Impaired Contextual Fear Conditioning Research Articles

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

Although immunization against amyloid-beta (Abeta) holds promise as a disease-modifying therapy for Alzheimer disease (AD), it is associated with an undesirable accumulation of amyloid in the cerebrovasculature [i.e., cerebral amyloid angiopathy (CAA)] and a heightened risk of micro-hemorrhages. The central and peripheral mechanisms postulated to modulate amyloid with anti-Abeta immunotherapy remain largely elusive. Here, we compared the effects of prolonged intracerebroventricular (i.c.v.) versus systemic delivery of anti-Abeta antibodies on the behavioral and pathological changes in an aged Tg2576 mouse model of AD. Prolonged i.c.v. infusions of anti-Abeta antibodies dose-dependently reduced the parenchymal plaque burden, astrogliosis, and dystrophic neurites at doses 10- to 50-fold lower than used with systemic delivery of the same antibody. Both i.c.v. and systemic anti-Abeta antibodies reversed the behavioral impairment in contextual fear conditioning. More importantly, unlike systemically delivered anti-Abeta antibodies that aggravated vascular pathology, i.c.v.-infused antibodies globally reduced CAA and associated micro-hemorrhages. We present data suggesting that the divergent effects of i.c.v.-delivered anti-Abeta antibodies result from gradually engaging the local (i.e., central) mechanisms for amyloid clearance, distinct from the mechanisms engaged by high doses of anti-Abeta antibodies that circulate in the vasculature following systemic delivery. With robust efficacy in reversing AD-related pathology and an unexpected benefit in reducing CAA and associated micro-hemorrhages, i.c.v.-targeted passive immunotherapy offers a promising therapeutic approach for the long-term management of AD.

Analyzing the role of adult hippocampal neurogenesis in contextual fear conditioning

Event Abstract Back to Event Analyzing the role of adult hippocampal neurogenesis in contextual fear conditioning Michael R. Drew1*, Christine A. Denny1 and Rene Hen1 1 Columbia University, Department of Psychiatry, United States Recent studies suggest that adult hippocampal neurogenesis is required for contextual fear conditioning, a form of Pavlovian conditioning in which a spatial context is paired with an aversive stimulus such as footshock. Rodents in which adult neurogenesis was arrested acquired less fear of the shock-paired context than did controls, suggesting that adult-born hippocampal neurons are integral to context memory and/or other aspects of associative learning. However, the validity of this finding is questioned by other recent studies that failed to detect effects of arresting neurogenesis on contextual fear conditioning. In hopes of resolving the discrepancy, we evaluated the generality of contextual fear conditioning deficits induced by low-dose, targeted irradiation in mice, which produces a complete and lasting ablation of hippocampal neurogenesis, while sparing other neurogenic niches. We found that 1-trial contextual fear conditioning was more sensitive to the arrest of neurogenesis than was multiple-trial conditioning. In addition, deficits in 1-trial contextual fear conditioning were rescued when mice were provided with extra exposure to the conditioning context prior to training. The results suggest that neurogenesis is required only in procedures that demand rapid encoding of contextual information. The behavioral effects of irradiation were also highly time-dependent. The impairment in contextual fear conditioning was absent 2 weeks post-irradiation, suggesting that very young adult-born neurons are not required for this form of learning. By 6 weeks post-irradiation a significant impairment had appeared, but at 8 and 10 weeks post-irradiation, the impairment disappeared, suggesting that over time the brain compensates for the loss of adult neurogenesis. Our results suggest that contextual fear conditioning is sensitive to the arrest of adult neurogenesis, but only when the conditioning procedure demands rapid learning and is conducted within a limited window of time after the arrest of neurogenesis. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Oral Presentation Topic: Symposia lectures Citation: Drew MR, Denny CA and Hen R (2009). Analyzing the role of adult hippocampal neurogenesis in contextual fear conditioning. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.022 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Jun 2009; Published Online: 04 Jun 2009. * Correspondence: Michael R Drew, Columbia University, Department of Psychiatry, New York, United States, mrd001@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Michael R Drew Christine A Denny Rene Hen Google Michael R Drew Christine A Denny Rene Hen Google Scholar Michael R Drew Christine A Denny Rene Hen PubMed Michael R Drew Christine A Denny Rene Hen Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Hippocampal and extrahippocampal systems compete for control of contextual fear: Role of ventral subiculum and amygdala

