Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nes... more Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our results support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders may represent the output of a fear-entrained clock.One-Sentence SummaryCyclic fearful stimuli can entrain circadian rhythms in mice, and the molecular clock within the central circadian pacemaker is necessary...
Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nes... more Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our results support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders may represent the output of a fear-entrained clock.One-Sentence SummaryCyclic fearful stimuli can entrain circadian rhythms in mice, and the molecular clock within the central circadian pacemaker is necessary...
The hippocampus is vulnerable to uncontrollable stress and is enriched with oxytocin receptors, b... more The hippocampus is vulnerable to uncontrollable stress and is enriched with oxytocin receptors, but their interactive influences on hippocampal functioning are unknown. This study aimed to determine the effects of intranasal oxytocin administration on stress-induced alterations in synaptic plasticity and spatial memory in male rats. While vehicle-administered stressed rats showed impairment in long-term potentiation, enhancement in long-term depression, and weakened spatial memory, these changes were not observed in oxytocin-administered stressed rats. To reveal the potential signaling mechanism mediating these effects, levels of phosphorylated extracellular signal-regulated kinases (pERK) in the hippocampus was examined. Western blotting showed that oxytocin treatment blocked stress-induced alterations of pERK. Additionally, the oxytocin receptor antagonist L-368,899 inhibited the oxytocin's protective effects on hippocampal memory to stress. Thus, intranasal administration of ...
Proceedings of the National Academy of Sciences, 2007
Acute, inescapable, and unpredictable stress can profoundly modify brain and cognition in humans ... more Acute, inescapable, and unpredictable stress can profoundly modify brain and cognition in humans and animals. The present study investigated the ensuing effects of 2-h variable “audiogenic” stress on three related levels of hippocampal functions in rats: long-term potentiation, place cell activity, and spatial memory. In agreement with prior findings, we observed that stress reduced the magnitude of Schaffer collateral/commissural–Cornu Ammonis field 1 long-term potentiation in vitro , and selectively impaired spatial memory on a hidden platform version of the Morris water maze task. We also observed that stress impaired the stability of firing rates (but not firing locations) of place cells recorded from dorsal Cornu Ammonis field 1 in rats foraging freely on a novel open-field platform located in a familiar surrounding room. These findings suggest that stress-induced modifications in synaptic plasticity may prevent the storage of stable “rate maps” by hippocampal place cells, whic...
The neural substrates of fear conditioning in rats have been well characterized, with converging ... more The neural substrates of fear conditioning in rats have been well characterized, with converging lines of evidence indicating that conditioned stimulus (CS) and unconditioned stimulus (US) information form a CS–US association in the amygdala. Auditory CS information can reach the amygdala via two routes: a direct thalamo‐amygdala pathway, and an indirect thalamo‐cortico‐amygdala pathway. Although either pathway can fully support learning when the alternate pathway is disrupted, many studies to date have argued that the thalamo‐amygdala pathway is the principal auditory CS pathway in intact brains. To test this hypothesis, we trained rats in auditory fear conditioning, and 24 h later lesioned either pathway, leaving the alternate pathway intact. Later, animals were tested for conditioned freezing to the auditory CS. We report that lesions of the thalamo‐amygdala pathway produced severe but incomplete deficits in freezing during the tone retention test, while lesions of the thalamo‐cortico‐amygdala pathway completely abolished freezing during tone presentation. These results suggest that the thalamo‐cortico‐amygdala pathway is the principal auditory CS pathway when the brain is intact.
C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of ... more C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of the intralaminar complex (PINT) and caudal insular cortex (INS) block acquisition but not expression of fear-potentiated startle to discrete conditioned stimuli (CSs) and a footshock unconditioned stimulus (US) and proposed that PINT-INS projections to the amygdala constitute the essential US pathways involved in fear conditioning. The present study further tested this hypothesis by examining whether PINT-INS lesions block fear conditioning (as measured by freezing) to diffuse-context and discrete-tone CSs, and whether posttraining lesions with continued CS-US training result in extinction to the CSs. Posttraining lesions resulted in a selective attenuation of tone conditioning, but context conditioning was unaffected by pre- and posttraining lesions. These results do not support the view that the PINT-INS represent the essential US pathway in fear conditioning.
