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M S Fanselow

Publications and source records attributed to M S Fanselow.

At least 19 recordsLinked to original sources
PubMed2001

Hippocampus and contextual fear conditioning: recent controversies and advances.

Dorsal hippocampal (DH) lesions produce a severe deficit in recently, but not remotely, acquired contextual fear without impairing memory of discrete training stimuli, i.e., DH lesions produce an anterograde and time-limited retrograde amnesia specific to contextual memory. These data are consistent with the standard model which posits temporary involvement of the hippocampus in recent memory maintenance. However, three recent controversies apparently weaken the case for a selective mnemonic role for the hippocampus in contextual fear. First, although retrograde amnesia (from posttraining lesions) is severe, anterograde amnesia (from pretraining lesions) may be mild or nonexistent. Second, a performance, rather than mnemonic, account of contextual freezing deficits in hippocampal-lesioned animals has been offered. Third, damage to the entire hippocampus, including the ventral hippocampus, can produce a dramatic and temporally stable disruption of context and tone fear. These data are reviewed and explanations are offered as to why they do not necessarily challenge the standard model of hippocampal memory function in contextual fear. Finally, a more complete description of the hippocampus' proposed role in contextual fear is offered, along with new data supporting this view. In summary, the data support a specific mnemonic role for the DH in the acquisition and consolidation of contextual representations.

Amnesia↗
PubMed2001

Cholinergic modulation of pavlovian fear conditioning: effects of intrahippocampal scopolamine infusion.

Cholinergic neurotransmission has been implicated in the acquisition of a variety of tasks, including Pavlovian fear conditioning. To more precisely define the role of cholinergic modulation in this process, the effect of site-specific cholinergic antagonism was assessed. Male Long-Evans rats were implanted with chronic, bilateral cannulae aimed at the dorsal hippocampus. Infusions of scopolamine hydrobromide (50 microg bilaterally) or phosphate-buffered saline (PBS) were made immediately prior to a signaled Pavlovian fear conditioning procedure. On consecutive days following training, all rats were given independent tests assessing freezing to both the training context and the tone conditional stimulus (CS). Relative to PBS infused controls, rats that received intrahippocampal infusions of scopolamine showed a significant attenuation of contextual freezing but comparable levels of freezing to the tone CS. Neither shock sensitivity nor general activity levels differed between rats infused with scopolamine or PBS. These findings suggest that fear conditioning to context, but not discrete CS, requires intact cholinergic neurotransmission in the hippocampus.

Animals↗
PubMed2001

Sex differences, context preexposure, and the immediate shock deficit in Pavlovian context conditioning with mice.

The acquisition of context fear in rats is affected by variables such as the sex of the animal, the placement to shock interval (PSI), and preexposure to the context. The current experiments assessed the effects of these variables on context conditioning in mice (C57BL/6). In Experiment 1, mice were placed in a chamber and received a single shock 5s, 20 s, 40s, 60s, 180s, or 720s later. Increasing the PSI produced corresponding increases in conditional freezing during the context test. In addition, male mice acquired more context conditioning than female mice did but only at intermediate PSIs. In Experiment 2, preexposure to the context before training alleviated the sex difference found with an intermediate PSI. The results are discussed in terms of configural learning theory and are argued to be contrary to the predictions of scalar expectancy theory.

Animals↗
PubMed2001

The concentration of isoflurane required to suppress learning depends on the type of learning.

BACKGROUND: Recent reports suggest that one type of learning, fear conditioning to context, requires more neural processing than a related type, fear conditioning to tone. To determine whether these types of learning were differentially affected by anesthesia, the authors applied isoflurane during the training phases of fear conditioning paradigms for freezing to context and freezing to tone. METHODS: The authors trained seven groups of eight rats to fear tone by administering a tone (conditioned stimulus) while breathing various concentrations of isoflurane from 0.00 to 0.75 minimum alveolar concentration (MAC; one concentration per group) separated by 0.12-MAC steps. On the succeeding day, and in the absence of isoflurane, the authors presented the tone (without shock) in a different context (different cage shape and odor) and measured the time each rat froze (became immobile). Six other groups of eight rats were trained to fear context by applying the shock in the absence of a tone but in the presence of environmental cues such as cage shape, texture, and odor. Fear to context was determined the succeeding day by returning the rat to the training cage (without shock) and measuring duration of freezing. Control groups (16 per group) received 0.75 MAC isoflurane but no foot shocks. Group scores were compared using analysis of variance, and the ED50 values for quantal responses of individual rats were calculated using logistic regression. RESULTS: Conditioning to context occurred at 0.00 and 0.13 MAC (P < 0.05 compared with unshocked control) but not 0.25 MAC; the ED50 was 0.25 +/- 0.03 MAC (mean +/- SEM). In contrast, conditioning to tone occurred at 0.48 MAC (P < 0.05) but not 0.62 MAC; the ED50 was 0.47 +/- 0.02 MAC (P < 0.01 for the difference between ED50 values). CONCLUSIONS: Suppression of fear conditioning to tone required approximately twice the isoflurane concentration that suppressed fear conditioning to context. Thus, the concentration of anesthetic required to suppress learning may depend on the neural substrates of learning. Our results suggest that isoflurane concentrations greater than 0.5 MAC may be needed to suppress both forms of fear conditioning.

