Fear Conditioning Processes Research Articles

Fear Conditioning and Affective Modulation of the Startle Reflex in Male Adolescents with Early-Onset or Adolescence-Onset Conduct Disorder and Healthy Control Subjects

Impairments in emotional processing may play an etiological role in the development of aggressive or antisocial behavior such as is seen in conduct disorder (CD). These findings may be developmentally sensitive, with neuropsychological impairments confined to those with the early-onset form of CD, which emerges in childhood. We investigated whether adolescents with early- or adolescence-onset CD would acquire fear conditioned responses to a visual conditioned stimulus and show a normal pattern of affective modulation of the startle reflex. Electrodermal activity was measured during the fear conditioning process, and electromyographic recording methods were used to assess blink magnitudes elicited by acoustic startle probes during the viewing of emotionally valenced pictures. Forty-one early-onset CD, 28 adolescence-onset CD, and 54 healthy control adolescents participated in the study. Both CD groups showed impaired differential fear conditioning relative to control subjects, while retaining the ability to generate normal skin conductance responses to the aversive unconditioned stimulus. There was a similar relationship between emotional valence of the slides and startle magnitude in CD and control adolescents, but startle-elicited blinks were lower across all emotion categories in both CD subtypes. Fear conditioning deficits and reduced startle amplitudes were observed in participants with early- and adolescence-onset forms of CD. These findings are consistent with impairments in neural systems subserving emotion and involving the amygdala in CD, regardless of age of onset.

Effects of inactivation of serotonergic neurons of the median raphe nucleus on learning and performance of contextual fear conditioning

Several studies have shown that the median raphe nucleus (MRN) is involved in anxiety. However, no study assessed the role of 5-HT mechanisms of MRN in both freezing and fear-potentiated startle (FPS) within a single form of conditioned learning. In this work we examined the effects of neurotoxic lesions of the MRN with NMDA on freezing and FPS of rats submitted to a contextual fear conditioning paradigm, in which they were tested in the same chamber where they received foot-shocks 24 h before. Compared to controls NMDA-injected rats showed a reduction of freezing and FPS in response to contextual cues. Next, we examined the effects of stimulation of 5-HT 1A somatodendritic autoreceptors of the MRN with local injections of 8-OH-DPAT either before training or testing sessions conducted 2 or 24 h post-conditioning. Pre-training injections of 8-OH-DPAT intra-MRN reduced both freezing and FPS whereas post-training injections reduced only freezing to the aversive context without changing the FPS. Thus, freezing is easily disrupted by post-training MRN injections of 8-OH-DPAT while memory for FPS remained unchanged. It is proposed that the consolidation of contextual conditioned fear promoting freezing takes place through a slow mechanism of transference of information through 5-HT mechanisms of the MRN-hippocampus pathway. On the other hand, a rapid fear conditioning process operates for FPS, probably through other pathways.

5-HT mechanisms of median raphe nucleus in the conditioned freezing caused by light/foot-shock association

We have shown that 5-HT mechanisms of the median raphe nucleus (MRN) are involved in contextual fear-conditioning processes as electrolytic or neurotoxic lesions with N-methyl- d-aspartate (NMDA) or injections of 8-hydroxy-2-(di- n-propilamino)-tetralin (8-OH-DPAT) into this structure inhibit freezing behavior in a contextual fear paradigm. In this work, we extend these studies by analyzing the behavioral responses in a classical fear-conditioning paradigm (light or tone/foot-shock association) in rats with either neurochemical lesion with NMDA or injected with 8-OH-DPAT into the MRN. The animals received NMDA or 8-OH-DPAT or saline microinjections into the MRN and were submitted to conditioning trials in an experimental chamber, where they received 10 foot-shocks (0.6 mA, 1 s, variable interval between 10 and 50 s) paired with tone or light (CS). On the next day, they were tested in a different experimental chamber, with or without CS presentation, where the duration of freezing and the number of rearing episodes were recorded. Light or tone alone caused a significant amount of freezing. NMDA lesions or 8-OH-DPAT injections into the MRN clearly inhibited freezing behavior in rats conditioned to light/foot-shock association, but not in the conditioning sessions with tones. Besides the proposed role in contextual fear conditioning, these results clearly show that MRN is involved in the fear conditioning with light as conditioned stimuli. Distinct neural substrates seem to subserve conditioning fear with acoustic stimuli.

Expression of fear-conditioning is accompanied by increased paired-pulse depression within the amygdala

Fear-conditioning is a model of fear learning and anxiety. The lateral nucleus of the amygdala (LA) provides a critical link for relaying thalamic and cortical auditory information to the rest of the amygdala during the fear conditioning process. Alterations in excitatory synaptic transmission in the thalamic to LA pyramidal cells was studied using whole-cell patch clamp recordings in brain slices from fear-conditioned animals. Following paired stimulation of the thalamic afferents, paired-pulse depression (PPD) could be recorded at 200-ms to 2-s intervals. Increasing transmitter release by decreasing the Mg 2+/Ca 2+ ratio enhanced PPD suggesting that PPD is reflective of changes in release probability. Analysis of the pairs of composite, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl- d-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) showed that there was no correlation between EPSC pairs suggesting that PPD may be mediated through a release-independent mechanism of presynaptic origin. However, AMPA and NMDA receptor mediated PPD had a different time course and magnitude suggesting postsynaptic factors may be involved in PPD. After fear-conditioning PPD of the composite and AMPA receptor-mediated EPSCs was enhanced suggesting that neurotransmitter release may be increased in learned fear. The NMDA receptor-mediated PPD was however not altered in fear-conditioned animals. The differences in response of AMPA and NMDA receptor-mediated PPD suggest that postsynaptic mechanisms may also be involved in the expression of fear conditioning.

Organization of primate amygdalo-prefrontal projections

The amygdalo-prefrontal network is thought to play an important role in fear conditioning and other associative learning processes. We investigated amygdalo-prefrontal connectivity data from anatomical tracing studies using an advanced databasing approach (www.cocomac.org) and multivariate statistics. Both amygdaloid and prefrontal cortical areas were found to form three distinct clusters with (i) widespread, (ii) absent, and (iii) highly specific connections, respectively. Major amygdaloid sources of projections were the accessory basal (AB), basal (B), lateral (L) nuclei and the periamygdaloid cortex (PAC). Major prefrontal targets were orbital areas 13 and 14, as well as medial areas 24 and 25.