Acquisition Of Contextual Fear Memory Research Articles

Synapse formation and plasticity by cell adhesion molecules cadherin and nectin

Synapses are sticky structures that physically connect neurons to one another as well as locations of cell-to-cell communication generated between the axons and dendrites of neurons. Synapse formation is hypothesized to be facilitated by a number of molecular processes, including cadherins and nectins. Calcium is necessary for the cadherin cell adhesion molecule. It has been shown that cadherins and catenins localize between axons and dendrites in neurons from the earliest stages of synaptogenesis. Cadherins affect how synapses form and change throughout time. In addition to cadherins, nectins are known to contribute to the construction and upkeep of intercellular adhesions. The brain expresses nectin-1,2 and 3. Here, the author reviews the specific effects of N-cadherin deletion on synapses and its relationship to diseases. Additionally, it has been discovered that nectin-1 and 3 play physiological roles in the development of synapses, alteration of mossy fibers' travel patterns, inter-neurite affinity, acquisition of contextual fear memory, and stress-related mental diseases. Nectin-2 has critical roles in the establishment of synapses as well as the homeostasis of astrocytes and neurons in the particular areas of the brain where it is generated. Additionally, a human NECTIN2 gene variant has been associated with Alzheimer's disease.

Contextual fear response is modulated by M-type K+ channels and is associated with subtle structural changes of the axon initial segment in hippocampal GABAergic neurons

In the fear memory network, the hippocampus modulates contextual aspects of fear learning while mutual connections between the amygdala and the medial prefrontal cortex are widely involved in fear extinction. G-protein-coupled receptors (GPCRs) are involved in the regulation of fear and anxiety, so the regulation of GPCRs in fear signaling pathways can modulate the mechanisms of fear memory acquisition, consolidation and extinction. Various studies suggested a role of M-type K+ channels in modulating fear expression and extinction, although conflicting data prevented drawing of clear conclusions. In the present work, we examined the impact of M-type K+ channel blockade or activation on contextual fear acquisition and extinction. In addition, regarding the pivotal role of the hippocampus in contextual fear conditioning (CFC) and the involvement of the axon initial segment (AIS) in neuronal plasticity, we investigated whether structural alterations of the AIS in hippocampal neurons occurred during contextual fear memory acquisition and short-time extinction in mice in a behaviorally relevant context. When a single systemic injection of the M-channel blocker XE991 (2 mg/kg, IP) was carried out 15 minutes before the foot shock session, fear expression was significantly reduced. Expression of c-Fos was increased following CFC, mostly in GABAergic neurons at day 1 and day 2 post-fear training in CA1 and dentate gyrus hippocampal regions. A significantly longer AIS segment was observed in GABAergic neurons of the CA1 hippocampal region at day 2. Our results underscore the role of M-type K + channels in CFC and the importance of hippocampal GABAergic neurons in fear expression.

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

Total sleep deprivation impairs fear memory retrieval by decreasing the basolateral amygdala activity

It is well known that sleep deprivation impairs fear memory processes, but little is known about the underlying mechanisms or circuits. The aim of this study was to evaluate the effects of total sleep deprivation (24 h) on contextual fear memory acquisition, consolidation, and retrieval, as well as c-Fos activity in the hippocampus and amygdala. Fear memory recall was associated with an increase in the number of c-Fos-positive cells in the hippocampal CA1 and CA3 regions and the basolateral amygdala (BLA). Total sleep deprivation before to the acquisition and during consolidation of memory impaired retrieval and blocked the associated c-Fos activity in the hippocampus and amygdala. In contrast, total sleep deprivation before memory recall also impaired retrieval, but selectively prevented the increase of c-Fos activity in the amygdala (but not in the hippocampus). Our data indicate that sleep is essential not only for acquisition and consolidation but also for the retrieval of fear memories. They also suggest a differential susceptibility of specific memory-related neural circuits (hippocampus and BLA) to the absence of sleep.

Direct Neuronal Glucose Uptake Is Required for Contextual Fear Acquisition in the Dorsal Hippocampus.

