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PubMed2001

Involvement of the amygdala in classical conditioning of eyeblink response in the rat.

The two-factor theory postulates that classical conditioning proceeds through two stages, which support successive acquisition of emotional and motor responses. Emotional conditioning is thought to facilitate the subsequent acquisition of the motor response. This form of interaction between the two stages of learning can be investigated while considering the central role of the amygdala and the cerebellum in emotional and motor conditioning, respectively. Rats with bilateral lesions of the amygdala or the cerebellar interpositus or intact rats were subjected to a fear conditioning session followed by four eyeblink conditioning sessions. Another group of intact rats was subjected to eyeblink conditioning only. The CS in the fear conditioning session was a 73 dB tone, paired with a 100 dB noise-US. The same CS was paired with a periorbital electroshock-US during eyeblink conditioning. Results showed that fear preconditioning facilitated the subsequent eyeblink conditioning among the intact groups. Amygdaloid lesions abolished this facilitatory effect of fear conditioning. These findings demonstrate that amygdala-mediated emotional conditioning facilitates the subsequent acquisition of cerebellum-mediated motor responses.

Amygdala↗
PubMed2001

Activation of somatodendritic 5-HT(1A) autoreceptors in the median raphe nucleus disrupts the contextual conditioning in rats.

We have shown that the median raphe nucleus (MRN) is involved in the control of contextual fear conditioning. Also, electrolytic lesion in the MRN causes signs of behavioral disinhibition, with an increase in locomotor activity measured in an open field. In this work, we have extended this study by analyzing the behavioral and autonomic responses in a contextual conditioning paradigm in rats with either neurochemical lesions from N-methyl-D-aspartate (NMDA), or microinjected with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the MRN. The animals received NMDA, 8-OH-DPAT or saline microinjections into the MRN before the conditioning experiments, during which they were subjected to ten conditioning trials in an experimental chamber (same context) where they received foot-shocks (0.7 mA, 1 s with 20 s intervals). The next day, the animals were tested again either in the same or in a different experimental chamber, where the duration of freezing, number of rearings, bouts of micturition and number of fecal boli were recorded. Control rats placed in the same chamber showed more freezing than rats exposed to a different context. This freezing behavior was clearly inhibited in rats with NMDA lesions or with 8-OH-DPAT microinjections into the MRN. These MRN manipulations also produced a reduction in micturition. Such effects were context-specific since 8-OH-DPAT in MRN did not affect fear conditioned responses to tone previously associated with foot-shocks. In the open-field test, rats with neurotoxic lesions or with 8-OH-DPAT microinjections into the MRN had higher horizontal locomotor activity than control rats, without the number of rearings changing. As rats injected with 8-OH-DPAT into the MRN may freeze to a tone in a conditioned test paradigm and also show increased activity in an open field test the functional role of MRN on locomotor activity and contextual fear conditioning are clearly dissociated. Altogether, these results clearly show that such 5-HT mechanisms of the MRN serve as a neural substrate for the storage process of the context fear.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Muscarinic acetylcholine receptor immunoreactivity in the amygdala--II. Fear-induced plasticity.

Changes in the distribution of muscarinic acetylcholine receptor-immunoreactive neurons were examined in the amygdaloid complex at different time-intervals following a single training session of active shock avoidance in a two-way shuttle-box. Muscarinic acetylcholine receptors were visualized using M35, a monoclonal antibody raised against purified muscarinic acetylcholine receptor protein. Both in naive animals and 2 h after active shock avoidance training, muscarinic acetylcholine receptor immunoreactivity was high in the central nucleus, and only low to moderate in other amygdaloid regions. Twenty-four hours after training, however, the muscarinic acetylcholine receptor immunoreactivity distribution pattern was reversed, showing a dramatic increase in the corticomedial nucleus, while in contrast, in other amygdaloid regions including the central nucleus, muscarinic acetylcholine receptor immunoreactivity was reduced to only a few scattered neurons. Additional studies with a modified experimental design indicated that fear conditioning mechanisms in association with the severity of the aversive stimuli, and not the learning of the avoidance response, may account for the changes in muscarinic acetylcholine receptor immunoreactivity in the amygdala. These results are consistent with the prominent role of the central nucleus in the conditioning and expression of the fear response. A closer examination revealed that 8 h after training the changes in both the central and corticomedial nuclei became significant. The differences still existed after 25 days, but three months after the training session the receptor distribution was returned to normal. The long-lasting, but reversible nature of these changes indicates that fear conditioning is accompanied by a dynamic plasticity of muscarinic acetylcholine receptor immunoreactivity in the amygdaloid complex.