Acoustic Stimulation↗
PubMed2000

Contextual fear, gestalt memories, and the hippocampus.

This review examines the relationship between exploration and contextual fear conditioning. The fear acquired to places or contexts associated with aversive events is a form of Pavlovian conditioning. However, an initial period of exploration is necessary to allow the animal to form an integrated memory of the features of the context before conditioning can take place. The hippocampal formation plays a critical role in this process. Cells within the dorsal hippocampus are involved in the formation, storage and consolidation of this integrated representation of context. Projections from the subiculum to the nucleus accumbens regulate the exploration necessary for the acquisition of information about the features of the context. This model explains why electrolytic but not excitotoxic lesions of the dorsal hippocampus cause enhanced exploratory activity but both cause deficits in contextual fear. It also explains why retrograde amnesia of contextual fear is greater than anterograde amnesia.

Animals↗
PubMed1999

Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase.

The Sanfilippo syndrome type B is an autosomal recessive disorder caused by mutation in the gene (NAGLU) encoding alpha-N-acetylglucosaminidase, a lysosomal enzyme required for the stepwise degradation of heparan sulfate. The most serious manifestations are profound mental retardation, intractable behavior problems, and death in the second decade. To generate a model for studies of pathophysiology and of potential therapy, we disrupted exon 6 of Naglu, the homologous mouse gene. Naglu-/- mice were healthy and fertile while young and could survive for 8-12 mo. They were totally deficient in alpha-N-acetylglucosaminidase and had massive accumulation of heparan sulfate in liver and kidney as well as secondary changes in activity of several other lysosomal enzymes in liver and brain and elevation of gangliosides G(M2) and G(M3) in brain. Vacuolation was seen in many cells, including macrophages, epithelial cells, and neurons, and became more prominent with age. Although most vacuoles contained finely granular material characteristic of glycosaminoglycan accumulation, large pleiomorphic inclusions were seen in some neurons and pericytes in the brain. Abnormal hypoactive behavior was manifested by 4.5-mo-old Naglu-/- mice in an open field test; the hyperactivity that is characteristic of affected children was not observed even in younger mice. In a Pavlovian fear conditioning test, the 4.5-mo-old mutant mice showed normal response to context, indicating intact hippocampal-dependent learning, but reduced response to a conditioning tone, perhaps attributable to hearing impairment. The phenotype of the alpha-N-acetylglucosaminidase-deficient mice is sufficiently similar to that of patients with the Sanfilippo syndrome type B to make these mice a good model for study of pathophysiology and for development of therapy.

Acetylglucosaminidase↗
PubMed1999

Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice.

gamma-Aminobutyric acid (GABA) type A receptors mediate fast inhibitory synaptic transmission and have been implicated in responses to sedative/hypnotic agents (including neuroactive steroids), anxiety, and learning and memory. Using gene targeting technology, we generated a strain of mice deficient in the delta subunit of the GABA type A receptors. In vivo testing of various behavioral responses revealed a strikingly selective attenuation of responses to neuroactive steroids, but not to other modulatory drugs. Electrophysiological recordings from hippocampal slices revealed a significantly faster miniature inhibitory postsynaptic current decay time in null mice, with no change in miniature inhibitory postsynaptic current amplitude or frequency. Learning and memory assessed with fear conditioning were normal. These results begin to illuminate the novel contributions of the delta subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provide insights into the physiology of neurosteroids.

Animals↗
PubMed1999

Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination.

We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone-shock pairings in one context (remote memory) and 10 tone-shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.

Acoustic Stimulation↗
PubMed1999

The neuroanatomical and neurochemical basis of conditioned fear.

After a few pairings of a threatening stimulus with a formerly neutral cue, animals and humans will experience a state of conditioned fear when only the cue is present. Conditioned fear provides a critical survival-related function in the face of threat by activating a range of protective behaviors. The present review summarizes and compares the results of different laboratories investigating the neuroanatomical and neurochemical basis of conditioned fear, focusing primarily on the behavioral models of freezing and fear-potentiated startle in rats. On the basis of these studies, we describe the pathways mediating and modulating fear. We identify several key unanswered questions and discuss possible implications for the understanding of human anxiety disorders.

Animals↗
PubMed1999

Scopolamine and Pavlovian fear conditioning in rats: dose-effect analysis.

Muscarinic-cholinergic antagonism produces learning and memory deficits in a wide variety of hippocampal-dependent tasks. Hippocampal lesions produce both acquisition deficits and retrograde amnesia of contextual fear (fear of the place of conditioning), but do not impact fear conditioning to discrete cues (such as a tone). In order to examine the effects of muscarinic antagonism in this paradigm, rats were given 0.01 to 100 mg/kg of scopolamine (or methylscopolamine) either before or after a fear conditioning session in which tones were paired with aversive footshocks. Fear to the context and the tone were assessed by measuring freezing in separate tests. It was found that pretraining, but not post-training, scopolamine severely impaired fear conditioning; methylscopolamine was ineffective in disrupting conditioning. Although contextual fear conditioning was more sensitive to cholinergic disruption, high doses of scopolamine also disrupted tone conditioning. Scopolamine did not affect footshock reactivity, but did produce high levels of activity. However, hyperactivity was not directly responsible for deficits in conditioning. It was concluded that scopolamine disrupts CS-US association formation or CS processing, perhaps through an attenuation of hippocampal theta rhythm.

