Disrupting dorsal hippocampus impairs category learning in rats.

Categorization requires a balance of mechanisms that can generalize across common features and discriminate against specific details. A growing literature suggests that the hippocampus may accomplish these mechanisms by using fundamental mechanisms like pattern separation, pattern completion, and memory integration. Here, we assessed the role of the rodent dorsal hippocampus (HPC) in category learning by combining inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) and simulations using a neural network model. Using touchscreens, we trained rats to categorize distributions of visual stimuli containing black and white gratings that varied along two continuous dimensions. Inactivating the dorsal HPC impaired category learning and generalization, suggesting that the rodent HPC plays an important role during categorization. Hippocampal inactivation had no effect on a control discrimination task that used identical trial procedures as the categorization tasks, suggesting that the impairments were specific to categorization. Model simulations were conducted with variants of a neural network to assess the impact of selective deficits on category learning. The hippocampal inactivation groups were best explained by a model that injected random noise into the computation that compared the similarity between category stimuli and existing memory representations. This model is akin to a deficit in mechanisms of pattern completion, which retrieves similar memory representations using partial information.

Central amygdala contributes to stimulus facilitation and pre-stimulus vigilance during cerebellar learning.

Our previous studies found that the central amygdala (CeA) modulates cerebellum-dependent eyeblink conditioning (EBC) using muscimol inactivation. We also found that CeA inactivation decreases cerebellar neuronal activity during the conditional stimulus (CS) from the start of training. Based on these findings, we hypothesized that the CeA facilitates CS input to the cerebellum. The current study tested the CS facilitation hypothesis using optogenetic inhibition with archaerhodopsin (Arch) and excitation with channelrhodopsin (ChR2) of the CeA during EBC in male rats. Optogenetic manipulations were administered during the 400 ms tone CS or during a 400 ms pre-CS period. As predicted by the CS facilitation hypothesis CeA inhibition during the CS impaired EBC and CeA excitation during the CS facilitated EBC. Unexpectedly, CeA inhibition just prior to the CS also impaired EBC, while CeA excitation during the pre-CS pathway did not facilitate EBC. The results suggest that the CeA contributes to CS facilitation and vigilance during the pre-CS period. These putative functions of the CeA may be mediated through separate output pathways from the CeA to the cerebellum.

Knockdown of the Non-canonical Wnt Gene Prickle2 Leads to Cerebellar Purkinje Cell Abnormalities While Cerebellar-Mediated Behaviors Remain Intact.

Autism spectrum disorders (ASD) involve brain wide abnormalities that contribute to a constellation of symptoms including behavioral inflexibility, cognitive dysfunction, learning impairments, altered social interactions, and perceptive time difficulties. Although a single genetic variation does not cause ASD, genetic variations such as one involving a non-canonical Wnt signaling gene, Prickle2, has been found in individuals with ASD. Previous work looking into phenotypes of Prickle2 knock-out (Prickle2-/-) and heterozygous mice (Prickle2-/+) suggest patterns of behavior similar to individuals with ASD including altered social interaction and behavioral inflexibility. Growing evidence implicates the cerebellum in ASD. As Prickle2 is expressed in the cerebellum, this animal model presents a unique opportunity to investigate the cerebellar contribution to autism-like phenotypes. Here, we explore cerebellar structural and physiological abnormalities in animals with Prickle2 knockdown using immunohistochemistry, whole-cell patch clamp electrophysiology, and several cerebellar-associated motor and timing tasks, including interval timing and eyeblink conditioning. Histologically, Prickle2-/- mice have significantly more empty spaces or gaps between Purkinje cells in the posterior lobules and a decreased propensity for Purkinje cells to fire action potentials. These structural cerebellar abnormalities did not impair cerebellar-associated behaviors as eyeblink conditioning and interval timing remained intact. Therefore, although Prickle-/- mice show classic phenotypes of ASD, they do not recapitulate the involvement of the adult cerebellum and may not represent the pathophysiological heterogeneity of the disorder.

