The acquisition of context fear in rats is affected by variables such as the sex of the animal, t... more 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 5 s, 20 s, 40 s, 60 s, 180 s, or 720 s 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.
Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation... more 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 GABA A receptor  3 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.
Proceedings of the National Academy of Sciences, 2009
Mammals evolved a potent fear-motivated defensive system capable of single-trial fear learning th... more Mammals evolved a potent fear-motivated defensive system capable of single-trial fear learning that shows no forgetting over the lifespan of the animal. The basolateral amygdala complex (BLA) is considered an essential component of this conditional fear learning system. However, recent studies challenge this view and suggest that plasticity within other brain regions (i.e., central nucleus of the amygdala) may be crucial for fear conditioning. In the present study, we examine the mnemonic limits of contextual fear conditioning in the absence of the BLA using overtraining and by measuring remote fear memories. After excitotoxic lesions of the BLA were created, animals underwent overtraining and were tested at recent and remote memory intervals. Here we show that animals with BLA lesions can learn normal levels of fear. However, this fear memory loses its adaptive features: it is acquired slowly and shows substantial forgetting when remote memory is tested. Collectively, these finding...
Background-Fears that are maladaptive or inappropriate can be reduced through extinction training... more Background-Fears that are maladaptive or inappropriate can be reduced through extinction training. However, extinction is highly context-sensitive, resulting in the renewal of fear following shifts in context, and limiting the clinical efficacy of extinction training. Lesion and inactivation studies have shown that the contextualization of extinction depends on the hippocampus. Parallel studies have found that intrahippocampal scopolamine blocks contextual fear conditioning. Importantly, this effect was replicated using a non-invasive technique in which a low dose of scopolamine was administered systemically. We aimed to transfer the effects of this non-invasive approach to block the contextualization of fear extinction. Methods-Rats were tone fear conditioned and extinguished under various systemic doses of scopolamine or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (controls) or shifted (renewal group) with respect to the extinction context. Results-The lowest dose of scopolamine produced a significant attenuation of fear renewal when renewal was tested either in the original training context or a novel context. The drug also slowed the rate of long-term extinction memory formation, which was readily overcome by extending extinction training. Scopolamine only gave this effect when it was administered during, but not after extinction training. Higher doses of scopolamine severely disrupted extinction learning. Conclusions-We discovered that disrupting contextual processing during extinction with the cholinergic antagonist scopolamine blocked subsequent fear renewal. Low doses of scopolamine may be a clinically promising adjunct to exposure therapy by making extinction more relapseresistant.
The Pavlovian conditioning model of drug tolerance was examined in the context of tolerance to th... more The Pavlovian conditioning model of drug tolerance was examined in the context of tolerance to the locomotor activity-suppressing effects of morphine (10 mg/kg) on rats. Tolerance was found to be situation specific--it only occurred in a place that was previously paired with morphine. Morphine delivery explicitly unpaired with the test site retarded the development of subsequent tolerance. This explicitly unpaired procedure was more successful in extinguishing tolerance than was a morphine omission procedure. It is suggested that this explicitly unpaired procedure may be applied to clinical situations where the manipulation of opiate tolerance is of importance.
Lesions of the rodent hippocampus invariably abolish context fear memories formed in the recent p... more Lesions of the rodent hippocampus invariably abolish context fear memories formed in the recent past but do not always prevent new learning. To better understand this discrepancy, we thoroughly examined the acquisition of context fear in rats with pretraining excitotoxic lesions of the dorsal hippocampus. In the first experiment, animals received a shock immediately after placement in the context or after variable delays. Immediate shock produced no context fear learning in lesioned rats or controls. In contrast, delayed shock produced robust context fear learning in both groups. The absence of fear with immediate shock occurs because animals need time to form a representation of the context before shock is presented. The fact that it occurs in both sham and lesioned rats suggests that they learn about the context in a similar manner. However, despite learning about the context in the delay condition, lesioned rats did not acquire as much fear as controls. The second experiment showed that this lesion-induced deficit could be overcome by increasing the number of conditioning trials. Lesioned animals learned normally after multiple shocks, regardless of freezing level or trial spacing. The last experiment showed that animals with complete hippocampus lesions could also learn about the context, although the same lesions produced devastating retrograde amnesia. These results demonstrate that alternative systems can acquire context fear but do so less efficiently than the hippocampus.