Amygdala↗
PubMed2006

Behavioral effects of corpus callosum transection and environmental enrichment in adult rats.

A common assumption about the corpus callosum transection (CCX) is that it only affects behaviors heavily relying on interhemispheric communication. However, cerebral laterality is ubiquitous across motor and perceptual, cognitive and emotional domains, and the corpus callosum is important for its establishment. Several recent studies showed that the partial denervation of the sensorimotor isocortex through CCX derepressed neural growth processes that were sensitive to motor demand (experience-dependent neural plasticity). We investigated whether the facilitatory effects of CCX on cortical neural plasticity, shaped by differential housing, extended beyond the motor domain. Adult rats were housed in enriched (EE), standard (SE) or impoverished environments (IE) for 10 weeks, that is, 2 weeks before they underwent CCX or sham surgery, and, then, 8 weeks throughout the experiments. After they recovered from surgery, the behavioral performance of rats was tested using open-field, spontaneous alternation in the T-maze, paw preference, Morris water maze, and tone fear conditioning. The results indicated that the effects of CCX and housing on open-field behavior were independent, with CCX increasing the time spent in the center of the field at the beginning of the observation (i.e., emotionality), and EE and IE increasing rearing (emotionality) and reducing teeth-chattering (habituation), respectively. CCX reduced the frequency of spontaneous alternation, denoting spatial working memory deficits, while housing did not influence this performance. Neither CCX, nor housing significantly affected paw preference lateralization, although CCX was associated with a leftward bias in paw preference. In the Morris water maze, housing had effects on spatial acquisition, while CCX reduced activity, without interfering with spatial memory. CCX did not influence tone fear conditioning, but context fear conditioning seemed to benefit from EE. We conclude that CCX in adult rats has subtle, but specific behavioral effects pertaining to emotionality, spatial working memory, and, possibly, aversively motivated exploration, and these effects are either independent or only peripherally interact with the effects of housing.

Algorithms↗
PubMed2004

Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory.

Memory consolidation is mediated by new protein synthesis. However, the transcriptional pathways induced in neurons by behavioral training that activate gene responses have yet to be fully delineated. We have previously shown that nuclear factor kappaB (NF-kappaB) is activated in the amygdala after fear conditioning. Here we report that fear conditioning resulted in an increase in histone acetyl-transferase activity, the association between NF-kappaB p65 and CBP, and the increase in acetylated p65. Pretreating animals with histone deacetylase (HDAC) inhibitors prolonged the nuclear expression of acetyl-p65 and increased its DNA binding activity. Consistent with these results, HDAC inhibitors enhanced long-term but not short-term fear memory, and this effect was attenuated by kappaB decoy DNA, whereas scrambled DNA was without effect. This study provides evidence that HDAC-mediated deacetylation functions as an intranuclear molecular switch culminating in the termination of NF-kappaB transcriptional response that is involved in the formation of fear memory.

Acetylation↗
PubMed2000

Disruption of contextual freezing, but not contextual blocking of fear-potentiated startle, after lesions of the dorsal hippocampus.

The role of the dorsal hippocampus in contextual fear conditioning was investigated with a contextual blocking paradigm. In Experiment 1, rats were given pairings of a light conditioned stimulus (CS) and footshock after preexposure either to footshock or to the context alone. The group preexposed to footshock showed poorer fear conditioning to the light CS, as measured by the fear-potentiated startle reflex. In Experiment 2, a group preexposed to footshock in the same context showed poorer fear conditioning to the light CS than did a group preexposed to footshock in a different context, indicating contextual blocking of fear-potentiated startle. In Experiment 3, lesions of the dorsal hippocampus had no effect on contextual blocking, even though contextual freezing was disrupted. The sparing of contextual blocking indicated that contextual memory was intact following hippocampal lesions, despite the disruption of contextual freezing.