Dynamic Changes in Local Activity and Network Interactions among the Anterior Cingulate, Amygdala, and Cerebellum during Associative Learning.

Communication between the cerebellum and forebrain structures is necessary for motor learning and has been implicated in a variety of cognitive functions. The exact nature of cerebellar-forebrain interactions supporting behavior and cognition is not known. We examined how local and network activity support learning by simultaneously recording neural activity in the cerebellum, amygdala, and anterior cingulate cortex while male and female rats were trained in trace eyeblink conditioning. Initially, the cerebellum and forebrain signal the contingency between external stimuli through increases in theta power and synchrony. Neuronal activity driving expression of the learned response was observed in the cerebellum and became evident in the anterior cingulate and amygdala as learning progressed. Aligning neural activity to the training stimuli or learned response provided a way to differentiate between learning-related activity driven by different mechanisms. Stimulus and response-related increases in theta power and coherence were observed across all three areas throughout learning. However, increases in slow gamma power and coherence were only observed when oscillations were aligned to the cerebellum-driven learned response. Percentage of learned responses, learning-related local activity, and slow gamma communication from cerebellum to forebrain all progressively increased during training. The relatively fast frequency of slow gamma provides an ideal mechanism for the cerebellum to communicate learned temporal information to the forebrain. This cerebellar response-aligned slow gamma then provides enrichment of behavior-specific temporal information to local neuronal activity in the forebrain. These dynamic network interactions likely support a wide range of behaviors and cognitive tasks that require coordination between the forebrain and cerebellum.SIGNIFICANCE STATEMENT This study presents new evidence for how dynamic learning-related changes in single neurons and neural oscillations in a cerebellar-forebrain network support associative motor learning. The current results provide an integrated mechanism for how bidirectional communication between the cerebellum and forebrain represents important external events and internal neural drive. This bidirectional communication between the cerebellum and forebrain likely supports a wide range of behaviors and cognitive tasks that require temporal precision.

Dorsomedial striatum, but not dorsolateral striatum, is necessary for rat category learning.

Categorization is an adaptive cognitive function that allows us to generalize knowledge to novel situations. Converging evidence from neuropsychological, neuroimaging, and neurophysiological studies suggest that categorization is mediated by the basal ganglia; however, there is debate regarding the necessity of each subregion of the basal ganglia and their respective functions. The current experiment examined the roles of the dorsomedial striatum (DMS; homologous to the head of the caudate nucleus) and dorsolateral striatum (DLS; homologous to the body and tail of the caudate nucleus) in category learning by combining selective lesions with computational modeling. Using a touchscreen apparatus, rats were trained to categorize distributions of visual stimuli that varied along two continuous dimensions (i.e., spatial frequency and orientation). The tasks either required attention to one stimulus dimension (spatial frequency or orientation; 1D tasks) or both stimulus dimensions (spatial frequency and orientation; 2D tasks). Rats with NMDA lesions of the DMS were impaired on both the 1D tasks and 2D tasks, whereas rats with DLS lesions showed no impairments. The lesions did not affect performance on a discrimination task that had the same trial structure as the categorization tasks, suggesting that the category impairments effected processes relevant to categorization. Model simulations were conducted using a neural network to assess the effect of the DMS lesions on category learning. Together, the results suggest that the DMS is critical to map category representations to appropriate behavioral responses, whereas the DLS is not necessary for categorization.

The dorsal hippocampus' role in context-based timing in rodents.