The metabolism of glucose is a nearly exclusive source of energy for maintaining neuronal survival, synaptic transmission and information processing in the brain. Two glucose metabolism pathways have been reported, direct neuronal glucose uptake and the astrocyte-neuron lactate shuttle (ANLS), which can be involved in these functions simultaneously or separately. Although ANLS in the dorsal hippocampus (DH) has been proved to be required for memory consolidation, the specific metabolic pathway involved during memory acquisition remains unclear. The DH and amygdala are two key brain regions for acquisition of contextual fear conditioning (CFC). In 2-NBDG experiments, we observed that 2-NBDG-positive neurons were significantly increased during the acquisition of CFC in the DH. However, in the amygdala and cerebellum, 2-NBDG-positive neurons were not changed during CFC training. Strikingly, microinjection of a glucose transporter (GLUT) inhibitor into the DH decreased freezing values during CFC training and 1 h later, while injection of a monocarboxylate transporter (MCT) inhibitor into the amygdala also reduced freezing values. Therefore, we demonstrated that direct neuronal glucose uptake was the primary means of energy supply in the DH, while ANLS might supply energy in the amygdala during acquisition. Furthermore, knockdown of GLUT3 by a lentivirus in the DH impaired the acquisition of CFC. Taken together, the results indicated that there were two different glucose metabolism pathways in the DH and amygdala during acquisition of contextual fear memory and that direct neuronal glucose uptake in the DH may be regulated by GLUT3.

Pre-adolescent and adolescent mice are less sensitive to the effects of acute nicotine on extinction and spontaneous recovery

Adolescence is a period of high risk for the initiation of nicotine product usage and exposure to traumatic events. In parallel, nicotine exposure has been found to age-dependently modulate acquisition of contextual fear memories; however, it is unknown if adolescent nicotine exposure alters extinction of fear related memories. Age-related differences in sensitivity to the effects of nicotine on fear extinction could increase or decrease susceptibility to anxiety disorders. In this study, we examined the effects of acute nicotine administration on extinction and spontaneous recovery of contextual fear memories in pre-adolescent (PND 23), late adolescent (PND 38), and adult (PND 53) C57B6/J mice. Mice were first trained in a background contextual fear conditioning paradigm and given an intraperitoneal injection of one of four doses of nicotine (0.045, 0.09, 0.18, or 0.36mg/kg, freebase) prior to subsequent extinction or spontaneous recovery sessions. Results indicated that all acute nicotine doses impaired extinction of contextual fear in adult mice. Late adolescent mice exhibited impaired extinction of contextual fear only following higher doses of acute nicotine, and extinction of contextual fear was unaffected by acute nicotine exposure in pre-adolescent mice. Finally, acute nicotine exposure enhanced spontaneous recovery of fear memory, but only in adult mice. Overall, our results suggest that younger mice were less sensitive to nicotine’s impairing effects on extinction of contextual fear and to nicotine’s enhancing effects on spontaneous recovery of contextual fear memory.

Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats

The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus.

Improvement in γ-hydroxybutyrate-induced contextual fear memory deficit by systemic administration of NCS-382.

Low, nonsedative doses of γ-hydroxybutyric acid (GHB) produce short-term anterograde amnesia in humans and memory impairments in experimental animals. We have previously shown that acute systemic treatment of GHB in adolescent female rats impairs the acquisition, but not the expression, of contextual fear memory while sparing both the acquisition and the expression of auditory cued fear memory. In the brain, GHB binds to specific GHB-binding sites as well as to γ-aminobutyric acid type B (GABAB) receptors. Although many of the behavioral effects of GHB at high doses have been attributed to its effects on the GABAB receptor, it is unclear which receptor mediates its relatively low-dose memory-impairing effects. The present study examined the ability of the putative GHB receptor antagonist NCS-382 to block the disrupting effects of GHB on fear memory in adolescent rat. Groups of rats received either a single dose of NCS-382 (3–10 mg/kg, intraperitoneally) or vehicle, followed by an injection of either GHB (100 mg/kg, intraperitoneally) or saline. All rats were trained in the fear paradigm, and tested for contextual fear memory and auditory cued fear memory. NCS-382 dose-dependently reversed deficits in the acquisition of contextual fear memory induced by GHB in adolescent rats, with 5 mg/kg of NCS-382 maximally increasing freezing to the context compared with the group administered GHB alone. When animals were tested for cued fear memory, treatment groups did not differ in freezing responses to the tone. These results suggest that low-dose amnesic effects of GHB are mediated by GHB receptors.