Two neural systems, a hippocampal system and an extrahippocampal system compete for control over contextual fear, and the hippocampal system normally dominates. Our experiments reveal that output provided by the ventral subiculum is critical for the hippocampal system to win this competition. Bilateral electrolytic lesions of the ventral subiculum after conditioning, but not before conditioning, impaired contextual fear conditioning. Reversibly inactivating this region by bilateral injections of muscimol produced the same results-no impairment when the injection occurred prior to conditioning but a significant impairment when this region was inactivated after conditioning. Thus, the extrahippocampal system can support contextual fear conditioning if the ventral subiculum is disabled before conditioning but not if it is disabled after conditioning. Our experiments also reveal that the basolateral region of the amygdala (BLA) is where the two systems compete for associative control of the fear system. To test this hypothesis we reasoned that the extrahippocampal system would also acquire associative control over the fear system, even if the hippocampal system were functional, if the basal level of plasticity potential in the BLA could be increased. We did this by injecting the D1 dopamine agonist, SKF82958, into the BLA just prior to conditioning. This treatment resulted in a significant increase in freezing when the ventral subiculum was disabled prior to the test. These results are discussed in relationship to the idea that D1 agonists increase plasticity potential by increasing the pool of available extrasynaptic GluR1 receptors in the population of neurons supporting acquired fear.

Dysregulated CREB signaling pathway in the brain of neural cell adhesion molecule (NCAM)-deficient mice

The neural cell adhesion molecule (NCAM) mediates cell–cell interactions and plays an important role in processes associated with neural plasticity, including learning and memory formation. It has been shown that mice deficient in all isoforms of NCAM (NCAM−/− mice) demonstrate impairment in long-term plasticity at multiple hippocampal synapses, disrupted spatial learning, and impaired contextual and auditory-cued fear conditioning. The formation of long-term memory is associated with activation of transcription factor CREB (cAMP response element binding protein). The aims of this study were to investigate NCAM-mediated signaling transduction pathways and the levels of the phosphorylated (Ser133) active form of the CREB in the brain structures (the pre- and frontal cortex, basolateral amygdala, and hippocampus) involved in the memory formation in NCAM-deficient mice. Immunohistochemical analysis revealed reduced levels of pCREB in the prefrontal cortex (PFC), frontal cortex (FC), CA3 subregion of the hippocampus (CA3) and basolateral nucleus of amygdala (BLA) in NCAM−/− mice. NCAM−/− mice had also reduced levels of the phosphorylated CaMKII and CaMKIV in PFC/FC and the hippocampus, which are the downstream signaling molecules of NCAM. The levels of non-phosphorylated kinases did not differ from those seen in the wild-type mice. These results provide evidence that NCAM deficiency results in the dysregulation of CREB-mediated signaling pathways in the brain regions, which is related to the formation of memory.

The effects of running and of inhibiting adult neurogenesis on learning and memory in rats

The presence of ongoing adult neurogenesis within the highly plastic hippocampal circuitry poses questions as to the relevance of new neurons to learning and memory. Correlational and causal evidence suggests that some, but not all, hippocampal tasks involve the new neurons. The evidence with regard to spatial learning in the water maze, one of the most commonly used hippocampal tasks, is contradictory. In this study we examined the effects of irradiation-induced reduction in neurogenesis on spatial learning and another standard hippocampal task, contextual fear conditioning, in rats that experienced normal cage conditions or voluntary running. The results indicate that reduced neurogenesis had little effect on spatial learning but severely impaired contextual fear conditioning. It was suggested that compensatory mechanisms within the hippocampus may have contributed selectively to sparing of spatial function. Performance on the fear conditioning task was weakly related to enhanced neurogenesis or running. The results improve our understanding of the functional role of adult neurogenesis in behaving animals.