Animals↗
PubMed2006

Dual circuitry for odor-shock conditioning during infancy: corticosterone switches between fear and attraction via amygdala.

Rat pups must learn maternal odor to support attachment behaviors, including nursing and orientation toward the mother. Neonates have a sensitive period for rapid, robust odor learning characterized by increased ability to learn odor preferences and decreased ability to learn odor aversions. Specifically, odor-0.5 mA shock association paradoxically causes an odor preference and coincident failure of amygdala activation in pups until postnatal day 10 (P10). Because sensitive-period termination coincides with a declining "stress hyporesponsive period" when corticosterone release is attenuated, we explored the role of corticosterone in sensitive-period termination. Odor was paired with 0.5 mA shock in either sensitive-period (P8) or postsensitive-period (P12) pups while manipulating corticosterone. We then assessed preference/aversion learning and the olfactory neural circuitry underlying its acquisition. Although sensitive-period control paired odor-shock pups learned an odor preference without amygdala participation, systemic (3 mg/kg, i.p.; 24 h and 30 min before training) or intra-amygdala corticosterone (50 or 100 ng; during training) permitted precocious odor-aversion learning and evoked amygdala neural activity similar to that expressed by older pups. In postsensitive-period (P12) pups, control paired odor-shock pups showed an odor aversion and amygdala activation, whereas corticosterone-depleted (adrenalectomized) paired odor-shock pups showed odor-preference learning and activation of an odor learning circuit characteristic of the sensitive period. Intra-amygdala corticosterone receptor antagonist (0.3 ng; during training) infused into postsensitive-period (P12) paired odor-shock pups also showed odor-preference learning. These results suggest corticosterone is important in sensitive-period termination and developmental emergence of olfactory fear conditioning, acting via the amygdala as a switch between fear and attraction. Because maternal stimulation of pups modulates the pups' endogenous corticosterone, this suggests maternal care quality may alter sensitive-period duration.

Adrenalectomy↗
PubMed2003

Possible regulatory mechanism of DHA-induced anti-stress reaction in rats.

To determine whether docosahexaenoic acid (DHA) affects stress responses in rats, we investigated its influence on several behavioral tests. Female rats were fed a diet deficient in (n-3) fatty acid from mating through pregnancy and lactation. Male pups fed the same diet as their dams were used for experiments. The effects of dietary (n-3) fatty acid deficiency and supplementation with DHA on psychological stress and conditioned-fear stress were investigated. The effect of DHA on psychological stress was examined by an elevated plus-maze test. The (n-3) deficient rats spent significantly (P<0.05) less time in the open arms; after 1 week of supplementation with DHA, they showed a significant (P<0.01) improvement. We then examined the paired effects of DHA and CRH on stress manifestations by an intracerebroventricular (i.c.v.) cannulation and behavior testing. An i.c.v. infusion of CRH (500 pmol) under resting conditions was shown to have stress-inducing effects on behavior such as decreases of rearing, smelling and feeding, and increases of face washing; the supplementation of DHA significantly improved these distress behaviors. Finally, conditioned fear was induced by 40 min forced exposure to a cage in which the rat had experienced footshocks (30 x 1 mA x 1 s) 1 day before. Freezing behavior was dramatically suppressed by the supplementation of DHA, even 48 h after the conditioning treatment. Furthermore, the effect of DHA on the conditioned fear stress response is maintained over a long-term period. The i.c.v. pre-treatment of rats with bicuculline, a GABA(A) receptor antagonist, enhanced the conditioned-fear-induced freezing time in a dose-dependent fashion in the (n-3) fatty acid deficient animals. Significantly, the DHA supplemented group was not affected by the pre-treatment with bicuculline. From these findings, it is concluded that the involvement of DHA in stress responses may act via a GABA(A) receptor-mediated mechanism.