To act proactively, we must predict when future events will occur. Individuals generate temporal predictions using cues that indicate an event will happen after a certain duration elapses. Neural models of timing focus on how the brain represents these cue-duration associations. However, these models often overlook the fact that situational factors frequently modulate temporal expectations. For example, in realistic environments, the intervals associated with different cues will often covary due to a common underlying cause. According to the 'common cause hypothesis,' observers anticipate this covariance such that, when one cue's interval changes, temporal expectations for other cues shift in the same direction. Furthermore, as conditions will often differ across environments, the same cue can mean different things in different contexts. Therefore, updates to temporal expectations should be context-specific. Behavioral work supports these predictions, yet their underlying neural mechanisms are unclear. Here, we asked whether the dorsal hippocampus mediates context-based timing, given its broad role in context-conditioning. Specifically, we trained rats with either hippocampal or sham lesions that two cues predicted reward after either a short or long duration elapsed (e.g., tone-8 s/light-16 s). Then, we moved rats to a new context and extended the long cue's interval (e.g., light-32 s). This caused rats to respond later to the short cue, despite never being trained to do so. Importantly, when returned to the initial training context, sham rats shifted back toward both cues' original intervals. In contrast, lesion rats continued to respond at the long cue's newer interval. Surprisingly, they still showed contextual modulation for the short cue, responding earlier like shams. These data suggest the hippocampus only mediates context-based timing if a cue is explicitly paired and/or rewarded across distinct contexts. Furthermore, as lesions did not impact timing measures at baseline or acquisition for the long cue's new interval, our data suggests that the hippocampus only modulates timing when context is relevant.

The Lords of the Rings: People and pigeons take different paths mastering the concentric-rings categorization task.

COVIS (COmpetition between Verbal and Implicit Systems; Ashby, Alfonso-Reese, & Waldron, 1998) is a prominent model of categorization which hypothesizes that humans have two independent categorization systems - one declarative, one associative - that can be recruited to solve category learning tasks. To date, most COVIS-related research has focused on just two experimental tasks: linear rule-based (RB) tasks, which purportedly encourage declarative rule use, and linear information-integration (II) tasks, which purportedly require associative learning mechanisms. We introduce and investigate a novel alternative: the concentric-rings task, a nonlinear category structure that both humans and pigeons can successfully learn and transfer to untrained exemplars. Yet, despite their broad behavioral similarities, humans and pigeons achieve their successful learning through decidedly different means. As predicted by COVIS, pigeons appear to rely solely on associative learning mechanisms, whereas humans appear to initially test but subsequently reject unidimensional rules. We discuss how variants of our concentric-rings task might yield further insights into which category-learning mechanisms are shared across species, as well as how categorization strategies might change throughout training.

Theta oscillations in rat infralimbic cortex are associated with the inhibition of cocaine seeking during extinction.

Infralimbic cortical (IL) manipulations indicate that this region mediates extinction learning and suppresses cocaine seeking following cocaine self-administration. However, little work has recorded IL activity during the inhibition of cocaine seeking due to the difficulty of determining precisely when cocaine-seeking behaviour is inhibited within a cocaine-seeking session. The present study used in vivo electrophysiology to examine IL activity across extinction as well as during cocaine self-administration and reinstatement. Sprague-Dawley rats underwent 6-h access cocaine self-administration in which the response lever was available during discrete signalled trials, a procedure which allowed for the comparison between epochs of cocaine seeking versus the inhibition thereof. Subsequently, rats underwent extinction and cocaine-primed reinstatement using the same procedure. Results indicate that theta rhythms (4-10 Hz) dominated IL local-field potential (LFP) activity during all experimental stages. During extinction, theta power fluctuated significantly surrounding the lever press and was lower when rats engaged in cocaine seeking versus when they withheld from doing so. These patterns of oscillatory activity differed from self-administration and reinstatement stages. Single-unit analyses indicate heterogeneity of IL unit responses, supporting the idea that multiple neuronal subpopulations exist within the IL and promote the expression of different and even opposing cocaine-seeking behaviours. Together, these results are consistent with the idea that aggregate synaptic and single-unit activity in the IL represent the engagement of the IL in action monitoring to promote adaptive behaviour in accordance with task contingencies and reveal critical insights into the relationship between IL activity and the inhibition of cocaine seeking.

Prelimbic cortex maintains attention to category-relevant information and flexibly updates category representations.