Determination of the EC50Amnesic Concentration of Etomidate and Its Diffusion Profile in Brain Tissue

Etomidate is a widely used general anesthetic that has become a useful tool to investigate mechanisms of anesthetic action in vivo and in brain slices. However, the free aqueous concentration of etomidate that corresponds to amnesia in vivo and the diffusion profile of etomidate in brain slices are not known. The authors assessed the effect of intraperitoneally injected etomidate on contextual fear conditioning in mice. Etomidate concentrations in brain tissue were obtained by high-performance liquid chromatography. Uptake studies in 400-microm-thick brain slices were used to calculate the diffusion and partition coefficients of etomidate. A diffusion model was used to calculate the expected concentration profile within a brain slice as a function of time and depth. The predicted rate of drug equilibration was compared with the onset of electrophysiologic effects on inhibitory circuit function in recordings from hippocampal brain slices. Etomidate impaired contextual fear conditioning with an ED50 dose of 11.0+/-0.1 mg after intraperitoneal injection, which corresponded to an EC50 brain concentration of 208+/-9 ng/g. The brain:artificial cerebrospinal fluid partition coefficient was 3.35, yielding an EC50,amnesia aqueous concentration of 0.25 microm. The diffusion coefficient was approximately 0.2x10 cm/s. The development of etomidate action in hippocampal brain slices was compatible with the concentration profile predicted by this diffusion coefficient. The free aqueous concentration of etomidate corresponding to amnesia, as defined by impaired contextual fear conditioning in mice, is 0.25 microM. Diffusion of etomidate into brain slices requires approximately an hour to reach 80% equilibration at a typical recording depth of 100 microm. This information will be useful in designing and interpreting in vitro studies using etomidate.

Males Afraid, Females Brave

There are different kinds of memories. In mice, differences have been noted in contextual fear memory formation and spatial memory formation, although both forms of memory appear to involve a calcium signal and the activation of calcium/calmodulin-dependent kinases (CaMKs). In mice, there are two isoforms of CaMK that have been implicated in memory formation (CaMKI and CaMKIV) and two upstream kinases that phosphorylate CaMK (CaM kinase kinases: CaMKKα and CaMKKβ). CaMKKβ has been implicated in spatial memory formation, and CaMKIV has been implicated in long-term potentiation and fear conditioning. Two groups, Blaeser et al . and Mizuno et al ., created mice deficient in CaMKKα function and found that the mice showed normal spatial memory, normal motor activity, and normal sensory perception; however, male mice were impaired in the formation of contextual fear memories. Synaptic transmission was not impaired in the CamKKα-deficient mice, nor was formation of hippocampal long-term potentiation. Blaeser et al . showed that, compared with wild-type mice, the CamKKα-deficient male mice exhibited decreased phosphorylation of CaMKIV and the transcriptional regulator CREB (a substrate of CaMKIV) in response to fear conditioning. Phosphorylation of CREB under basal conditions was increased in the mutant mice in certain brain regions; however, the fear-induced increases in phosphorylation were absent. Mizuno et al . investigated memory formation in both male and female mice deficient for CaMKKα and noted that females did not show impairment of contextual fear conditioning. (It was known that female mice tend to exhibit contextual fear conditioning to a lesser extent than do male mice.) In wild-type mice, contextual fear conditioning promoted an increase in brain-derived neurotrophic factor (BDNF) in males only and a decrease in BDNF in females (transcript abundance was measured by real-time polymerase chain reaction). In the CaMKKα-deficient mice, the increase in BDNF in males was compromised, but the decrease in females was unaffected. The gene encoding BDNF is a CREB target; however, expression of another gene regulated by CREB, the gene encoding nerve growth factor-inducible gene B (NGF-1B), was increased in response to fear conditioning in both males and females and was not affected by lack of CaMKKα. Thus, in addition to specific forms of memory requiring specific signaling cascades, there is an additional gender-specific layer of regulation. F. Blaeser, M. J. Sanders, N. Truong, S. Ko, L. J. Wu, D. F. Wozniak. M. S. Fanselow, M. Zhuo, T. A. Chatila, Long-term memory deficits in Pavlovian fear conditioning in Ca 2+ /calmodulin kinase kinase α-deficient mice. Mol. Cell. Biol. 26 , 9105-9115 (2006). [Abstract] [Full Text] K. Mizuno, L. Ris, A. Sánchez-Capelo, E. Godaux, K. P. Giese, Ca 2+ /calmodulin kinase kinase α is dispensable for brain development but is required for distinct memories in male, though not in female, mice. Mol. Cell. Biol. 26 , 9094-9104 (2006). [Abstract] [Full Text]

Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus

Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.

Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of beta-amyloid (Abeta)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Abeta42/Abeta40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until approximately 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.

WIN 55212-2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors

The memory deficits induced by cannabinoid agonists have been found in several behavioral paradigms. Nevertheless, there is evidence that not all types of memory are impaired after cannabinoid administration. The aim of this study was to investigate whether the cannabinoid agonist WIN 55212-2 (WIN) is able to influence the acquisition of fear conditioning using tone and contextual versions. For tone-fear conditioning, male Wistar rats were placed in the conditioning chamber and after 3 min, a sound (CS) was presented for 10 s that terminated with a 1-s electric footshock (1.5 mA). For contextual-fear conditioning, a similar procedure was used but no sound was presented. Twenty-four hours after, the animals were re-exposed to the respective CS (tone or conditioning chamber) and the freezing behavior was registered. A subsequent experiment investigated a possible state-dependent effect of WIN by administering WIN or control solution 30 min before conditioning and before testing. WIN (2.5 and 5.0 mg/kg) administered i.p. 30 min before impaired contextual fear conditioning but did not modify the freezing behavior elicited by tone presentation. These animals did not show any state-dependent effects of WIN. Further, the impaired contextual conditioning was prevented by preadministration of SR141716A (1.0 mg/kg, i.p.) or SR147778 (1.0 mg/kg, i.p.), selective cannabinoid CB1 receptor antagonists. The present findings highlight that cannabinoid agonists effects are selective for the hippocampus-dependent aversive memories in rats. This effect appears to be related to the activation of CB1 cannabinoid receptors and confirms that cannabinoids might provide a novel approach for the treatment of unpleasant memories.

Impaired trace and contextual fear conditioning in aged rats.

Trace and contextual fear conditioning were evaluated in adult (3-6 months), early middle-aged (8-12 months), late middle-aged (16-20 months), and aged (24-33 months) Sprague-Dawley rats. After trace conditioning, aged animals exhibited significantly less freezing to the tone conditioned stimulus and training context. Levels of trace-cue and context conditioning were negatively correlated with age (r = -0.56 and -0.59, respectively) and positively correlated with each other (r = +0.52). Aged rats showed robust conditioning in short- and long-delay fear paradigms, suggesting that the trace interval, rather than the use of a long interstimulus interval, is responsible for the aging-related deficits in trace fear conditioning. The authors suggest that these aging-related conditioning deficits furnish useful indices of functional changes within hippocampus or perirhinal cortex.

Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease

Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of beta-amyloid. Acute treatment before training (but not after training or before testing) with the gamma-secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of beta-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of beta-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.

Effects of pre- or post-training entorhinal cortex AP5 injection on fear conditioning

Fear conditioning is one of the most studied paradigms to assess the neural basis of emotional memory. The circuitry involves NMDA receptor activation in the amygdala and, in the case of contextual conditioning, in the hippocampus. Entorhinal cortex is one of the major input/output structures to the hippocampus and also projects to the amygdala, both through glutamatergic transmission. Other learning tasks involving hippocampus and amygdala, such as inhibitory avoidance, require entorhinal cortex during acquisition and consolidation. However, the involvement of NMDA receptors mediated transmission in entorhinal cortex in fear conditioning acquisition and consolidation is not clear. To investigate that issue, rats were trained in fear conditioning to both contextual and tone conditioned stimulus. Immediately before, immediately, 30 or 90 min after training they received NMDA antagonist AP5 or saline injections bilaterally in the entorhinal cortex (AP—6.8 mm, L ± 5.0 mm DV—6.8 mm). Contextual fear conditioning was measured 24 h after training, and tone fear conditioning 48 h after training. AP5 injections selectively impaired contextual fear conditioning only when injected pre-training. Post-training injections had no effect. These findings suggest that entorhinal cortex NMDA receptors are necessary for acquisition, but not for consolidation, of contextual fear conditioning. On the other hand, both acquisition and consolidation of tone fear conditioning seem to be independent of NMDA receptors in the entorhinal cortex.

