c-Fos expression reveals aberrant neural network activity during cued fear conditioning in APPswe transgenic mice

The neural circuitry underlying emotional learning and memory is known to involve both the amygdala and hippocampus. Both of these structures undergo anatomical and functional changes during the course of Alzheimer's disease. The present study used expression of the immediate early gene c-Fos to examine the effect of amyloid-induced synaptic pathology on neural activity in the hippocampus and amygdala immediately following Pavlovian fear conditioning. Tg2576 mice underwent cued fear conditioning and the regional interdependencies of c-Fos expression in the hippocampus and the amygdala were assessed using structural equation modelling. Tg2576 mice displayed normal acquisition of conditioned freezing to a punctate auditory cue paired with shock. However, the analysis of c-Fos expression indicated abnormal regional activity in the hippocampal dentate gyrus of Tg2576 mice. Structural equation modelling also supported the view that activity within the amygdala was independent of hippocampal activity in Tg2576 mice (unlike control mice) and regional interaction between the dentate gyrus and CA3 region was disrupted. The results provide novel insight into the effects of excess amyloid production on brain region interdependencies underpinning emotional learning.     

Amygdaloid function in the central cholinergic mediation of shock-induced aggression in the rat

A series of experiments was designed to examine the role of central cholinergic mechanisms in shock-induced aggression. Cholinergic blockade in the basolateral amygdala, ventral hippocampus, or dorsal hippocampus resulted in greatly reduced levels of fighting in response to footshock. However, while pain sensitivity remained unaltered in the amygdala group, both of the hippocampal groups exhibited decreased shock sensitivity. Further investigation of the amygdala revealed (1) increased fighting in response to increased cholinergic levels, (2) neuroanatomical specificity to the basolateral division of this complex, (3) that an intact basolateral amygdala is essential to the normal manifestation of shock-induced aggression, and (4) that social attraction remains unaltered by cholinergic blockade of the basolateral amygdala. Motor coordination and motor activity were not significantly affected in any treatment condition.     

Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning

Previous functional magnetic resonance imaging (fMRI) studies have characterized brain systems involved in conditional response acquisition during Pavlovian fear conditioning. However, the functional neuroanatomy underlying the extinction of human conditional fear remains largely undetermined. The present study used fMRI to examine brain activity during acquisition and extinction of fear conditioning. During the acquisition phase, participants were either exposed to light (CS) presentations that signaled a brief electrical stimulation (paired group) or received light presentations that did not serve as a warning signal (control group). During the extinction phase, half of the paired group subjects continued to receive the same treatment, whereas the remainder received light alone. Control subjects also received light alone during the extinction phase. Changes in metabolic activity within the amygdala and hippocampus support the involvement of these regions in each of the procedural phases of fear conditioning. Hippocampal activity developed during acquisition of the fear response. Amygdala activity increased whenever experimental contingencies were altered, suggesting that this region is involved in processing changes in environmental relationships. The present data show learning-related amygdala and hippocampal activity during human Pavlovian fear conditioning and suggest that the amygdala is particularly important for forming new associations as relationships between stimuli change.     

Human anterior and posterior hippocampus respond distinctly to state and trait anxiety

We examined whether anterior and posterior hippocampal subregions in humans show distinct relationships to state and trait anxiety. In rodents, the ventral (but not dorsal) hippocampus is critically involved in contextual anxiety, whereas dorsal hippocampus is affected by chronic stress and genetically bred trait anxiety. These studies suggest that state forms of anxiety may be more associated with anterior (ventral in rodents) hippocampus, whereas trait forms of anxiety maybe more associated with posterior (dorsal in rodents) hippocampus. Participants were placed under alternating blocks of threat of shock and safety conditions while performing a secondary task, and state and trait anxiety measures were obtained. Using subject-specific anatomically defined masks, we found that state anxiety was related to activity in anterior but not posterior hippocampus, whereas trait anxiety showed the opposite pattern. Additionally, a psychophysiological connectivity analysis showed that activity in anterior hippocampus was more strongly related to activity in ventromedial prefrontal cortex under threat than under safety conditions, significantly more so than activity in posterior hippocampus was. Hence, anterior hippocampus shows a distinct moment-to-moment connectivity profile with other neural regions during threat relative to posterior hippocampus. The findings provide several lines of evidence for functional differentiation of anterior and posterior hippocampal involvement across state and trait components of anxiety in humans.     