Category learning groups stimuli according to similarity or function. This involves finding and attending to stimulus features that reliably inform category membership. Although many of the neural mechanisms underlying categorization remain elusive, models of human category learning posit that prefrontal cortex plays a substantial role. Here, we investigated the role of the prelimbic cortex (PL) in rat visual category learning by administering excitotoxic lesions before category training and then evaluating the effects of the lesions with computational modeling. Using a touchscreen apparatus, rats (female and male) learned to categorize distributions of category stimuli that varied along two continuous dimensions. For some rats, categorizing the stimuli encouraged selective attention towards a single stimulus dimension (i.e., 1D tasks). For other rats, categorizing the stimuli required divided attention towards both stimulus dimensions (i.e., 2D tasks). Testing sessions then examined generalization to novel exemplars. PL lesions impaired learning and generalization for the 1D tasks, but not the 2D tasks. Then, a neural network was fit to the behavioral data to examine how the lesions affected categorization. The results suggest that the PL facilitates category learning by maintaining attention to category-relevant information and updating category representations.

Factors influencing developmental differences in retention of Pavlovian fear conditioning.

Modern nonhuman animal research on the rapid forgetting of memories formed early in life-often termed "infantile amnesia"-has focused on neurobiological changes occurring between learning and retention testing to explain age differences in memory. Developmental differences in initial learning have received less attention as a contributing factor to infantile amnesia effects. The present study identifies conditions under which associative learning and memory are comparable between pre and postweaning rats across multiple training-testing intervals. Postnatal day (P) 17-18 or P24-25 littermates were trained with white noise conditional stimuli (CSs) alone, forward-paired, or explicitly unpaired with floor shock unconditional stimuli (USs), and tested for retention at intervals ranging between 5 min and 15 days later. Findings from within- and across-institution replications revealed that age differences in CS freezing were influenced by (a) the associative nature of the CS and US at training, (b) the number of CS, US presentations at training, and (c) the interval between training and testing. Rats trained on P17 or 18 displayed robust retention comparable to rats trained on P24 or 25 only when training in younger rats involved additional forward-paired CS-US presentations. Poor long-term retention observed at multiple training-testing intervals in rats trained on P17 or 18 was overcome with many additional forward-paired CS-US presentations at training. Conditions necessary for appropriate developmental comparisons of learning and memory relevant to the future neurobiological studies are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Amygdala central nucleus modulation of cerebellar learning in female rats.

Previous studies found that inactivation of the central amygdala (CeA) severely impaired acquisition of cerebellum-dependent delay eye-blink conditioning (EBC) in male rats and rabbits. Sex differences in EBC and the effects of stress on EBC have been reported and might be related to sex differences in amygdala modulation of cerebellar learning. The current study examined the effects of CeA inactivation with muscimol on acquisition and retention of EBC in female rats. Like male rats, CeA inactivation in female rats severely impaired EBC acquisition and retention. Comparison of the female data with previously published data from males indicates no substantive sex differences in the effects of CeA inactivation on acquisition or retention of EBC. The results indicate that amygdala modulation of cerebellar learning is not sex-specific. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Category learning in rodents using touchscreen-based tasks.

Categorization is a fundamental cognitive function that organizes our experiences into meaningful "chunks." This category knowledge can then be generalized to novel stimuli and situations. Multiple clinical populations, including people with Parkinson's disease, amnesia, autism, ADHD and schizophrenia, have impairments in the acquisition and use of categories. Although rodent research is well suited for examining the neural mechanisms underlying cognitive functions, many rodent cognitive tasks have limited translational value. To bridge this gap, we use touchscreens to permit greater flexibility in stimulus presentation and task design, track key dependent measures, and minimize experimenter involvement. Touchscreens offer a valuable tool for creating rodent cognitive tasks that are directly comparable to tasks used with humans. Touchscreen tasks are also readily used with cutting-edge neuroscientific methods that are difficult to do in humans such as optogenetics, chemogenetics, neurophysiology and calcium imaging (using miniscopes). In this review, we show advantages of touchscreen-based tasks for studying category learning in rats. We also address multiple factors for consideration when designing category learning tasks, including the limitations of the rodent visual system, experimental design, and analysis strategies.

