Rose-Marie Vouimba

Effects of inescapable stress on LTP in the amygdala versus the dentate gyrus of freely behaving rats

Stress impairs hippocampal long‐term potentiation (LTP), a model of synaptic plasticity that is assumed to underlie memory formation. In the amygdala, little is known about the effects of stress on LTP, or about its longevity. Here we assessed the ability of entorhinal cortex (EC) stimulation to induce LTP simultaneously in the basal amygdaloid nucleus (B) and in the dentate gyrus (DG) of freely behaving Wistar rats. We also tested whether LTP persists over days. Once established, we investigated the effects of acute vs. repeated inescapable stressful experiences on LTP in both structures. Results show that B, like DG, sustained LTP for 7 days. Furthermore, a single exposure to moderate stress facilitated LTP in B but did not affect DG LTP. Stress re‐exposure inhibited LTP in DG but only long‐lasting LTP (>3 days) in B. Behaviourally, animals exhibited a higher immobility when re‐exposed to the stressor than with a single/first exposure. These data support a role for B in memory storage. Furthermore, they support a differential involvement of the amygdala and hippocampus in memory formation and storage depending on the emotional characteristics of the experience.

Amygdala modulation of memory-related processes in the hippocampus: potential relevance to PTSD

A key assumption in the study of stress-induced cognitive and neurobiological modifications is that alterations in hippocampal functioning after stress are due to an excessive activity exerted by the amygdala on the hippocampus. Research so far focused on stress-induced impairment of hippocampal plasticity and memory but an exposure to stress may simultaneously also result in strong emotional memories. In fact, under normal conditions emotionally charged events are better remembered compared with neutral ones. Results indicate that under these conditions there is an increase in activity within the amygdala that may lead to memory of a different quality. Studying the way emotionality activates the amygdala and the functional impact of this activation we found that the amygdala modulates memory-related processes in other brain areas, such as the hippocampus. However, this modulation is complex, involving both enhancing and suppressing effects, depending on the way the amygdala is activated and the hippocampal subregion examined. The current review summarizes our findings and attempts to put them in context with the impact of an exposure to a traumatic experience, in which there is a mixture of a strong memory of some aspects of the experience but impaired memory of other aspects of that experience. Toward that end, we have recently developed an animal model for the induction of predisposition to stress-related disorders, focusing on the consequences of exposure to stressors during juvenility on the ability to cope with stress in adulthood. Exposing juvenile-stressed rats to an additional stressful challenge in adulthood revealed their impairment to cope with stress and resulted in significant elevation of the amygdala. Interestingly, and similar to our electrophysiological findings, differential effects were observed between the impact of the emotional challenge on CA1 and dentate gyrus subregions of the hippocampus. Taken together, the results indicate that long-term alterations within the amygdala contribute to stress-related mnemonic symptoms and suggest that elucidating further these intra-amygdala alterations and their effects on modulating other brain regions is likely to be beneficial for the development of novel approaches to treat stress-related disorders.

Glucocorticoid receptors and β-adrenoceptors in basolateral amygdala modulate synaptic plasticity in hippocampal dentate gyrus, but not in area CA1

The basolateral amygdala (BLA) is a key structure in a memory-modulatory system that regulates stress and stress hormones (glucocorticoid and noradrenaline) effects on hippocampal functioning. We have shown previously that priming the amygdala differentially affects plasticity in the hippocampal dentate gyrus (DG) and CA1, and mimicked acute stress effect on plasticity in these two subregions. In the present study, we investigated the mechanisms that mobilize the BLA to differentially alter plasticity in DG and CA1. Glucocorticoid receptors antagonist RU 38486 or beta-adrenoceptor antagonist propranolol were microinfused in the BLA, 10 min prior to BLA activation-induced modulation of long-term potentiation (LTP) in DG and CA1. The results showed that neither glucocorticoid nor noradrenergic transmissions in the BLA are necessary for LTP induction and for the impairing effect of amygdala activation on CA1 LTP. In contrast, blockade of glucocorticoid or noradrenergic transmission in BLA, increased baseline synaptic transmission in the DG, but suppressed the enhancing effect of BLA activation on DG LTP. These findings provide further evidence for a differential amygdala control of hippocampal subregions as well as for differential memory processes involving CA1 and DG. They also provide insight into how stress hormones exert their actions on the circuits involved in these processes.

Learning-Induced Changes in mPFC–BLA Connections After Fear Conditioning, Extinction, and Reinstatement of Fear

The neural circuit linking the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) has crucial roles in both the acquisition and the extinction of fear. However, the mechanism by which this circuit encodes fear and extinction remains unknown. In this study, we monitored changes in the magnitude of evoked field potentials (EFPs) in the mPFC–BLA and BLA–mPFC pathways following auditory fear conditioning and extinction, in freely moving rats. We report that extinction of fear is mediated by depression of the EFPs in the mPFC–BLA and by potentiation in the reciprocal pathway of BLA–mPFC. Interestingly, reinstatement of fear was associated with recovery of freezing and with reversal of the changes in EFPs that were observed following extinction in both pathways. The findings indicate that the mPFC–BLA circuit expresses differential changes following fear and extinction and point to dynamic and plastic changes underlying fear, extinction, and reinstatement. Manipulations targeting these different types of plasticity could constitute a therapeutic tool for the treatment of anxiety disorders.