Animals↗
PubMed1995

Effects of the serotonin1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin on neurochemical responses to stress.

The effects of intracerebroventricular administration of the 5-hydroxytryptamine (5-HT)1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 pmol) on adrenocortical and neurochemical responses to stress were examined in conscious male rats. The following stress paradigms were used: acoustic stimulation (105 dB for 2 min); footshock (0.2 mA, five shocks over 5 min); conditioned fear (animals placed in a footshock chamber for 5 min, 24 h after footshock); restraint (5 min); intraperitoneal (i.p.) injection of recombinant human interleukin-1 alpha (rHu-IL-1 alpha, 20 micrograms/kg); and injection of cocaine hydrochloride (20 mg/kg, i.p.). As previously shown, 8-OH-DPAT was able to attenuate the adrenocortical response to acoustic stress, conditioned fear, rHu-IL-1 alpha, and cocaine administration. Cocaine decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios and norepinephrine (NE) concentration in the prefrontal cortex, hypothalamus, and brainstem in all experiments, and 8-OH-DPAT reversed the changes in DOPAC/DA ratio without affecting 5-HIAA/5-HT ratios or NE content. 8-OH-DPAT alone had no effect on these parameters, although it decreased NE content in the prefrontal cortex in several experiments, and in the brainstem in one experiment. Significant decreases in NE content were observed in some brain regions following some of the stressors, but these changes were not generally affected by 8-OH-DPAT. Increases in the 5-HIAA/5-HT and DOPAC/DA ratios were also observed in some brain sites following some stressors, but these changes were not affected by 8-OH-DPAT except in the case of the increased 5-HIAA/5-HT ratio in the prefrontal cortex following the conditioned fear response. These results indicate that although 8-OH-DPAT is able to decrease plasma corticosterone responses following acoustic stress, conditioned fear, rHu-IL-1 alpha, and cocaine administration, these effects do not appear to be related to an action of the 5-HT1A agonist on biogenic amine metabolism. This observation indicates that the predominant effect of 8-OH-DPAT on adrenocortical responses is mediated at postsynaptic sites not involved in the regulation of cerebral biogenic amine metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues.

Experiment 1 investigated the effects of catecholaminergic deafferentation or cell body lesions of the amygdala on fear conditioning to explicit and contextual cues. Bilateral infusions of quinolinic acid mainly damaged neurons within the basolateral region of the amygdala. 6-Hydroxydopamine infusions at the same coordinates resulted in an 86% depletion of noradrenaline and a 63% depletion of dopamine from the amygdala, but had no effect on the concentration of 5-hydroxytryptamine. After recovery from surgery, lesioned rats and controls were exposed to pairings of an auditory (clicker) conditioned stimulus and (foot shock) unconditioned stimulus in a distinctive environment. During testing, rats with both 6-hydroxydopamine and cell body lesions showed severely impaired conditioning to explicit cues, compared with controls, indicated by their reduced suppression of drinking when the conditioned stimulus was introduced into a separate, lick-operant chamber. Neither lesion affected fear conditioning to contextual cues, measured as preference for a "safe" environment over the one in which they were shocked. In Experiment 2, rats received bilateral, ibotenic acid-induced lesions of the hippocampal formation. Lesioned rats and controls were again tested for aversive conditioning to explicit and contextual cues. Rats with cell body lesions of the hippocampus showed normal suppression of drinking in the presence of the conditioned stimulus, but were severely impaired in choosing the safe environment based on contextual cues alone. These results suggest a double dissociation of the effects of amygdala and hippocampal damage on fear conditioning to explicit and contextual cues.

Amygdala↗
PubMed1996

Postconditioning isolation disrupts contextual conditioning: an experimental analysis.