Cholinergic neurotransmission has been implicated in the acquisition of a variety of tasks, inclu... more 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 g 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. Hippocampus 2001;11:371-376.
Pavlovian conditioning is the process by which we learn relationships between stimuli and thus co... more Pavlovian conditioning is the process by which we learn relationships between stimuli and thus constitutes a basic building block for how the brain constructs representations of the world. We first review the major concepts of Pavlovian conditioning and point out many of the pervasive misunderstandings about just what conditioning is. This brings us to a modern redefinition of conditioning as the process whereby experience with a conditional relationship between stimuli bestows these stimuli with the ability to promote adaptive behavior patterns that did not occur before the experience. Working from this framework, we provide an in-depth analysis of two examples, fear conditioning and food-based appetitive conditioning, which include a description of the only partially overlapping neural circuitry of each. We also describe how these circuits promote the basic characteristics that define Pavlovian conditioning, such as error-correction-driven regulation of learning.
The brain does not learn and remember in a unitary fashion. Rather, different circuits specialize... more The brain does not learn and remember in a unitary fashion. Rather, different circuits specialize in certain classes of problems and encode different types of information. Damage to one of these systems typically results in amnesia only for the form of memory that is the specialty of the affected region. However, the question of how the brain allocates a specific category of memory to a particular circuit has received little attention. The currently dominant view (multiple memory systems theory) assumes that such abilities are hard wired. Using fear conditioning as a paradigmatic case, I propose an alternative model in which mnemonic processing is allocated to specific circuits through a dynamic process. Potential circuits compete to form memories, with the most efficient circuits emerging as winners. However, alternate circuits compensate when these 'primary' circuits are compromised.
We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a sever... more 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 (Kim and Fanselow, 1992). 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.
Synaptic plasticity in the amygdala is essential for emotional learning. Fear conditioning, for e... more Synaptic plasticity in the amygdala is essential for emotional learning. Fear conditioning, for example, depends on changes in excitatory transmission that occur following NMDA receptor activation and AMPA receptor modifi cation in this region. The role of these and other glutamatergic mechanisms have been studied extensively in this circuit while relatively little is known about the contribution of inhibitory transmission. The current experiments addressed this issue by examining the role of the GABA(A) receptor subunit α1 in fear learning and plasticity. We fi rst confi rmed previous fi ndings that the α1 subunit is highly expressed in the lateral nucleus of the amygdala. Consistent with this observation, genetic deletion of this subunit selectively enhanced plasticity in the lateral amygdala and increased auditory fear conditioning. Mice with selective deletion of α1 in excitatory cells did not exhibit enhanced learning. Finally, infusion of a α1 receptor antagonist into the lateral amygdala selectively impaired auditory fear learning. Together, these results suggest that inhibitory transmission mediated by α1-containing GABA(A) receptors plays a critical role in amygdala plasticity and fear learning.
Dorsal hippocampal (DH) lesions produce a severe deficit in recently, but not remotely, acquired ... more 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. Hippocampus 2001;11:8-17.
Pairs of male and female rats were injected with either tertiary naltrexone (NTX) which readily c... more Pairs of male and female rats were injected with either tertiary naltrexone (NTX) which readily crosses the blood-brain barrier, or quaternary naltrexone (QNTX) which does not, to determine the importance of central opioid systems in the elaboration of juvenile social behavior. In the first experiment, only intraperitoneal injections of NTX (1.0 mg/kg) suppressed the frequency of wrestling pins. Peripheral injections of QNTX (10.0 mg/kg) were without effect. In a second experiment, QNTX (2.0, 4.0, or 8.0 pLg/4.0 p,1) was injected directly into the lateral ventricles. Intracerebroventricular injection of the moderate dose reliably reduced frequency of pinning while the higher dose was severely incapacitating and the low dose was without effect. The results of these two experiments confirm an important role for brain opioid systems in the control of juvenile social interaction.