Different types of exercise induce differential effects on neuronal adaptations and memory performance

Different exercise paradigms show differential effects on various forms of memory. We hypothesize that the differential effects of exercises on memory performance are caused by different neuroplasticity changes in relevant brain regions in response to different exercise trainings. We examined the effects of treadmill running (TR) and wheel running (WR) on the Pavlovian fear conditioning task that assesses learning and memory performance associated with the amygdala (cued conditioning) and both the amygdala and hippocampus (contextual conditioning). The skeletal muscle citrate synthase activity, an indicator of aerobic capacity, was elevated in rats received 4 w of TR, but not WR. While both TR and WR elevated the contextual conditional response, only TR facilitated the cued conditional response. Using a single-neuron labeling technique, we found that while both TR and MR enlarged the dendritic field and increased the spine density in hippocampal CA3 neurons, only TR showed these effects in basolateral amygdalar neurons. Moreover, both types of exercise upregulated synaptic proteins (i.e., TrkB and SNAP-25) in the hippocampus; however only TR showed similar effects in the amygdala. Injection of K252a, a TrkB kinase inhibitor, in the dorsal hippocampus or basolateral amygdala abolished the exercise-facilitated contextual or cued fear learning and memory performance, respectively, regardless of the types of exercise. In summary, our results supported that different types of exercise affect the performance of learning and memory via BDNF-TrkB signaling and neuroplasticity in specific brain regions. The brain region-specific neuronal adaptations are possibly induced by various levels of intensity/stress elicited by different types of exercise.     

Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala

Stress can profoundly affect memory and alter the functioning of the hippocampus and amygdala. Studies have also shown that the antidepressant tianeptine can block the effects of stress on hippocampal and amygdala morphology and synaptic plasticity. We examined the effects of acute predator stress and tianeptine on long-term potentiation (LTP; induced by 100 pulses in 1 s) and primed burst potentiation (PB; a low threshold form of LTP induced by only five physiologically patterned pulses) in CA1 and in the basolateral nucleus (BLA) of the amygdala in anesthetized rats. Predator stress blocked the induction of PB potentiation in CA1 and enhanced LTP in BLA. Tianeptine blocked the stress-induced suppression of PB potentiation in CA1 without affecting the stress-induced enhancement of LTP in BLA. In addition, tianeptine administered under non-stress conditions enhanced PB potentiation in the hippocampus and LTP in the amygdala. These findings support the hypothesis that acute stress impairs hippocampal functioning and enhances amygdaloid functioning. The work also provides insight into the actions of tianeptine with the finding that it enhanced electrophysiological measures of plasticity in the hippocampus and amygdala under stress, as well as non-stress, conditions.     

Parallel processing across neural systems: implications for a multiple memory system hypothesis

A common conceptualization of the organization of memory systems in brain is that different types of memory are mediated by distinct neural systems. Strong support for this view comes from studies that show double (or triple) dissociations between spatial, response, and emotional memories following selective lesions of hippocampus, striatum, and the amygdala. Here, we examine the extent to which hippocampal and striatal neural activity patterns support the multiple memory systems view. A comparison is made between hippocampal and striatal neural correlates with behavior during asymptotic performance of spatial and response maze tasks. Location- (or place), movement, and reward-specific firing patterns were found in both structures regardless of the task demands. Many, but not all, place fields of hippocampal and striatal neurons were similarly affected by changes in the visual and reward context regardless of the cognitive demands. Also, many, but not all, hippocampal and striatal movement-sensitive neurons showed significant changes in their behavioral correlates after a change in visual context, irrespective of cognitive strategy. Similar partial reorganization was observed following manipulations of the reward condition for cells recorded from both structures, again regardless of task. Assuming that representations that persist across context changes reflect learned information, we make the following conclusions. First, the consistent pattern of partial reorganization supports a view that the analysis of spatial, response, and reinforcement information is accomplished via an error-driven, or match-mismatch, algorithm across neural systems. Second, task-relevant processing occurs continuously within hippocampus and striatum regardless of the cognitive demands of the task. Third, given the high degree of parallel processing across allegedly different memory systems, we propose that different neural systems may effectively compete for control of a behavioral expression system. The strength of the influence of any one neural system on behavioral output is likely modulated by factors such as motivation, experience, or hormone status.     

