Leverpress escape/avoidance training increases neurotrophin levels in rat brain

In addition to their well-known role in neural development, the neurotrophins BDNF and NGF help mediate the plasticity that occurs in the brain to promote learning. Exposure to learning procedures often leads to increases in neurotrophins, while exposure to stress often results in decreases. It is unclear how the neurotrophins would respond to an aversive learning task. Therefore, BDNF and NGF content in the dorsal striatum, hippocampus, and basal forebrain was measured following discrete trial lever-press escape/avoidance conditioning. Conditioning significantly increased levels of both neurotrophins in hippocampus and basal forebrain, relative to home cage controls (HCC). Contrary to expectations, the dorsal striatum did not show any significant changes. However, significant correlations were observed between dorsal striatal neurotrophins and aspects of avoidance performance. This may indicate that the dorsal striatum is involved in the performance aspects of the task. Results are discussed in terms of the role of neurotrophins in the acquisition of new information, and the neural structures involved in different types of memory.     

Immediate early gene activation in hippocampus and dorsal striatum: effects of explicit place and response training

Evidence from lesion, electrophysiological, and neuroimaging studies support the hypothesis that the hippocampus and dorsal striatum process afferent inputs in such a way that each structure regulates expression of different behaviors in learning and memory. The present study sought to determine whether rats explicitly trained to perform one of two different learning strategies, spatial or response, would display disparate immediate early gene activation in hippocampus and striatum. c-Fos and Zif268 immunoreactivity (IR) was measured in both hippocampus and striatum 30 or 90 min following criterial performance on a standard plus-maze task (place learners) or a modified T-maze task (response learners). Place and response learning differentially affected c-Fos-IR in striatum but not hippocampus. Specifically, explicit response learning induced greater c-Fos-IR activation in two subregions of the dorsal striatum. This increased c-Fos-IR was dependent upon the number of trials performed prior to reaching behavioral criterion and accuracy of performance during post-testing probe trials. Quantification of Zif268-IR in both hippocampus and striatum failed to distinguish between place and response learners. The changes in c-Fos-IR occurred 30 min, but not 90 min, post-testing. The synthesis of c-Fos early in testing could reflect the recruitment of key structures in learning. Consequently, animals that were able to learn the response task efficiently displayed greater amounts of c-Fos-IR in dorsal striatum.     

Rats depend on habit memory for discrimination learning and retention

We explored the circumstances in which rats engage either declarative memory (and the hippocampus) or habit memory (and the dorsal striatum). Rats with damage to the hippocampus or dorsal striatum were given three different two-choice discrimination tasks (odor, object, and pattern). These tasks differed in the number of trials required for learning (~10, 60, and 220 trials). Dorsal striatum lesions impaired discrimination performance to a greater extent than hippocampal lesions. Strikingly, performance on the task learned most rapidly (the odor discrimination) was severely impaired by dorsal striatum lesions and entirely spared by hippocampal lesions. These findings suggest that discrimination learning in the rat is primarily supported by the dorsal striatum (and habit memory) and that rats engage a habit-based memory system even for a task that takes only a few trials to acquire. Considered together with related studies of humans and nonhuman primates, the findings suggest that different species will approach the same task in different ways.     

Androgens' effects to enhance learning may be mediated in part through actions at estrogen receptor-beta in the hippocampus

Testosterone (T) may enhance cognitive performance. However, its mechanisms are not well understood. First, we hypothesized that if T's effects are mediated in part through actions of its 5alpha-reduced metabolites, dihydrotestosterone (DHT) and/or 3alpha-androstanediol (3alpha-diol) in the hippocampus, then T, DHT, and 3alpha-diol-administration directly to the hippocampus should enhance learning and memory in the inhibitory avoidance task. In order to test this hypothesis, gonadectomized (GDX) male rats were administered T, DHT, or 3alpha-diol via intrahippocampal inserts immediately following training in the inhibitory avoidance task. We found that T tended to increase, and DHT and 3alpha-diol significantly increased, performance in the inhibitory avoidance task compared to vehicle-administered GDX rats. Second, we hypothesized that, if androgens' effects are due in part to actions of 3alpha-diol in the hippocampus, then systemic or intrahippocampal administration of 3alpha-diol should significantly enhance cognitive performance of GDX male rats. Third, we hypothesized that, if androgen metabolites can have actions at estrogen receptors (ERs) in the hippocampus, then administration of ER antisense oligonucleotides (AS-ODNs) directly to the hippocampus of GDX, 3alpha-diol replaced, rats would decrease learning in the inhibitory avoidance task. We found that intrahippocampal administration of AS-ODNs for ERbeta, but not ERalpha, significantly decreased learning and memory of 3alpha-diol replaced rats. Together, these findings suggest that T's effects to enhance learning and memory may take place, in part, through actions of its metabolite, 3alpha-diol, at ERbeta in the dorsal hippocampus.     