Intracerebellar cannabinoid administration impairs delay but not trace eyeblink conditioning.

Intracerebellar administration of cannabinoid agonists impairs cerebellum-dependent delay eyeblink conditioning (EBC) in rats. It is not known whether the cannabinoid-induced impairment in EBC is found with shorter interstimulus intervals (ISI), longer ISIs, or with trace EBC. Moreover, systemic administration of cannabinoid agonists does not impair trace EBC, suggesting that cannabinoid receptors within the cerebellum are not involved in trace EBC. To more precisely assess the effects of cannabinoids on cerebellar learning mechanisms the current study examined the effects of the cannabinoid agonist WIN55,212-2 (WIN) infusion into the area of the cerebellar cortex necessary for EBC (the eyeblink microzone) in rats during short delay (250 ms CS), long delay (750 ms CS), and trace (250 ms CS, 500 ms trace interval) EBC. WIN was infused into the eyeblink microzone 30 min before pretraining sessions and five EBC training sessions, followed by five EBC training sessions without infusions to assess recovery from drug effects and savings. WIN had no effect on spontaneous blinks or non-associative responses to the CS or US during the pretraining sessions. Short and long delay EBC were impaired by WIN but trace EBC was unaffected. The results indicate that trace EBC is mediated by mechanisms that are resistant to cannabinoid agonists.

Cannabinoid agonist administration within the cerebellar cortex impairs motor learning.

Systemic administration of cannabinoid agonists impairs cerebellum-dependent motor learning. The cannabinoid-induced impairment of motor learning has been hypothesized to be due to disruption of Purkinje cell plasticity within the cerebellar cortex. In the current study, we tested this hypothesis in rats with localized microinfusions of cannabinoid agonists and antagonists into the cerebellar cortex during eyeblink conditioning, a type of cerebellum-dependent motor learning. Infusions of the cannabinoid agonists WIN55,212-2 or ACEA directly into the eyeblink conditioning microzone of the cerebellar cortex severely impaired acquisition of eyeblink conditioning, whereas the CB1R antagonist SR141716A did not produce a significant impairment. Infusions of WIN55,212-2 outside of the eyeblink conditioning microzone did not impair motor learning, establishing anatomical specificity for the agonist effects. The motor learning impairment caused by WIN55,212-2 and ACEA was rescued by SR141716A, indicating that the learning deficit was produced through CB1Rs. The current findings demonstrate that the effects of cannabinoid receptor agonists on motor learning are localized to CB1Rs within a discrete microzone of the cerebellar cortex.

Selective attention in rat visual category learning.

A prominent theory of category learning, COVIS, posits that new categories are learned with either a declarative or procedural system, depending on the task. The declarative system uses the prefrontal cortex (PFC) to learn rule-based (RB) category tasks in which there is one relevant sensory dimension that can be used to establish a rule for solving the task, whereas the procedural system uses corticostriatal circuits for information integration (II) tasks in which there are multiple relevant dimensions, precluding use of explicit rules. Previous studies have found faster learning of RB versus II tasks in humans and monkeys but not in pigeons. The absence of a learning rate difference in pigeons has been attributed to their lacking a PFC. A major gap in this comparative analysis, however, is the lack of data from a nonprimate mammalian species, such as rats, that have a PFC but a less differentiated PFC than primates. Here, we investigated RB and II category learning in rats. Similar to pigeons, RB and II tasks were learned at the same rate. After reaching a learning criterion, wider distributions of stimuli were presented to examine generalization. A second experiment found equivalent RB and II learning with wider category distributions. Computational modeling revealed that rats extract and selectively attend to category-relevant information but do not consistently use rules to solve the RB task. These findings suggest rats are on a continuum of PFC function between birds and primates, with selective attention but limited ability to utilize rules relative to primates.

Amygdala central nucleus modulation of cerebellar learning with a visual conditioned stimulus.