The neural substrates of fear conditioning in rats have been well characterized, with converging ... more The neural substrates of fear conditioning in rats have been well characterized, with converging lines of evidence indicating that conditioned stimulus (CS) and unconditioned stimulus (US) information form a CS–US association in the amygdala. Auditory CS information can reach the amygdala via two routes: a direct thalamo‐amygdala pathway, and an indirect thalamo‐cortico‐amygdala pathway. Although either pathway can fully support learning when the alternate pathway is disrupted, many studies to date have argued that the thalamo‐amygdala pathway is the principal auditory CS pathway in intact brains. To test this hypothesis, we trained rats in auditory fear conditioning, and 24 h later lesioned either pathway, leaving the alternate pathway intact. Later, animals were tested for conditioned freezing to the auditory CS. We report that lesions of the thalamo‐amygdala pathway produced severe but incomplete deficits in freezing during the tone retention test, while lesions of the thalamo‐co...
In Pavlovian eyeblink conditioning, the conditioned response (CR) is highly lateralized to the ey... more In Pavlovian eyeblink conditioning, the conditioned response (CR) is highly lateralized to the eye to which the unconditioned stimulus (US) has been directed. However, the initial conditioning of one eye can facilitate subsequent conditioning of the other eye, a phenomenon known as the intereye transfer (IET) effect. Because a conditioned emotional response (CER), as well as the eyeblink CR, is acquired during eyeblink conditioning and influences the development of the CR, the CER acquired in initial training can plausibly account for the IET effect. To evaluate this possibility, the present study utilized previously determined eyeblink conditioning procedures that effectively decouple the degree of CER and CR development to investigate the IET effect. In each of 3 experiments rabbits were initially trained with comparison procedures that differentially favored the development of the eyeblink CR or the CER, prior to a shift of the US to the alternate eye. The observed differences in the IET suggest that the effect depends largely on the specific development of eyeblink CRs rather than the CER. The neurobiological implications of this apparent bilaterality of the eyeblink CR are discussed.
C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of ... more C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of the intralaminar complex (PINT) and caudal insular cortex (INS) block acquisition but not expression of fear-potentiated startle to discrete conditioned stimuli (CSs) and a footshock unconditioned stimulus (US) and proposed that PINT-INS projections to the amygdala constitute the essential US pathways involved in fear conditioning. The present study further tested this hypothesis by examining whether PINT-INS lesions block fear conditioning (as measured by freezing) to diffuse-context and discrete-tone CSs, and whether posttraining lesions with continued CS-US training result in extinction to the CSs. Posttraining lesions resulted in a selective attenuation of tone conditioning, but context conditioning was unaffected by pre- and posttraining lesions. These results do not support the view that the PINT-INS represent the essential US pathway in fear conditioning.
Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nes... more Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our results support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders may represent the output of a fear-entrained clock.One-Sentence SummaryCyclic fearful stimuli can entrain circadian rhythms in mice, and the molecular clock within the central circadian pacemaker is necessary...
Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nes... more Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our results support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders may represent the output of a fear-entrained clock.One-Sentence SummaryCyclic fearful stimuli can entrain circadian rhythms in mice, and the molecular clock within the central circadian pacemaker is necessary...
The hippocampus is vulnerable to uncontrollable stress and is enriched with oxytocin receptors, b... more The hippocampus is vulnerable to uncontrollable stress and is enriched with oxytocin receptors, but their interactive influences on hippocampal functioning are unknown. This study aimed to determine the effects of intranasal oxytocin administration on stress-induced alterations in synaptic plasticity and spatial memory in male rats. While vehicle-administered stressed rats showed impairment in long-term potentiation, enhancement in long-term depression, and weakened spatial memory, these changes were not observed in oxytocin-administered stressed rats. To reveal the potential signaling mechanism mediating these effects, levels of phosphorylated extracellular signal-regulated kinases (pERK) in the hippocampus was examined. Western blotting showed that oxytocin treatment blocked stress-induced alterations of pERK. Additionally, the oxytocin receptor antagonist L-368,899 inhibited the oxytocin's protective effects on hippocampal memory to stress. Thus, intranasal administration of ...
Proceedings of the National Academy of Sciences, 2007
Acute, inescapable, and unpredictable stress can profoundly modify brain and cognition in humans ... more Acute, inescapable, and unpredictable stress can profoundly modify brain and cognition in humans and animals. The present study investigated the ensuing effects of 2-h variable “audiogenic” stress on three related levels of hippocampal functions in rats: long-term potentiation, place cell activity, and spatial memory. In agreement with prior findings, we observed that stress reduced the magnitude of Schaffer collateral/commissural–Cornu Ammonis field 1 long-term potentiation in vitro , and selectively impaired spatial memory on a hidden platform version of the Morris water maze task. We also observed that stress impaired the stability of firing rates (but not firing locations) of place cells recorded from dorsal Cornu Ammonis field 1 in rats foraging freely on a novel open-field platform located in a familiar surrounding room. These findings suggest that stress-induced modifications in synaptic plasticity may prevent the storage of stable “rate maps” by hippocampal place cells, whic...