Endogenous BDNF is required for long-term memory formation in the rat parietal cortex

Information storage in the brain is a temporally graded process involving different memory phases as well as different structures in the mammalian brain. Cortical plasticity seems to be essential to store stable long-term memories, although little information is available at the moment regarding molecular and cellular events supporting memory consolidation in the neocortex. Brain-derived neurotrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in hippocampal and cortical neurons. We have recently demonstrated that endogenous BDNF in the hippocampus is involved in memory formation. Here we examined the role of BDNF in the parietal cortex (PCx) in short-term (STM) and long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the PCx impaired both STM and LTM retention scores and decreased the phosphorylation state of cAMP response element-binding protein (CREB). In contrast, intracortical administration of recombinant human BDNF facilitated LTM and increased CREB activation. Moreover, inhibitory avoidance training is associated with a rapid and transient increase in phospho-CREB/total CREB ratio in the PCx. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of inhibitory avoidance learning, possibly involving CREB activation-dependent mechanisms. The present data support the idea that early sensory areas constitute important components of the networks subserving memory formation and that information processing in neocortex plays an important role in memory formation.     

Effects of intrahippocampal injections of the cholinergic neurotoxin AF64A on open-field activity and avoidance learning in the rat

The effects of direct intrahippocampal administration of the cholinergic neurotoxin, AF64A, were investigated in male rats. Bilateral injections of AF64A (5 nmole/2 microliters) produced a significant decrease in choline acetyltransferase (CAT) activity in the dorsal hippocampus (25%) and overlying frontoparietal cortex (30%) but no changes in the striatum. Rats lesioned with AF64A exhibited increased levels of open-field activity, which was most marked at 1 week after the lesion; however, the rates of intrasession habituation were similar in lesioned and control rats. Lesioned rats also displayed deficits in acquisition and retention of a passive avoidance task and less dramatic deficits in acquisition of two-way shuttle box avoidance. These findings indicate that lesioning of cholinergic terminals in the hippocampus and/or cerebral cortex with AF64A leads to long-term deficits in learning and memory as well as increases in open-field activity.     

Patterns of brain acetylcholine release predict individual differences in preferred learning strategies in rats

Acetylcholine release was measured simultaneously in the hippocampus and dorsal striatum of rats before and during training on a maze that could be learned using either a hippocampus-dependent spatial strategy or a dorsal striatum-dependent turning strategy. A probe trial administered after rats reached a criterion of 9/10 correct responses revealed that about half of the rats used a spatial strategy and half a turning strategy to solve the task. Acetylcholine release in the hippocampus, as well as the ratio of acetylcholine release in the hippocampus vs. the dorsal striatum, measured either before or during training, predicted these individual differences in strategy selection during learning. These findings suggest that differences in release of acetylcholine across brain areas may provide a neurobiological marker of individual differences in selection of the strategies rats use to solve a learning task.     

Functional specialization within the striatum along both the dorsal/ventral and anterior/posterior axes during associative learning via reward and punishment

The goal of the present study was to elucidate the role of the human striatum in learning via reward and punishment during an associative learning task. Previous studies have identified the striatum as a critical component in the neural circuitry of reward-related learning. It remains unclear, however, under what task conditions, and to what extent, the striatum is modulated by punishment during an instrumental learning task. Using high-resolution functional magnetic resonance imaging (fMRI) during a reward- and punishment-based probabilistic associative learning task, we observed activity in the ventral putamen for stimuli learned via reward regardless of whether participants were correct or incorrect (i.e., outcome). In contrast, activity in the dorsal caudate was modulated by trials that received feedback--either correct reward or incorrect punishment trials. We also identified an anterior/posterior dissociation reflecting reward and punishment prediction error estimates. Additionally, differences in patterns of activity that correlated with the amount of training were identified along the anterior/posterior axis of the striatum. We suggest that unique subregions of the striatum--separated along both a dorsal/ventral and anterior/posterior axis--differentially participate in the learning of associations through reward and punishment.     

Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy

192IgG-saporin (SAP) was used to selectively destroy cholinergic neurons in the rostral basal forebrain (e.g., medial septum (MS) and vertical limb of the diagonal band of Broca (VDB)) and/or the caudal basal forebrain (e.g., nucleus basalis magnocellularis (NBM)) of ovariectomized Sprague-Dawley rats. The effects of these lesions on two different cognitive tasks, a delayed matching to position (DMP) T-maze task, and a configural association (CA) operant conditioning task, were evaluated and compared. Injecting SAP into either the MS or NBM significantly impaired acquisition of the DMP task. Analysis showed that the effects were due largely to an affect on response patterns adopted by the rats during training, as opposed to an effect on working memory performance. Notably, the impairment in DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. Despite the deficit, most animals eventually learned the task and reached criterion; however by the end of training, controls and animals that received SAP into either the MS or NBM appeared more likely to use an allocentric place strategy to solve the task, whereas animals that received SAP into both the MS and NBM were more likely to use an egocentric response strategy. Cholinergic lesions also produced a small but significant affect on acquisition of the CA task, but only with respect to response time, and only in the SAP-NBM-treated animals. SAP-NBM lesions also produced small but significant impairments in both the number of responses and response time during the acquisition of simple associations, possibly reflecting an effect on alertness or attention. Notably, the effects on CA acquisition were small, and like the effects on DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. We conclude that selective basal forebrain cholinergic lesions produce learning deficits that are task specific, and that cholinergic denervation of either the frontal cortex or hippocampus can affect response patterns and strategy in ways that affect learning, without necessarily reflecting deficits in working memory performance.     

Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.     

Glucocorticoid administration into the dorsal striatum [corrected] facilitates memory consolidation of inhibitory avoidance training but not of the context or footshock components

It is well established that glucocorticoid administration into a variety of brain regions facilitates memory consolidation of fear-conditioning tasks, including inhibitory avoidance. The present findings indicate that the natural glucocorticoid corticosterone administered into the dorsal striatum (i.e., caudate nucleus) of male Wistar rats produced dose- and time-dependent enhancement of inhibitory avoidance memory consolidation. However, as assessed with a modified inhibitory avoidance procedure that took place on two sequential days to separate context training from footshock training, corticosterone administration into the dorsal striatum did not enhance memory of either the contextual or aversively motivational aspects of the task.     

A neural model of normal and abnormal learning and memory consolidation: adaptively timed conditioning,hippocampus, amnesia,neurotrophins, and consciousness

How do the hippocampus and amygdala interact with thalamocortical systems to regulate cognitive and cognitive-emotional learning? Why do lesions of thalamus, amygdala, hippocampus, and cortex have differential effects depending on the phase of learning when they occur? In particular, why is the hippocampus typically needed for trace conditioning, but not delay conditioning, and what do the exceptions reveal? Why do amygdala lesions made before or immediately after training decelerate conditioning while those made later do not? Why do thalamic or sensory cortical lesions degrade trace conditioning more than delay conditioning? Why do hippocampal lesions during trace conditioning experiments degrade recent but not temporally remote learning? Why do orbitofrontal cortical lesions degrade temporally remote but not recent or post-lesion learning? How is temporally graded amnesia caused by ablation of prefrontal cortex after memory consolidation? How are attention and consciousness linked during conditioning? How do neurotrophins, notably brain-derived neurotrophic factor (BDNF), influence memory formation and consolidation? Is there a common output path for learned performance? A neural model proposes a unified answer to these questions that overcome problems of alternative memory models.     

Distinct mechanisms in visual category learning

The ways in which visual categories are learned, and in which well-established categories are represented and retrieved, are fundamental issues of cognitive neuroscience. Researchers have typically studied these issues separately, and the transition from the initial phase of category learning to expertise is poorly characterized. The acquisition of novel categories has been shown to depend on the striatum, hippocampus, and prefrontal cortex, whereas visual category expertise has been shown to involve changes in inferior temporal cortex. The goal of the present experiment is to understand the respective roles of these brain regions in the transition from initial learning to expertise when category judgments are being made. Subjects were explicitly trained, over 2 days, to classify realistic faces. Subjects then performed the categorization task during fMRI scanning, as well as a perceptual matching task, in order to characterize how brain regions respond to these faces when not explicitly categorizing them. We found that, during face categorization, face-selective inferotemporal cortex, lateral prefrontal cortex, and dorsal striatum are more responsive to faces near the category boundary, which are most difficult to categorize. In contrast, the hippocampus and left superior frontal sulcus responded most to faces farthest from the category boundary. These dissociable effects suggest that there are several distinct neural mechanisms involved in categorization, and provide a framework for understanding the contribution of each of these brain regions in categorization.     