Acoustic Stimulation↗
PubMed1998

Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11-13. The genes in 15q11-13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduction in the GABAA receptor beta3 subunit (GABRB3) gene, contained within the AS deletion region, may contribute to the overall severity of AS. Disrupting the gabrb3 gene in mice produces electroencephalographic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacological response profile to antiepileptic medications similar to that observed in AS. Additionally, these mice exhibited learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest-activity cycle, features all common to AS. The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome. At least one other gene, the E6-associated protein ubiquitin-protein ligase (UBE3A) gene, has been implicated in AS, so the relative contribution of the GABRB3 gene alone or in combination with other genes remains to be established.

Age Factors↗
PubMed1998

Immediate-early gene expression in the amygdala following footshock stress and contextual fear conditioning.

This study investigated the increase in expression in the amygdala of 2 immediate-early genes, c-fos and NGFI-A, following contextual fear conditioning. The immediate-shock freezing deficit paradigm was used to compare rats that received footshock after exploring a context to rats that received footshock immediately after placement in the chamber. The former procedure produces contextual fear conditioning while the latter does not. Rats were either handled (handled group), placed in a test chamber without receiving footshock (context-no-footshock group), received footshock immediately upon being placed in the chamber (immediate-footshock group), or received footshock after a 1 min delay (delayed-footshock group). Only the delayed-footshock group displayed a fear response (freezing behavior). Rats were sacrificed either 15 min after the experience or after a retention test 24 h later. The c-fos mRNA was increased in the medial nucleus of the amygdala in all of the groups that were placed in the test chamber. However, rats that received footshock (immediate- and delayed-footshock groups) had greater levels of c-fos mRNA expression than rats of the context-no-footshock group. The c-fos mRNA expression in the immediate- and delayed-footshock groups did not differ. However, after the retention test, the expression of c-fos mRNA in the medial nucleus of the amygdala did not differ between groups. In contrast to c-fos, NGFI-A mRNA expression in the lateral nucleus of the amygdala was greater in the delayed-footshock group than the handled and context-no-footshock groups 15 min after the footshock. This elevation in NGFI-A mRNA was not seen in the immediate-footshock group. This suggests that NGFI-A mRNA in the lateral nucleus of the amygdala may play a role in contextual fear conditioning.

Amygdala↗
PubMed1998

Distinct regions of the periaqueductal gray are involved in the acquisition and expression of defensive responses.

In fear conditioning, a rat is placed in a distinct environment and delivered footshock. The response to the footshock itself is called an activity burst and includes running, jumping, and vocalization. The fear conditioned to the distinct environment by the footshock elicits complete immobility termed freezing. Lesions of the ventral periaqueductal gray (vPAG) strongly attenuate freezing. However, lesions of the dorsolateral periaqueductal gray (dlPAG) increase the amount of freezing seen to conditional fear cues acquired under conditions in which intact rats do not demonstrate much fear conditioning. To examine the necessity of these regions in the acquisition and expression of fear, we performed five experiments that examined the effects of electrolytic lesions of the dlPAG and the vPAG in learned and unlearned fear. In experiment 1, lesions of the vPAG strongly attenuated, whereas lesions of the dlPAG enhanced, unconditional freezing to a cat. In experiment 2, lesions of the dlPAG made before but not after training enhanced the amount of freezing shown to conditional fear cues acquired via immediate footshock delivery. In experiment 3, vPAG lesions made either before or after training with footshock decreased the level of freezing to conditional fear cues. Neither dlPAG lesions nor vPAG lesions affected footshock sensitivity (experiment 4) or consumption on a conditioned taste aversion test that does not elicit antipredator responses (experiment 5). On the basis of these results, it is proposed that activation of the dlPAG produces inhibition of the vPAG and forebrain structures involved with defense. In contrast, the vPAG seems to be necessary for postencounter freezing defensive behavior.

Animals↗
PubMed1998

Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant-path long-term potentiation in adult male rats.

We recently reported that Pavlovian fear conditioning and hippocampal perforant-path long-term potentiation (LTP) are sexually dimorphic in rats. Males show greater contextual fear conditioning, which depends on the hippocampus, as well as greater hippocampal LTP. In order to examine the role of circulating gonadal hormones in adult male rats, animals were castrated in two experiments, and Pavlovian fear conditioning and in vivo perforant-path LTP were examined. It was found that sexually-dimorphic LTP and fear conditioning are not regulated by the activational effects of testicular hormones in adult male rats. That is, in every respect, castrated male rats were similar to intact male rats in Pavlovian fear conditioning and hippocampal LTP. It is likely that sexual dimorphism in this system is established earlier in development by the organizational effects of gonadal hormones.

Animals↗