The neural substrates of fear conditioning in rats have been well characterized, with converging ... more The neural substrates of fear conditioning in rats have been well characterized, with converging lines of evidence indicating that conditioned stimulus (CS) and unconditioned stimulus (US) information form a CS–US association in the amygdala. Auditory CS information can reach the amygdala via two routes: a direct thalamo‐amygdala pathway, and an indirect thalamo‐cortico‐amygdala pathway. Although either pathway can fully support learning when the alternate pathway is disrupted, many studies to date have argued that the thalamo‐amygdala pathway is the principal auditory CS pathway in intact brains. To test this hypothesis, we trained rats in auditory fear conditioning, and 24 h later lesioned either pathway, leaving the alternate pathway intact. Later, animals were tested for conditioned freezing to the auditory CS. We report that lesions of the thalamo‐amygdala pathway produced severe but incomplete deficits in freezing during the tone retention test, while lesions of the thalamo‐cortico‐amygdala pathway completely abolished freezing during tone presentation. These results suggest that the thalamo‐cortico‐amygdala pathway is the principal auditory CS pathway when the brain is intact.
C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of ... more C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of the intralaminar complex (PINT) and caudal insular cortex (INS) block acquisition but not expression of fear-potentiated startle to discrete conditioned stimuli (CSs) and a footshock unconditioned stimulus (US) and proposed that PINT-INS projections to the amygdala constitute the essential US pathways involved in fear conditioning. The present study further tested this hypothesis by examining whether PINT-INS lesions block fear conditioning (as measured by freezing) to diffuse-context and discrete-tone CSs, and whether posttraining lesions with continued CS-US training result in extinction to the CSs. Posttraining lesions resulted in a selective attenuation of tone conditioning, but context conditioning was unaffected by pre- and posttraining lesions. These results do not support the view that the PINT-INS represent the essential US pathway in fear conditioning.
The neural substrates of fear conditioning in rats have been well characterized, with converging ... more The neural substrates of fear conditioning in rats have been well characterized, with converging lines of evidence indicating that conditioned stimulus (CS) and unconditioned stimulus (US) information form a CS–US association in the amygdala. Auditory CS information can reach the amygdala via two routes: a direct thalamo‐amygdala pathway, and an indirect thalamo‐cortico‐amygdala pathway. Although either pathway can fully support learning when the alternate pathway is disrupted, many studies to date have argued that the thalamo‐amygdala pathway is the principal auditory CS pathway in intact brains. To test this hypothesis, we trained rats in auditory fear conditioning, and 24 h later lesioned either pathway, leaving the alternate pathway intact. Later, animals were tested for conditioned freezing to the auditory CS. We report that lesions of the thalamo‐amygdala pathway produced severe but incomplete deficits in freezing during the tone retention test, while lesions of the thalamo‐co...
In Pavlovian eyeblink conditioning, the conditioned response (CR) is highly lateralized to the ey... more In Pavlovian eyeblink conditioning, the conditioned response (CR) is highly lateralized to the eye to which the unconditioned stimulus (US) has been directed. However, the initial conditioning of one eye can facilitate subsequent conditioning of the other eye, a phenomenon known as the intereye transfer (IET) effect. Because a conditioned emotional response (CER), as well as the eyeblink CR, is acquired during eyeblink conditioning and influences the development of the CR, the CER acquired in initial training can plausibly account for the IET effect. To evaluate this possibility, the present study utilized previously determined eyeblink conditioning procedures that effectively decouple the degree of CER and CR development to investigate the IET effect. In each of 3 experiments rabbits were initially trained with comparison procedures that differentially favored the development of the eyeblink CR or the CER, prior to a shift of the US to the alternate eye. The observed differences in the IET suggest that the effect depends largely on the specific development of eyeblink CRs rather than the CER. The neurobiological implications of this apparent bilaterality of the eyeblink CR are discussed.
C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of ... more C. Shi and M. Davis (1999) recently reported that combined lesions of the posterior extension of the intralaminar complex (PINT) and caudal insular cortex (INS) block acquisition but not expression of fear-potentiated startle to discrete conditioned stimuli (CSs) and a footshock unconditioned stimulus (US) and proposed that PINT-INS projections to the amygdala constitute the essential US pathways involved in fear conditioning. The present study further tested this hypothesis by examining whether PINT-INS lesions block fear conditioning (as measured by freezing) to diffuse-context and discrete-tone CSs, and whether posttraining lesions with continued CS-US training result in extinction to the CSs. Posttraining lesions resulted in a selective attenuation of tone conditioning, but context conditioning was unaffected by pre- and posttraining lesions. These results do not support the view that the PINT-INS represent the essential US pathway in fear conditioning.
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