Hippocampal regulation of context-dependent neuronal activity in the lateral amygdala

Pavlovian fear conditioning is a robust and enduring form of emotional learning that provides an ideal model system for studying contextual regulation of memory retrieval. After extinction the expression of fear conditional responses (CRs) is context-specific: A conditional stimulus (CS) elicits greater conditional responding outside compared with inside the extinction context. Dorsal hippocampal inactivation with muscimol attenuates context-specific CR expression. We have previously shown that CS-elicited spike firing in the lateral nucleus of the amygdala is context-specific after extinction. The present study examines whether dorsal hippocampal inactivation with muscimol disrupts context-specific firing in the lateral amygdala. We conditioned rats to two separate auditory CSs and then extinguished each CS in separate and distinct contexts. Thereafter, single-unit activity and conditional freezing were tested to one CS in both extinction contexts after saline or muscimol infusion into the dorsal hippocampus. After saline infusion, rats froze more to the CS when it was presented outside of its extinction context, but froze equally in both contexts after muscimol infusion. In parallel with the behavior, lateral nucleus neurons exhibited context-dependent firing to extinguished CSs, and hippocampal inactivation disrupted this activity pattern. These data reveal a novel role for the hippocampus in regulating the context-specific firing of lateral amygdala neurons after fear memory extinction.     

Persistent and stable biases in spatial learning mechanisms predict navigational style

A wealth of evidence in rodents and humans supports the central roles of two learning systems—hippocampal place learning and striatal response learning—in the formation of spatial representations to support navigation. Individual differences in the ways that these mechanisms are engaged during initial encoding and subsequent navigation may provide a powerful framework for explaining the wide range of variability found in the strategies and solutions that make up human navigational styles. Previous work has revealed that activation in the hippocampal and striatal networks during learning could predict navigational style. Here, we used functional magnetic resonance imaging to investigate the relative activations in these systems during both initial encoding and the act of dynamic navigation in a learned environment. Participants learned a virtual environment and were tested on subsequent navigation to targets within the environment. We observed that a given individual had a consistent balance of memory system engagement across both initial encoding and subsequent navigation, a balance that successfully predicted the participants’ tendencies to use novel shortcuts versus familiar paths during dynamic navigation. This was further supported by the observation that the activation during subsequent retrieval was not dependent on the type of solution used on a given trial. Taken together, our results suggest a model in which the place- and response-learning systems are present in parallel to support a variety of navigational behaviors, but stable biases in the engagement of these systems influence what solutions might be available for any given individual.     

Opposing amygdala and ventral striatum connectivity during emotion identification

Lesion and electrophysiological studies in animals provide evidence of opposing functions for subcortical nuclei such as the amygdala and ventral striatum, but the implications of these findings for emotion identification in humans remain poorly described. Here we report a high-resolution fMRI study in a sample of 39 healthy subjects who performed a well-characterized emotion identification task. As expected, the amygdala responded to THREAT (angry or fearful) faces more than NON-THREAT (sad or happy) faces. A functional connectivity analysis of the time series from an anatomically defined amygdala seed revealed a strong anticorrelation between the amygdala and the ventral striatum/ventral pallidum, consistent with an opposing role for these regions in during emotion identification. A second functional connectivity analysis (psychophysiological interaction) investigating relative connectivity on THREAT vs. NON-THREAT trials demonstrated that the amygdala had increased connectivity with the orbitofrontal cortex during THREAT trials, whereas the ventral striatum demonstrated increased connectivity with the posterior hippocampus on NON-THREAT trials. These results indicate that activity in the amygdala and ventral striatum may be inversely related, and that both regions may provide opposing affective bias signals during emotion identification.     

Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of memory for emotionally arousing events through interactions with the noradrenergic system of the basolateral complex of the amygdala (BLA). We previously reported that intra-BLA administration of a β-adrenoceptor agonist immediately after inhibitory avoidance training enhanced memory consolidation and increased hippocampal expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc). In the present experiments corticosterone (3 mg/kg, i.p.) was administered to male Sprague-Dawley rats immediately after inhibitory avoidance training to examine effects on long-term memory, amygdala norepinephrine levels, and hippocampal Arc expression. Corticosterone increased amygdala norepinephrine levels 15 min after inhibitory avoidance training, as assessed by in vivo microdialysis, and enhanced memory tested at 48 h. Corticosterone treatment also increased expression of Arc protein in hippocampal synaptic tissue. The elevation in BLA norepinephrine appears to participate in corticosterone-influenced modulation of hippocampal Arc expression as intra-BLA blockade of β-adrenoceptors with propranolol (0.5 μg/0.2 μL) attenuated the corticosterone-induced synaptic Arc expression in the hippocampus. These findings indicate that noradrenergic activity at BLA β-adrenoceptors is involved in corticosterone-induced enhancement of memory consolidation and expression of the synaptic-plasticity-related protein Arc in the hippocampus.     

Declarative memory consolidation: mechanisms acting during human sleep

Of late, an increasing number of studies have shown a strong relationship between sleep and memory. Here we summarize a series of our own studies in humans supporting a beneficial influence of slow-wave sleep (SWS) on declarative memory formation, and try to identify some mechanisms that might underlie this influence. Specifically, these experiments show that declarative memory benefits mainly from sleep periods dominated by SWS, whereas there is no consistent benefit of this memory from periods rich in rapid eye movement (REM) sleep. A main mechanism of declarative memory formation is believed to be the reactivation of newly acquired memory representations in hippocampal networks that stimulates a transfer and integration of these representations into neocortical neuronal networks. Consistent with this model, spindle activity and slow oscillation-related EEG coherence increase during early sleep after intense declarative learning in humans, signs that together point toward a neocortical reprocessing of the learned material. In addition, sleep seems to provide an optimal milieu for declarative memory reprocessing and consolidation by reducing cholinergic activation and the cortisol feedback to the hippocampus during SWS.     

The hippocampus: hub of brain network communication for memory

A complex brain network, centered on the hippocampus, supports episodic memories throughout their lifetimes. Classically, upon memory encoding during active behavior, hippocampal activity is dominated by theta oscillations (6-10Hz). During inactivity, hippocampal neurons burst synchronously, constituting sharp waves, which can propagate to other structures, theoretically supporting memory consolidation. This 'two-stage' model has been updated by new data from high-density electrophysiological recordings in animals that shed light on how information is encoded and exchanged between hippocampus, neocortex and subcortical structures such as the striatum. Cell assemblies (tightly related groups of cells) discharge together and synchronize across brain structures orchestrated by theta, sharp waves and slow oscillations, to encode information. This evolving dynamical schema is key to extending our understanding of memory processes.     

Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding

Emotionally arousing experiences are usually well retained, an effect that depends on the release of adrenal stress hormones. Animal studies have shown that corticosterone and noradrenaline – representing the two main stress hormone systems – act in concert to enhance memory formation by actions involving the amygdala, hippocampus and prefrontal cortex (PFC). Here we test whether interactions between these two stress hormone systems also affect human memory formation as well as the associated pattern of brain activation. To this end, forty-eight male human subjects received hydrocortisone, yohimbine or both before presentation of emotional and neutral pictures. Activity in the amygdala, hippocampus and PFC was monitored with functional Magnetic Resonance Imaging (fMRI) during encoding of these stimuli, when hormonal levels were elevated. Memory performance was tested 1 week later. We investigated whether an increased level of one of the two hormone systems would lead to differential effects compared to the combined application of the drugs on brain activation and memory performance. We report that the application of cortisol led to an overall enhancing effect on recognition memory, with no significant additional effect of yohimbine. However, during encoding the brain switched from amygdala/hippocampus activation with either hormone alone, to a strong deactivation of prefrontal areas under the influence of the combination of both exogenous hormones. Although we did not find evidence that exogenous stimulation of the noradrenergic and corticosteroid systems led to significant interaction effects on memory performance in this experiment, we conclude that stress hormone levels during encoding did differentially determine the activation pattern of the brain circuits here involved.     