Role of hippocampal NMDA receptors in trace eyeblink conditioning

We examined the effects of acute injections of competitive N-methyl- d-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) into the dorsal hippocampus on contextual fear conditioning and classical eyeblink conditioning in C57BL/6 mice. When injected 10 to 40 min before training, APV severely impaired contextual fear conditioning. Thus, APV injection under these conditions was sufficient to suppress hippocampal NMDA receptors. To investigate the role of hippocampal NMDA receptors on eyeblink conditioning, we carried out daily training of mice during 10–40 min after injection of APV. In the delay eyeblink conditioning, in which the unconditioned stimulus (US) is delayed and terminates simultaneously with the conditioned stimulus (CS), APV-injected mice acquired the conditioned responses (CRs) as well as artificial cerebrospinal fluid (aCSF)-injected control mice did. However, in the trace eyeblink conditioning, in which the CS and US were separated by a stimulus-free trace interval of 500 ms, APV-injected mice showed severe impairment in acquisition of the CR. There was no significant difference in pseudo-conditioning between APV- and aCSF-injected mice. These results provide evidence that the NMDA receptor in the dorsal hippocampus is critically involved in acquisition of the CR in long trace eyeblink conditioning.

ERK Signaling Translates to New Memories

Memory consolidation and the enduring changes in synaptic function that may underlie long-lasting memories both depend on synthesis of new mRNA and protein. The mechanisms by which synaptic activity affects transcription have been intensively explored, whereas the route to translational regulation is poorly understood. Kelleher et al. used cultured neurons and a mouse mutant to explore the involvement of the extracellular signal-regulated kinase (ERK) mitogen-associated protein kinase (MAPK) signaling pathway--which has been implicated in synaptic plasticity, learning, and memory--in stimulus-dependent translation. In primary hippocampal neurons, pharmacological analysis indicated that stimulus-dependent activation of a translational reporter and pulse labeling of endogenous transcripts depended on ERK signaling, as did phosphorylation of ribosomal protein S6 and the translation factors eIF4E and 4E-BP1. Transgenic mice expressing a dominant-negative form of the ERK kinase MAPK-extracellular signal regulated kinase-1 (dnMEK1) in postnatal forebrain exhibited impaired spatial reference memory and long-term contextual fear conditioning. Although basal hippocampal synaptic transmission, short-term plastic changes, and an early phase of long-term potentiation (LTP) appeared normal, pharmacological and kinetic analysis of late LTP (L-LTP, which depends on protein synthesis) suggested a selective deficit in the translational component of this process. Hippocampal slices from dnMEK1 mice showed reduced ERK phosphorylation, incorporation of 35 S-methionine, and phosphorylation of translation factors in response to L-LTP-inducing tetanic stimuli. Similarly, hippocampi from dnMEK1 mice showed reduced phosphorylation of ERK and translation factors in response to fear conditioning. Thus regulation of translation through the MAPK signaling pathway appears to play a critical role in long-lasting memory and long-term changes in synaptic function. R. J. Kelleher III, A. Govindarajan, H.-Y. Jung, H. Kang, S. Tonegawa, Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116 , 467-479 (2004). [Online Journal]

Impairment of contextual fear conditioning in rats by Group I mGluRs: Reversal by the nootropic nefiracetam

The blockade of Group I metabotropic glutamate receptors (mGluRs) may be a potential strategy for prevention therapy of neurotoxicity. We here confirm previous reports that systemic application of the Group I antagonist, 1-aminoindan-1,5-dicarboxylic acid (AIDA), causes amnesia in a contextual fear conditioning paradigm in rats. This deficit was fully reversed by long-term pretreatment with the nootropic nefiracetam, which in fact obtained supranormal performance. Our data suggest that application of Group I antagonists to prevent neurotoxicity, combined with nootropic treatment to prevent cognitive deficits, may be a therapeutic strategy for the development of novel antineurotoxic treatments.

Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala.