Muscarinic-cholinergic antagonism produces learning and memory deficits in a wide variety of hipp... more 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 posttraining, 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.
Recent studies indicate that the hippocampus has Muscarinic cholinergic antagonism produces learn... more Recent studies indicate that the hippocampus has Muscarinic cholinergic antagonism produces learning an important role in Pavlovian fear conditioning. and memory deficits in a variety of hippocampal-depen-During fear conditioning, a conditional stimulus (ofdent tasks. Hippocampal lesions produce both acquisition ten a tone) is paired with an aversive unconditional deficits and retrograde amnesia for contextual fear condistimulus (usually an electrical shock) in a novel contioning, but do not impact fear conditioning to discrete text. With repeated pairings, the animal learns to cues. In order to examine the effects of muscarinic antagofear both the tone and the training context. Hipponism in this paradigm, rats were given scopolamine (1 campal lesions produce an acquisition deficit (Philmg/kg) either before or for 3 days after a Pavlovian fearlips & LeDoux, 1992) and a time-limited retrograde conditioning session in which tones were paired with averamnesia that is selective for contextual fear (Kim & sive footshocks. Fear to the context and the tone was assessed by measuring freezing in separate tests. It was Fanselow, 1992). Moreover, there is a high correfound that pretraining, but not posttraining, scopolamine spondence between hippocampal theta rhythm and severely impaired contextual fear conditioning; tone condithe acquisition of contextual fear (Maren, DeCola, tioning was not affected under either condition (cf., Young,
The acquisition of context fear in rats is affected by variables such as the sex of the animal, t... more 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 5 s, 20 s, 40 s, 60 s, 180 s, or 720 s 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.
Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation... more 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 GABA A receptor  3 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.
Proceedings of the National Academy of Sciences, 2009
Mammals evolved a potent fear-motivated defensive system capable of single-trial fear learning th... more Mammals evolved a potent fear-motivated defensive system capable of single-trial fear learning that shows no forgetting over the lifespan of the animal. The basolateral amygdala complex (BLA) is considered an essential component of this conditional fear learning system. However, recent studies challenge this view and suggest that plasticity within other brain regions (i.e., central nucleus of the amygdala) may be crucial for fear conditioning. In the present study, we examine the mnemonic limits of contextual fear conditioning in the absence of the BLA using overtraining and by measuring remote fear memories. After excitotoxic lesions of the BLA were created, animals underwent overtraining and were tested at recent and remote memory intervals. Here we show that animals with BLA lesions can learn normal levels of fear. However, this fear memory loses its adaptive features: it is acquired slowly and shows substantial forgetting when remote memory is tested. Collectively, these finding...
Background-Fears that are maladaptive or inappropriate can be reduced through extinction training... more Background-Fears that are maladaptive or inappropriate can be reduced through extinction training. However, extinction is highly context-sensitive, resulting in the renewal of fear following shifts in context, and limiting the clinical efficacy of extinction training. Lesion and inactivation studies have shown that the contextualization of extinction depends on the hippocampus. Parallel studies have found that intrahippocampal scopolamine blocks contextual fear conditioning. Importantly, this effect was replicated using a non-invasive technique in which a low dose of scopolamine was administered systemically. We aimed to transfer the effects of this non-invasive approach to block the contextualization of fear extinction. Methods-Rats were tone fear conditioned and extinguished under various systemic doses of scopolamine or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (controls) or shifted (renewal group) with respect to the extinction context. Results-The lowest dose of scopolamine produced a significant attenuation of fear renewal when renewal was tested either in the original training context or a novel context. The drug also slowed the rate of long-term extinction memory formation, which was readily overcome by extending extinction training. Scopolamine only gave this effect when it was administered during, but not after extinction training. Higher doses of scopolamine severely disrupted extinction learning. Conclusions-We discovered that disrupting contextual processing during extinction with the cholinergic antagonist scopolamine blocked subsequent fear renewal. Low doses of scopolamine may be a clinically promising adjunct to exposure therapy by making extinction more relapseresistant.