Previous studies found that reversible inactivation of the central amygdala (CeA) severely impairs acquisition and retention of cerebellum-dependent eye-blink conditioning (EBC) with an auditory conditioned stimulus (CS). A monosynaptic pathway between the CeA and basilar pontine nuclei (BPN) may be capable of facilitating cerebellar learning. However, given that the CeA projects to the medial auditory thalamus, a critical part of the auditory CS pathway in EBC, the CeA influence on cerebellar learning could be specific to auditory stimuli. Here we examined the generality of CeA facilitation of EBC acquisition and retention in rats using a visual CS. As in our previous studies using an auditory CS, inactivation of the CeA with muscimol severely impaired acquisition and retention of EBC with a visual CS. Extending training to 15 100-trial sessions resulted in acquisition of EBC, indicating that the CeA plays a modulatory role in cerebellar learning and is not part of the necessary neural circuitry for EBC. Tract-tracing experiments verified that axons from the CeA reach both the BPN and medial auditory thalamus (part of the necessary auditory CS pathway), but were not found in the ventral lateral geniculate (part of the necessary visual CS pathway). The neuroanatomical results suggest that the CeA most likely modulates cerebellar learning through its projection to the BPN. The findings of the current study are consistent with the hypothesis that the CeA modulates cerebellar learning by increasing CS-related sensory input to the cerebellar cortex and interpositus nucleus via the BPN. This increase in CS-related input is thought to constitute an increase in attention to the CS during EBC.

Dorsal hippocampus is necessary for visual categorization in rats.

The hippocampus may play a role in categorization because of the need to differentiate stimulus categories (pattern separation) and to recognize category membership of stimuli from partial information (pattern completion). We hypothesized that the hippocampus would be more crucial for categorization of low-density (few relevant features) stimuli-due to the higher demand on pattern separation and pattern completion-than for categorization of high-density (many relevant features) stimuli. Using a touchscreen apparatus, rats were trained to categorize multiple abstract stimuli into two different categories. Each stimulus was a pentagonal configuration of five visual features; some of the visual features were relevant for defining the category whereas others were irrelevant. Two groups of rats were trained with either a high (dense, n = 8) or low (sparse, n = 8) number of category-relevant features. Upon reaching criterion discrimination (≥75% correct, on 2 consecutive days), bilateral cannulas were implanted in the dorsal hippocampus. The rats were then given either vehicle or muscimol infusions into the hippocampus just prior to various testing sessions. They were tested with: the previously trained stimuli (trained), novel stimuli involving new irrelevant features (novel), stimuli involving relocated features (relocation), and a single relevant feature (singleton). In training, the dense group reached criterion faster than the sparse group, indicating that the sparse task was more difficult than the dense task. In testing, accuracy of both groups was equally high for trained and novel stimuli. However, both groups showed impaired accuracy in the relocation and singleton conditions, with a greater deficit in the sparse group. The testing data indicate that rats encode both the relevant features and the spatial locations of the features. Hippocampal inactivation impaired visual categorization regardless of the density of the category-relevant features for the trained, novel, relocation, and singleton stimuli. Hippocampus-mediated pattern completion and pattern separation mechanisms may be necessary for visual categorization involving overlapping irrelevant features.

Basolateral Amygdala Inputs to the Medial Entorhinal Cortex Selectively Modulate the Consolidation of Spatial and Contextual Learning.