We investigated the effects of agents acting at histamine receptors on both, spontaneous release of ACh from the basolateral amygdala (BLA) of freely moving rats, and fear conditioning. Extensive evidence suggests that the effects of histamine on cognition might be explained by the modulation of cholinergic systems. Using the microdialysis technique in freely moving rats, we demonstrated that perfusion of the BLA with histaminergic compounds modulates the spontaneous release of ACh. The addition of 100 mm KCl to the perfusion medium strongly stimulated ACh release, whereas, 0.5 microm tetrodotoxin (TTX) inhibited spontaneous ACh release by more than 50%. Histaminergic H3 antagonists (ciproxifan, clobenpropit and thioperamide), directly administered to the BLA, decreased ACh spontaneous release, an effect fully antagonized by the simultaneous perfusion of the BLA with cimetidine, an H2 antagonist. Local administration of cimetidine alone increased ACh spontaneous release slightly, but significantly. Conversely, the administration of H1 antagonists failed to alter ACh spontaneous release. Rats receiving intra-BLA, bilateral injections of the H3 antagonists at doses similar to those inhibiting ACh spontaneous release, immediately after contextual fear conditioning, showed memory consolidation impairment of contextual fear conditioning. Post-training, bilateral injections of 50 microg scopolamine also had an adverse effect on memory retention. These observations provide the first evidence that histamine receptors are involved in the modulation of cholinergic tone in the amygdala and in the consolidation of fear conditioning.

Impairment of conditioned contextual fear of C57BL/6J mice by intracerebral injections of the NMDA receptor antagonist APV

The effects of acute injections of the NMDA receptor antagonist APV on one-trial fear conditioning of C57BL/6J mice were investigated in a time, dose (0.4–3.2 μg) and region-specific manner. Conditioned fear was determined by the assessment of freezing and the computer-controlled measurement of inactivity. Additionally, conditioned heart rate responses were evaluated in the tone-dependent memory test performed in the home cage with the help of implanted ECG transmitters. Injections of APV into the dorsal hippocampus (i.h.) 15 min before training, impaired dose-dependent contextual fear conditioning without discrimination between contextual foreground (unsignaled shock) and background (signaled shock) conditioning as tested 24 h after training. Short-term memory analyzed 1 h after training was also impaired. The observation that a smaller dose of APV was required for intracerebroventricular than for i.h. injection to achieve a similar memory impairment, pointed to the involvement of extrahippocampal NMDA receptors. APV treatment did not affect conditioned tone-dependent fear as indicated by unchanged freezing and heart rate responses of the freely moving mice. The results indicated the contribution of hippocampal and extrahippocampal NMDA receptors to multisensory contextual information processing during acquisition.

Effects of the selective M1 muscarinic receptor antagonist dicyclomine on emotional memory.

The nonselective muscarinic antagonist scopolamine is known to impair the acquisition of some learning tasks such as inhibitory avoidance. There has been recent research into the effects of this drug in contextual fear conditioning and tone fear conditioning paradigms. The purpose of the present study was to assess the role of the selective M1 muscarinic antagonist dicyclomine in these paradigms and in the inhibitory avoidance test. Rats were administered different doses of dicyclomine or saline 30 min before acquisition training. The animals were tested 24 hr later, and it was observed that 16 mg/kg of dicyclomine impaired both contextual fear conditioning and inhibitory avoidance. However, dicyclomine (up to 64 mg/kg) did not affect tone fear conditioning. These results suggest that the selective M1 muscarinic antagonist dicyclomine differentially affects aversively motivated tasks known to be dependent on hippocampal integrity (such as contextual fear conditioning and inhibitory avoidance) but does not affect similar hippocampus-independent tasks.

Is the hippocampus necessary for contextual fear conditioning?

The hippocampus is widely believed to be essential for learning about the context in which conditioning occurs. This view is based primarily on evidence that lesions of the dorsal hippocampus disrupt freezing to contextual cues after fear conditioning. However, lesions that disrupt freezing produce no effect on fear-potentiated startle, a second measure of contextual fear. Moreover, hippocampal lesions also do not disrupt the contextual ‘blocking’ phenomenon, which provides an indirect measure of contextual fear. In these paradigms, at least, it appears that hippocampal lesions disrupt the expression of freezing, rather than contextual fear itself. This interpretation is supported by the finding that rats showing preserved contextual blocking after hippocampal lesions show deficits not only in contextual freezing, but also in unconditioned freezing. These findings are consistent with a growing body of data from other conditioning paradigms that contextual learning is spared after lesions of the dorsal hippocampus. Nonetheless, there remain some reports of impaired contextual fear conditioning after hippocampal lesions that cannot be attributed easily to a disruption of freezing. Thus, it is concluded that the hippocampus may be involved in contextual learning under certain – as yet, unspecified – circumstances, but is not critical for contextual learning in general.