The Pavlovian conditioning model of drug tolerance was examined in the context of tolerance to th... more The Pavlovian conditioning model of drug tolerance was examined in the context of tolerance to the locomotor activity-suppressing effects of morphine (10 mg/kg) on rats. Tolerance was found to be situation specific--it only occurred in a place that was previously paired with morphine. Morphine delivery explicitly unpaired with the test site retarded the development of subsequent tolerance. This explicitly unpaired procedure was more successful in extinguishing tolerance than was a morphine omission procedure. It is suggested that this explicitly unpaired procedure may be applied to clinical situations where the manipulation of opiate tolerance is of importance.
Lesions of the rodent hippocampus invariably abolish context fear memories formed in the recent p... more Lesions of the rodent hippocampus invariably abolish context fear memories formed in the recent past but do not always prevent new learning. To better understand this discrepancy, we thoroughly examined the acquisition of context fear in rats with pretraining excitotoxic lesions of the dorsal hippocampus. In the first experiment, animals received a shock immediately after placement in the context or after variable delays. Immediate shock produced no context fear learning in lesioned rats or controls. In contrast, delayed shock produced robust context fear learning in both groups. The absence of fear with immediate shock occurs because animals need time to form a representation of the context before shock is presented. The fact that it occurs in both sham and lesioned rats suggests that they learn about the context in a similar manner. However, despite learning about the context in the delay condition, lesioned rats did not acquire as much fear as controls. The second experiment showed that this lesion-induced deficit could be overcome by increasing the number of conditioning trials. Lesioned animals learned normally after multiple shocks, regardless of freezing level or trial spacing. The last experiment showed that animals with complete hippocampus lesions could also learn about the context, although the same lesions produced devastating retrograde amnesia. These results demonstrate that alternative systems can acquire context fear but do so less efficiently than the hippocampus.
Cholinergic neurotransmission has been implicated in the acquisition of a variety of tasks, inclu... more 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 g 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. Hippocampus 2001;11:371-376.
Pavlovian conditioning is the process by which we learn relationships between stimuli and thus co... more Pavlovian conditioning is the process by which we learn relationships between stimuli and thus constitutes a basic building block for how the brain constructs representations of the world. We first review the major concepts of Pavlovian conditioning and point out many of the pervasive misunderstandings about just what conditioning is. This brings us to a modern redefinition of conditioning as the process whereby experience with a conditional relationship between stimuli bestows these stimuli with the ability to promote adaptive behavior patterns that did not occur before the experience. Working from this framework, we provide an in-depth analysis of two examples, fear conditioning and food-based appetitive conditioning, which include a description of the only partially overlapping neural circuitry of each. We also describe how these circuits promote the basic characteristics that define Pavlovian conditioning, such as error-correction-driven regulation of learning.
The brain does not learn and remember in a unitary fashion. Rather, different circuits specialize... more The brain does not learn and remember in a unitary fashion. Rather, different circuits specialize in certain classes of problems and encode different types of information. Damage to one of these systems typically results in amnesia only for the form of memory that is the specialty of the affected region. However, the question of how the brain allocates a specific category of memory to a particular circuit has received little attention. The currently dominant view (multiple memory systems theory) assumes that such abilities are hard wired. Using fear conditioning as a paradigmatic case, I propose an alternative model in which mnemonic processing is allocated to specific circuits through a dynamic process. Potential circuits compete to form memories, with the most efficient circuits emerging as winners. However, alternate circuits compensate when these 'primary' circuits are compromised.