Although evidence suggests that the basolateral amygdala (BLA) and dorsal hippocampus (DH) work together to influence the consolidation of spatial/contextual learning, the circuit mechanism by which the BLA selectively modulates spatial/contextual memory consolidation is not clear. The medial entorhinal cortex (mEC) is a critical region in the hippocampus-based system for processing spatial information. As an efferent target of the BLA, the mEC is a candidate by which the BLA influences the consolidation of such learning. To address several questions regarding this issue, male Sprague Dawley rats received optogenetic manipulations of different BLA afferents immediately after training in different learning tasks. Optogenetic stimulation of the BLA-mEC pathway using ChR2(E123A) after spatial and cued-response Barnes maze training enhanced and impaired retention, respectively, whereas optical inhibition of the pathway using eNpHR3.0 produced trends in the opposite direction. Similar stimulation of the BLA-posterior dorsal striatum pathway had no effect. BLA-mEC stimulation also selectively enhanced retention for the contextual, but not foot shock, component of a modified contextual fear-conditioning procedure. In both sets of experiments, only stimulation using bursts of 8 Hz light pulses significantly enhanced retention, suggesting the importance of driving activity in this frequency range. An 8 Hz stimulation of the BLA-mEC pathway increased local field potential power in the same frequency range in the mEC and in the DH. Together, the present findings suggest that the BLA modulates the consolidation of spatial/contextual memory via projections to the mEC and that activity within the 8 Hz range is critical for this modulation.SIGNIFICANCE STATEMENT The mechanism by which the basolateral amygdala (BLA) influences the consolidation of spatial/contextual memory is unknown. Using an optogenetic approach with multiple behavioral procedures, we found that immediate posttraining 8 Hz stimulation of BLA projections to the medial entorhinal cortex (mEC) enhanced retention for spatial/contextual memory, impaired retention for cued-response memory, and had no effect on foot shock learning for contextual fear conditioning. Electrophysiological recordings confirmed that 8 Hz stimulation of this pathway increased activity in the 8 Hz range in the mEC and in the dorsal hippocampus, a region critical for spatial memory consolidation. This suggests that coordinated BLA activity with downstream regions in the 8 Hz activity range immediately after training is important for consolidation of multiple memory forms.

Memory consolidation within the central amygdala is not necessary for modulation of cerebellar learning.

Amygdala lesions impair, but do not prevent, acquisition of cerebellum-dependent eyeblink conditioning suggesting that the amygdala modulates cerebellar learning. Two-factor theories of eyeblink conditioning posit that a fast-developing memory within the amygdala facilitates slower-developing memory within the cerebellum. The current study tested this hypothesis by impairing memory consolidation within the amygdala with inhibition of protein synthesis, transcription, and NMDA receptors in rats. Rats given infusions of anisomycin or DRB into the central amygdala (CeA) immediately after each eyeblink conditioning session were severely impaired in contextual and cued fear conditioning, but were completely unimpaired in eyeblink conditioning. Rats given the NMDA antagonist ifenprodil into the CeA before each eyeblink conditioning session also showed impaired fear conditioning, but no deficit in eyeblink conditioning. The results indicate that memory formation within the CeA is not necessary for its modulation of cerebellar learning mechanisms. The CeA may modulate cerebellar learning and retention through an attentional mechanism that develops within the training sessions.

Sensory system development influences the ontogeny of hippocampal associative coding and trace eyeblink conditioning.

Until recently, it was believed that hippocampal development was the primary rate-limiting factor in the developmental emergence of hippocampal forms of learning, such as trace eyeblink conditioning (EBC). Indeed, hippocampal neuronal activity shows an age-related increase in both complexity and task responsiveness during trace EBC. However, recent work from our laboratory suggests that sensory system development may also play a role. Training with the earlier-developing somatosensory system results in an earlier emergence of trace EBC in rats, suggesting that the development of sensory input to the hippocampus may influence the development of trace EBC. The goal of the current study was to examine the activity of hippocampal CA1 pyramidal cells during acquisition of trace EBC with an early-developing somatosensory CS. Rat pups were trained with a vibration CS on postnatal days (P) 17-19, P21-23, and P24-26 while CA1 pyramidal cell activity was recorded. Results indicated that CA1 neurons show an age-related increase in responsiveness to trial events. Although the magnitude of neuronal responding showed age-related increases in activity, all three age groups demonstrated learning-related increases in firing rate magnitude and peaks in firing rate were evident both at CS onset and offset. These findings suggest that the ontogeny of trace eyeblink conditioning is related to both hippocampal and sensory system development.