Contextual-fear conditioning requires a lengthy retention period to fully emerge. This phenomenon might reflect the consolidation of a representation of the context that can be used to evoke fear. To investigate this hypothesis, 25 day-old rats that were returned to their home cages after conditioning were compared with rats that were isolated in a novel room. Isolation disrupted contextual but not auditory-cue fear conditioning when the conditioning-isolation interval was 2 hr or less, but not when it was 24 hr. Preexposure to the context prevented the isolation effect, and isolation disrupted this effect of context preexposure. These results support the consolidation hypothesis and the view that contextual- and auditory-cue fear conditioning depend on different processes.

Acoustic Stimulation↗
PubMed1990

Potentiation of the acoustic startle response by a conditioned stimulus paired with acoustic startle stimulus in rats.

The hypothesis that the standard acoustic startle habituation paradigm contains the elements of Pavlovian fear conditioning was tested. In a potentiated startle response paradigm, a startle stimulus and a light conditioned stimulus (CS) were paired. A startle stimulus then was tested alone or following the CS. Freezing behavior was measured to index conditioned fear. The startle response was potentiated on CS trials, and rats froze more in CS than in non-CS periods. In Experiment 1, response to a previously habituated, weak startle stimulus was potentiated. In Experiment 2, response to the same stimulus used as the unconditioned stimulus (US) in training was potentiated. This CS-potentiated response retarded the course of response decrements over training sessions as compared with an explictly unpaired control group. Conditioned fear is a standard feature of this habituation paradigm, serves to potentiate the startle response, and provides an associative dimension lacking in the habituation process per se.

Animals↗
PubMed2005

Infralimbic cortex activation increases c-Fos expression in intercalated neurons of the amygdala.

Recently, it was reported that stimulation of the infralimbic cortex produces a feedforward inhibition of central amygdala neurons. The interest of this observation comes from the fact that the central nucleus is the main output station of the amygdala for conditioned fear responses and evidence that the infralimbic cortex plays a critical role in the extinction of conditioned fear. However, the identity of the neurons mediating this infralimbic-evoked inhibition of the central nucleus remains unknown. Likely candidates are intercalated amygdala neurons. Indeed, these cells receive glutamatergic afferents from the infralimbic cortex, use GABA as a transmitter, and project to the central amygdala. Thus, the present study was undertaken to test whether, in adult rats, the infralimbic cortex can affect the activity of intercalated neurons. To this end, disinhibition of the infralimbic cortex was induced by local infusion of the non-competitive GABA-A receptor antagonist picrotoxin. Subsequently, neuronal activation was determined bilaterally within the amygdala using induction of the immediate early gene Fos. Infralimbic disinhibition produced a significant increase in the number of Fos-immunoreactive intercalated cells bilaterally whereas no change was detected in the central nucleus. In the basolateral amygdaloid complex, increases in the number of Fos-immunoreactive cells only reached significance in the contralateral lateral nucleus. These results suggest that glutamatergic inputs from the infralimbic cortex directly activate intercalated neurons. Thus, our findings raise the possibility that the infralimbic cortex inhibits conditioned fear via the excitation of intercalated cells and the consequent inhibition of central amygdala neurons.

Amygdala↗
PubMed2005

Effects of the mGluR8 agonist (S)-3,4-DCPG in the lateral amygdala on acquisition/expression of fear-potentiated startle, synaptic transmission, and plasticity.

The lateral amygdala plays an important role in emotional learning. Previous studies found that amygdaloid plasticity processes involve the activation of metabotropic glutamate receptors. In the present study we examined the effect of the highly specific mGluR8 agonist (S)-3,4-DCPG on conditioned fear in vivo measuring fear-potentiated startle. Both, acquisition and expression of conditioned fear were dose-dependently inhibited by (S)-3,4-DCPG injections into the amygdala. Since synaptic long-term potentiation in the lateral amygdala has been correlated with the acquisition of conditioned fear in rats, the effect of (S)-3,4-DCPG in vitro on synaptic transmission, short- and long-term plasticity in the lateral amygdala was evaluated in parallel. Patch clamp recordings in rat brain slices revealed that (S)-3,4-DCPG strongly attenuated synaptic transmission from sensory afferents. The lack of detectable effects on postsynaptic neurons and altered short-term plasticity indicate that (S)-3,4-DCPG acts at presynaptic sites. Long-term potentiation of thalamic afferent fiber synapses induced by a pairing protocol was slightly attenuated in the presence of (S)-3,4-DCPG, but long-term potentiation by tetanic afferent stimulation was inhibited. We conclude that mGluR8 activation is not specifically involved in long-term plasticity processes but that it rather provides a powerful inhibitory control of synaptic transmission within the lateral amygdala, with the ability to reduce activity in such a way that the expression and the acquisition of learned fear become strongly impaired in vivo.