Lesions of the dorsolateral or dorsomedial striatum impair performance of a previously acquired simple discrimination task

Previous evidence has suggested a specific role for the dorsal striatum, especially the dorsolateral region of the dorsal striatum, in stimulus-response learning. In a previous study, we found an impairment in animals with dorsolateral striatal lesions on a simple discrimination task (CS+/CS-), thought to require the involvement of both stimulus-reward and stimulus-response learning. It is possible that the generally poor performance of dorsolateral lesioned animals on this experiment precluded adequate exposure to stimulus-reward pairings necessary for solving this task, and, thus, had little to do with stimulus-response learning. To test this hypothesis, the performance of animals with dorsolateral and dorsomedial striatal lesions was assessed on a previously acquired simple discrimination task. To independently assess the effects of each lesion on the performance of stimulus-reward learning, dorsolateral and dorsomedial lesioned animals were assessed on a previously acquired conditioned place preference task (CPP). In agreement with our earlier experiment, and the stimulus-response interpretation of dorsolateral striatal function, animals with dorsolateral striatal lesions were found to be impaired during post-lesion performance of the simple discrimination task, but not CPP learning. Additionally, dorsomedial lesioned animals were found to be impaired in performance of the simple discrimination task, but not on the CPP task. Possible explanations for the differences between the role of the dorsomedial striatum in acquisition and expression of the simple discrimination task are proposed.     

Locomotor, avoidance,and maze behavior in rats with selective disruption of hippocampal output.

Behavioral correlates of selective disruption of hippocampal output were investigated in a series of five experiments. In two experiments an attempt was made through behavioral investigation to determine whether the CA1 neurons project to the fimbria or to the subiculum. The results supported recent views that the subiculum is the recipient of CA1 axons. Disruption of the CA1 output in the dorsal hippocampus of rats produced increased open-field activity, whereas passive avoidance and spontaneous alternation behaviors remained unchanged. No differentiation was obtained between CA1 damage and neocortical lesions in maze learning. Blocking of the fimbrial CA3 output from the dorsal hippocampus improved passive avoidance performance and impaired active avoidance performance, whereas open-field and spontaneous alternation behaviors were unaffected. Interruption of the CA3 output from the ventral hippocampus improved active avoidance performance and reduced spontaneous alternation behavior. Open-field behavior and passive avoidance performance remained unchanged. Total fimbrial sections increased open-field activity, improved passive and active avoidance, and reduced spontaneous alternation. The results are discussed in terms of functional differentiation between the CA1 and CA3 of the dorsal hippocampus and in terms of functional differences in the fimbrial CA3 output from the dorsal and ventral hippocampus.     

The hippocampal contribution to “Learning and memory”: Information retrieval and comparison

The effects of limbic system after-discharges and ablation upon learning were investigated in 113 adult cats. Learning tasks consisted of active and passive avoidance and pattern and size discrimination. Limbic system after-discharges interfered with performance in learned-avoidance and size-discrimination paradigms. Discharges implicating the ventral hippocampus were the most effective in producing performance decrements; dorsal hippocampal discharges were least effective. The greater the involvement of brain-stem structures by propagated activity, the greater the decrement. There was no motor impairment. Size-discrimination response is impaired to a greater degree than shockavoidance response during limbic discharges. The degree of impairment is in part a function of the type of sensory stimulus and response contingency used. Hippocampal ablation resulted in impairment (response latency changes) in both active and passive avoidance tasks. Acquisition was not impaired. Hippocampal ablation facilitated the development of a stronger position habit in the pattern-discrimination task. Learning deficits which occurred were attributed to impairment of retrieval and comparator mechanisms of neural function. Results support the argument that defective retrieval and/or comparator mechanisms may account for the impaired learning of a diversity of tasks, from simple to complex.     

Conditional visuo-motor learning and dimension reduction

Conditional visuo-motor learning consists in learning by trial and error to associate visual cues with correct motor responses, that have no direct link. Converging evidence supports the role of a large brain network in this type of learning, including the prefrontal and the premotor cortex, the basal ganglia (BG) and the hippocampus. In this paper we focus on the role of a major structure of the BG, the striatum. We first present behavioral results and electrophysiological data recorded from this structure in monkeys engaged in learning new visuo-motor associations. Visual stimuli were presented on a video screen and the animals had to learn, by trial and error, to select the correct movement of a joystick, in order to receive a liquid reward. Behavioral results revealed that the monkeys used a sequential strategy, whereby they learned the associations one by one although they were presented randomly. Human subjects, tested on the same task, also used a sequential strategy. Neuronal recordings in monkeys revealed learning-related modulations of neural activity in the striatum. We then present a mathematical model inspired by viability theory developed to implement the use of strategies during learning. This model complements existing models of the BG based on reinforcement learning (RL), which do not take into account the use of strategies to reduce the dimension of the learning space.     

Dissociating Basal Forebrain and Medial Temporal Amnesic Syndromes: Insights from Classical Conditioning

In humans, anterograde amnesia can result from damage to the medial temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these emerging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.     

Dissociating basal forebrain and medial temporal amnesic syndromes: Insights from classical conditioning

In humans, anterograde amnesia can result from damage to the medical temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these merging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.