquisition and expression, respectively, of auditory trace fear conditioning. Pre-training lesions of dorsal hippocampus had no effect on the acquisition of trace fear conditioning, while post-training lesions of dorsal hippocampus dramatically impaired expression during subsequent testing. Although in some cases animals with lesions of ventral hippocampus exhibited locomotor hyperactivity, it is unlikely that the pattern of observed deficits can be attributed to this effect. Collectively these data suggest that the dorsal and ventral hippocampus may contribute differentially to the mnemonic processes underlying fear trace conditioning.

Strain and sex differences in fear conditioning: 22 kHz ultrasonic vocalizations and freezing in rats

Strain and sex differences in fear conditioning were investigated in two commonly used laboratory rats: Sprague Dawleys and Long-Evans. Twenty-two kHz ultrasonic vocalization (USV) distress calls and freezing behavior were used to measure fear responses to contextual and auditory conditioned stimuli (CSs), which were previously paired with a footshock unconditioned stimulus (US). Both strain and sex had significant effects on USVs and freezing during training and subsequent context and tone tests. Overall, the male Sprague Dawley rats froze and emitted USVs more than the other groups. Additionally, levels of freezing and USVs were differentially influenced by the type of CS (context or tone). These results suggest that species-specific defense responses in laboratory rats are highly influenced by the strain and sex of the subject, and that these factors should be considered in future fear conditioning studies.(AU)

Strain and sex differences in fear conditioning: 22 kHz ultrasonic vocalizations and freezing in rats

Strain and sex differences in fear conditioning were investigated in two commonly used laboratory rats: Sprague Dawleys and Long-Evans. Twenty-two kHz ultrasonic vocalization (USV) distress calls and freezing behavior were used to measure fear responses to contextual and auditory conditioned stimuli (CSs), which were previously paired with a footshock unconditioned stimulus (US). Both strain and sex had significant effects on USVs and freezing during training and subsequent context and tone tests. Overall, the male Sprague Dawley rats froze and emitted USVs more than the other groups. Additionally, levels of freezing and USVs were differentially influenced by the type of CS (context or tone). These results suggest that species-specific defense responses in laboratory rats are highly influenced by the strain and sex of the subject, and that these factors should be considered in future fear conditioning studies.