Amygdala↗
PubMedDate not supplied

Hippocampal dysfunction during aging I: deficits in memory consolidation.

Numerous ablation studies indicate a critical role for the hippocampal system in establishing or consolidating certain types of memory. Normal aging manifests by selective neurobiological changes in the hippocampal formation and on performance of tasks that require a functional hippocampus, including retention of contextual fear conditioning. To determine if impairments in the consolidation process contribute to memory dysfunction in aging, middle-aged and aged rats were fear conditioned and subsequently received dorsal hippocampal lesions or sham surgery after a 1, 7, 14, or 28-day interval. During retention tests, middle-aged rats exhibited a temporally graded retrograde amnesia of contextual fear conditioning, whereas aged rats manifested contextual memory impairments at all intervals. We postulate that the lack of consolidation in aged animals relates to previous findings of age-related changes in neuroanatomy and neurophysiological plasticity. The present findings suggest that impaired hippocampal consolidation contributes to age-related learning and memory deficits.

Aging↗
PubMed2005

The role of social groups in the persistence of learned fear.

Classical fear conditioning investigates how animals learn to associate environmental stimuli with an aversive event. We examined how the mechanisms of fear conditioning apply when humans learn to associate social ingroup and outgroup members with a fearful event, with the goal of advancing our understanding of basic learning theory and social group interaction. Primates more readily associate stimuli from certain fear-relevant natural categories, such as snakes, with a negative outcome relative to stimuli from fear-irrelevant categories, such as birds. We assessed whether this bias in fear conditioning extends to social groups defined by race. Our results indicate that individuals from a racial group other than one's own are more readily associated with an aversive stimulus than individuals of one's own race, among both white and black Americans. This prepared fear response might be reduced by close, positive interracial contact.

Black or African American↗
PubMed1997

Emotional memory and psychopathology.

A leading model for studying how the brain forms memories about unpleasant experiences is fear conditioning. A cumulative body of work has identified major components of the neural system mediating this form of learning. The pathways involve transmission of sensory information from processing areas in the thalamus and cortex to the amygdala. The amygdala's lateral nucleus receives and integrates the sensory inputs from the thalamic and cortical areas, and the central nucleus provides the interface with motor systems controlling specific fear responses in various modalities (behavioural, autonomic, endocrine). Internal connections within the amygdala allow the lateral and central nuclei to communicate. Recent studies have begun to identify some sites of plasticity in the circuitry and the cellular mechanisms involved in fear conditioning. Through studies of fear conditioning, our understanding of emotional memory is being taken to the level of cells and synapses in the brain. Advances in understanding emotional memory hold out the possibility that emotional disorders may be better defined and treatment improved.

Animals↗
PubMed1997

Microinjection of morphine into the nucleus accumbens impairs contextual learning in rats.

A unilateral microinjection of morphine into the amygdala impaired fear conditioning to both a conditioned stimulus (CS) paired with shock and the context where shock occurred, whereas a microinjection of morphine into the nucleus accumbens (NA) spared fear conditioning to the CS but impaired, in a dose-dependent and receptor-specific manner, fear conditioning to the context. Morphine in the NA also spared extinction and latent inhibition of a CS but abolished the context specificity of these effects and eliminated the increase in discriminability that results from preexposure to a to-be-shocked context. The results identify a role for the NA in the processes by which rats learn about a context and are discussed in terms of an opioid disruption of either within-context associations or of attentional processes that contribute to such associations.

Animals↗