We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a sever... more 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 (Kim and Fanselow, 1992). 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.
Synaptic plasticity in the amygdala is essential for emotional learning. Fear conditioning, for e... more Synaptic plasticity in the amygdala is essential for emotional learning. Fear conditioning, for example, depends on changes in excitatory transmission that occur following NMDA receptor activation and AMPA receptor modifi cation in this region. The role of these and other glutamatergic mechanisms have been studied extensively in this circuit while relatively little is known about the contribution of inhibitory transmission. The current experiments addressed this issue by examining the role of the GABA(A) receptor subunit α1 in fear learning and plasticity. We fi rst confi rmed previous fi ndings that the α1 subunit is highly expressed in the lateral nucleus of the amygdala. Consistent with this observation, genetic deletion of this subunit selectively enhanced plasticity in the lateral amygdala and increased auditory fear conditioning. Mice with selective deletion of α1 in excitatory cells did not exhibit enhanced learning. Finally, infusion of a α1 receptor antagonist into the lateral amygdala selectively impaired auditory fear learning. Together, these results suggest that inhibitory transmission mediated by α1-containing GABA(A) receptors plays a critical role in amygdala plasticity and fear learning.
Dorsal hippocampal (DH) lesions produce a severe deficit in recently, but not remotely, acquired ... more 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. Hippocampus 2001;11:8-17.
Pairs of male and female rats were injected with either tertiary naltrexone (NTX) which readily c... more Pairs of male and female rats were injected with either tertiary naltrexone (NTX) which readily crosses the blood-brain barrier, or quaternary naltrexone (QNTX) which does not, to determine the importance of central opioid systems in the elaboration of juvenile social behavior. In the first experiment, only intraperitoneal injections of NTX (1.0 mg/kg) suppressed the frequency of wrestling pins. Peripheral injections of QNTX (10.0 mg/kg) were without effect. In a second experiment, QNTX (2.0, 4.0, or 8.0 pLg/4.0 p,1) was injected directly into the lateral ventricles. Intracerebroventricular injection of the moderate dose reliably reduced frequency of pinning while the higher dose was severely incapacitating and the low dose was without effect. The results of these two experiments confirm an important role for brain opioid systems in the control of juvenile social interaction.
Muscarinic-cholinergic antagonism produces learning and memory deficits in a wide variety of hipp... more 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 posttraining, 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.
Recent studies indicate that the hippocampus has Muscarinic cholinergic antagonism produces learn... more Recent studies indicate that the hippocampus has Muscarinic cholinergic antagonism produces learning an important role in Pavlovian fear conditioning. and memory deficits in a variety of hippocampal-depen-During fear conditioning, a conditional stimulus (ofdent tasks. Hippocampal lesions produce both acquisition ten a tone) is paired with an aversive unconditional deficits and retrograde amnesia for contextual fear condistimulus (usually an electrical shock) in a novel contioning, but do not impact fear conditioning to discrete text. With repeated pairings, the animal learns to cues. In order to examine the effects of muscarinic antagofear both the tone and the training context. Hipponism in this paradigm, rats were given scopolamine (1 campal lesions produce an acquisition deficit (Philmg/kg) either before or for 3 days after a Pavlovian fearlips & LeDoux, 1992) and a time-limited retrograde conditioning session in which tones were paired with averamnesia that is selective for contextual fear (Kim & sive footshocks. Fear to the context and the tone was assessed by measuring freezing in separate tests. It was Fanselow, 1992). Moreover, there is a high correfound that pretraining, but not posttraining, scopolamine spondence between hippocampal theta rhythm and severely impaired contextual fear conditioning; tone condithe acquisition of contextual fear (Maren, DeCola, tioning was not affected under either condition (cf., Young,
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Papers by M. Fanselow