Juvenile Obesity Enhances Emotional Memory and Amygdala Plasticity through Glucocorticoids

In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence during adolescence is particularly alarming since recent evidence indicates that obesity can affect hippocampal function during this developmental period. Adolescence is a decisive period for maturation of the amygdala and the hypothalamic–pituitary–adrenal (HPA) stress axis, both required for lifelong cognitive and emotional processing. However, little data are available on the impact of obesity during adolescence on amygdala function. Herein, we therefore evaluate in rats whether juvenile high-fat diet (HFD)-induced obesity alters amygdala-dependent emotional memory and whether it depends on HPA axis deregulation. Exposure to HFD from weaning to adulthood, i.e., covering adolescence, enhances long-term emotional memories as assessed by odor–malaise and tone–shock associations. Juvenile HFD also enhances emotion-induced neuronal activation of the basolateral complex of the amygdala (BLA), which correlates with protracted plasma corticosterone release. HFD exposure restricted to adulthood does not modify all these parameters, indicating adolescence is a vulnerable period to the effects of HFD-induced obesity. Finally, exaggerated emotional memory and BLA synaptic plasticity after juvenile HFD are alleviated by a glucocorticoid receptor antagonist. Altogether, our results demonstrate that juvenile HFD alters HPA axis reactivity leading to an enhancement of amygdala-dependent synaptic and memory processes. Adolescence represents a period of increased susceptibility to the effects of diet-induced obesity on amygdala function.

Long-term potentiation and long-term depression in the lateral septum in spatial working and reference memory

We report two experiments conducted on a radial arm maze in the mouse showing that training could either enhance or reduce the efficacy of the fimbria-lateral septal synapses. It is suggested that the direction of change is determined by the kind of situation the animal is faced with (ie trial-dependent, respectively).

Different patterns of amygdala priming differentially affect dentate gyrus plasticity and corticosterone, but not CA1 plasticity

Stress-induced activation of the amygdala is involved in the modulation of memory processes in the hippocampus. However, stress effects on amygdala and memory remain complex. The activation of the basolateral amygdala (BLA) was found to modulate plasticity in other brain areas, including the hippocampus. We previously demonstrated a differential effect of BLA priming on long-term potentiation (LTP) in the CA1 and the dentate gyrus (DG). While BLA priming suppressed LTP in CA1, it was found to enhance it in the DG. However, since the amygdala itself is amenable to experience-induced plasticity it is thus conceivable that when activity within the amygdala is modified this will have impact on the way the amygdala modulates activity and plasticity in other brain areas. In the current study, we examined the effects of different patterns of BLA activation on the modulation of LTP in the DG and CA1, as well as on serum corticosterone (CORT). In CA1, BLA-priming impaired LTP induction as was reported before. In contrast, in the DG, varying BLA stimulation intensity and frequency resulted in differential effects on LTP, ranging from no effect to strong impairment or enhancement. Varying BLA stimulation patterns resulted in also differential alterations in Serum CORT, leading to higher CORT levels being positively correlated with LTP magnitude in DG but not in CA1. The results support the notion of a differential role for the DG in aspects of memory, and add to this view the possibility that DG-associated aspects of memory will be enhanced under more emotional or stressful conditions. It is interesting to think of BLA patterns of activation and the differential levels of circulating CORT as two arms of the emotional and stress response that attempt to synchronize brain activity to best meet the challenge. It is foreseeable to think of abnormal such synchronization under extreme conditions, which would lead to the development of maladaptive behavior.

Pretraining tetanic fimbrial stimulation impairs the expression but not the acquisition of contextual fear conditioning in mice.

We recently reported that the pretraining induction of long-term potentiation in the lateral septum by fimbrial tetanic stimulation altered contextual fear conditioning in mice. The aim of the present study was to examine at which stage of fear conditioning (i.e. either acquisition or expression) this impairment takes place. Mice implanted with stimulating electrodes in the fimbria and recording electrodes in the lateral septal were conditioned to acquire fear towards a novel context using a footshock procedure. Twenty-four hours after conditioning, animals were re-exposed to the conditioning environment and the level of freezing behavior served as the measure of conditioned fear. The level of fimbrial-lateral septal synaptic neurotransmission was manipulated using either fimbrial tetanic stimulation (which induced septal long-term potentiation) alone, or followed by fimbrial low-frequency stimulation producing depotentiation of the previously established long-term potentiation. The results showed that (i) septal long-term potentiation induced either prior to acquisition or only prior to retention testing impaired conditioned freezing; and (ii) the impairing effect of pretraining induction of long-term potentiation on conditioned freezing was not only abolished by fimbrial low-frequency stimulation administered prior to retention testing but actually produced enhanced conditioned freezing with respect to controls. These data suggest that the level of fimbrial-lateral septal synaptic neurotransmission may influence the expression, but not the acquisition, of contextual fear conditioning.