A role for the anteromedial thalamic nucleus in the acquisition of contextual fear memory to predatory threats.

Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.

Dopamine D1-like receptor signalling in the hippocampus and amygdala modulates the acquisition of contextual fear conditioning.

RationaleDopamine D1-like receptor signalling is involved in contextual fear conditioning, but the brain regions involved and its role in other contextual fear memory processes remain unclear.ObjectivesThe objective of this study was to investigate (1) the effects of SCH 23390, a dopamine D1/D5 receptor antagonist, on contextual fear memory encoding, retrieval and reconsolidation, and (2) if the effects of SCH 23390 on conditioning involve the dorsal hippocampus (DH) and/or basolateral amygdala (BLA).MethodsRats were used to examine the effects of systemically administering SCH 23390 on the acquisition, consolidation, retrieval and reconsolidation of contextual fear memory, and on locomotor activity and shock sensitivity. We also determined the effects of MK-801, an NMDA receptor antagonist, on contextual fear memory reconsolidation. The effects of infusing SCH 23390 locally into DH or BLA on contextual fear conditioning and locomotor activity were also examined.ResultsSystemic administration of SCH 23390 impaired contextual fear conditioning but had no effects on fear memory consolidation, retrieval or reconsolidation. MK-801 was found to impair reconsolidation, suggesting that the behavioural parameters used allowed for the pharmacological disruption of memory reconsolidation. The effects of SCH 23390 on conditioning were unlikely the result of any lasting drug effects on locomotor activity at memory test or any acute drug effects on shock sensitivity during conditioning. SCH 23390 infused into either DH or BLA impaired contextual fear conditioning and decreased locomotor activity.ConclusionsThese findings suggest that dopamine D1-like receptor signalling in DH and BLA contributes to the acquisition of contextual fear memory.

Differential involvement of protein synthesis and actin rearrangement in the reacquisition of contextual fear conditioning

Extinction learning is associated with a decline of the conditioned fear response (CR). However, re-exposure to the unconditioned stimulus (US, shock) is associated with the return of the fear response. This study aimed to study the role of protein synthesis and actin rearrangement in the CA1 hippocampal subregion and the basolateral amygdala (BLA) in acquisition and reacquisition of contextual fear conditioning. To that end, we trained rats on contextual fear conditioning and extinction, and on the last extinction training session we reconditioned the animals by re-exposure to the US. Immediately after, rats were microinfused with the protein synthesis inhibitor anisomycin or the actin rearrangement inhibitor cytochalasin D into either the BLA or the CA1. The results of this study show differential involvement of anisomycin and cytochalasin D in the acquisition and reacquisition of contextual fear conditioning. Specifically, while the microinfusion of anisomycin into the BLA or the CA1 immediately after reconditioning of fear did not inhibit the return of fear, the microinfusion of cytochalsin D into either the BLA or the CA1 attenuated fear responses. Interestingly, the initial acquisition of contextual fear memory is dependent on intra-BLA and CA1 protein synthesis and cytoskeletal rearrangement, since the microinfusion of these drugs blocked the formation of long-term fear memory. The results suggest that the two processes of acquisition and reacquisition of fear are not identical and they engage different mechanisms.

The enhancement of contextual fear conditioning by ABT-418

Activation of nicotinic acetylcholine receptors (nAChRs) is known to modulate various forms of learning and memory, including contextual fear conditioning. Although numerous studies have shown that high-affinity beta2-containing nAChRs are necessary for the nicotine-induced enhancement of contextual fear conditioning, it is unknown whether other high-affinity nAChR agonists are capable of enhancing this learning. To examine this issue, ABT-418, a high-affinity nAChR agonist with greater selectivity for high-affinity receptors than nicotine, was administered before acquisition and/or recall of contextual fear memories. ABT-418 enhanced acquisition of contextual fear memories in a dose-dependent manner.

Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity

Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.