Effects of aging on the neural correlates of successful item and source memory encoding

To investigate the neural basis of age-related source memory (SM) deficits, young and older adults were scanned with fMRI while encoding faces, scenes, and face-scene pairs. Successful encoding activity was identified by comparing encoding activity for subsequently remembered versus forgotten items or pairs. Age deficits in successful encoding activity in hippocampal and prefrontal regions were more pronounced for SM (pairs) as compared with item memory (faces and scenes). Age-related reductions were also found in regions specialized in processing faces (fusiform face area) and scenes (parahippocampal place area), but these reductions were similar for item and SM. Functional connectivity between the hippocampus and the rest of the brain was also affected by aging; whereas connections with posterior cortices were weaker in older adults, connections with anterior cortices, including prefrontal regions, were stronger in older adults. Taken together, the results provide a link between SM deficits in older adults and reduced recruitment of hippocampal and prefrontal regions during encoding. The functional connectivity findings are consistent with a posterior-anterior shift with aging previously reported in several cognitive domains and linked to functional compensation.     

Dissociation of data-based and expectancy-based memory following hippocampal lesions in rats

Sham-operated and nonoperated animals or animals with hippocampal lesions were presented with sets of trials to test both expectancy-based and data-based memory within the same task. During the study phase of each trial the animals were presented with a constant sequence of five arms on an eight-arm radial maze followed by a test phase in which a recognition test requiring a win-stay rule was used. Expectancy-based memory was measured during the study phase of the trials as a pattern of correct or incorrect orienting responses in anticipation of the ensuing doors in the constant sequence. Both groups of animals acquired correct orienting responses at the same rate, emitted the same pattern of correct orienting responses, and made the same number and pattern of intralist and extralist intrusion errors. Data-based memory was measured during the test phase of the trial as correct recognition test performance. During the test phase the animals with hippocampal lesions were impaired relative to controls on both immediate and 24-h recognition tests. These results suggest that the hippocampus might mediate only data-based, but not expectancy-based, memory and imply a possible dissociation between expectancy-based and data-based memory systems.     

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.     

Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory

Evidence suggests that plasticity of the amygdalar and hippocampal GABAergic system is critical for fear memory formation. In this study we investigated in wild-type and genetically manipulated mice the role of the activity-dependent 65-kDa isozyme of glutamic acid decarboxylase (GAD65) in the consolidation and generalization of conditioned fear. First, we demonstrate a transient reduction of GAD65 gene expression in the dorsal hippocampus (6 h post training) and in the basolateral complex of the amygdala (24 h post training) during distinct phases of fear memory consolidation. Second, we show that targeted ablation of the GAD65 gene in Gad65(-/-) mice results in a pronounced context-independent, intramodal generalization of auditory fear memory during long-term (24 h or 14 d) but not short-term (30 min) memory retrieval. The temporal specificity of both gene regulation and memory deficits in Gad65 mutant mice suggests that GAD65-mediated GABA synthesis is critical for the consolidation of stimulus-specific fear memory. This function appears to involve a modulation of neural activity patterns in the amygdalo-hippocampal pathway as indicated by a reduction in theta frequency synchronization between the amygdala and hippocampus of Gad65(-/-) mice during the expression of generalized fear memory.     

Lesions of the entorhinal cortex impair acquisition of hippocampal-dependent trace conditioning

Rabbits with the electrolytic lesions of bilateral entorhinal cortex (EC) were trained with the hippocampal-dependent trace conditioning of the nictitating membrane response. The multiple-unit activity of the hippocampal CA1 region was recorded during conditioning. The conditioned stimulus was a tone (1 kHz, 85 dB, 200-ms duration), the unconditioned stimulus was a corneal air puff (3 psi, 150-ms duration), and the interstimulus interval was 750 ms. The EC-lesioned animals showed only 30% conditioned response (CR) by the ninth session while the sham-operated animals showed above 80% CR. The lesioned animals did not show learning-related changes in the hippocampal activity. When the training was switched to the 300-ms interstimulus interval trace conditioning, both groups learned above 80% CR. The EC-lesioned animals, however, showed less learning-related activity in the hippocampus than the sham-operated animals. These results suggest that the development of the learning-related activity in the hippocampus depends on the intact EC, and that the EC may provide a possible pathway conveying learning information from the cerebellum or cerebral cortex to the hippocampus during the trace conditioning.