Hippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear ... more Hippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear conditioning (CFC). Although the content learned in the latter have been discussed, alternative regions supporting CFC learning were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using inter-regional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belongi...
Fear-related behaviors are prone to relapse following extinction. We tested in humans a compound ... more Fear-related behaviors are prone to relapse following extinction. We tested in humans a compound extinction design ("deepened extinction") shown in animal studies to reduce post-extinction fear recovery. Adult subjects underwent fear conditioning to a visual and an auditory conditioned stimulus (CSA and CSB, respectively) separately paired with an electric shock. The target CS (CSA) was extinguished alone followed by compound presentations of the extinguished CSA and nonextinguished CSB. Recovery of conditioned skin conductance responses to CSA was reduced 24 h after compound extinction, as compared with a group who received an equal number of extinction trials to the CSA alone.
Hippocampal damage results in profound retrograde, but no anterograde amnesia in con-textual fear... more Hippocampal damage results in profound retrograde, but no anterograde amnesia in con-textual fear conditioning (CFC). Although the content learned in the latter have been discussed , alternative regions supporting CFC learning were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using interregional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belonging to the SHAM network. These results suggest that dHPC network engaged in CFC learning is partially different, and engage alternative hubs. We next tested if pre-training lesions of dHPC and one of the new dHPC network hubs (peri-rhinal, Per; or disgranular retrosplenial, RSC, cortices) would impair CFC. Only dHPC-RSC, but not dHPC-Per, impaired CFC. Interestingly, only RSC showed a consistently higher cen-trality in the dHPC network, suggesting that the increased centrality reflects an increased functional dependence on RSC. Our results provide evidence that, without hippocampus, the RSC, an anatomically central region in the medial temporal lobe memory system might support CFC learning and memory. Author summary When determined cognitive performances are not affected by brain lesions of regions generally involved in that performance, the interpretation is that the remaining regions can promote function despite of (or compensate) the damaged one. In contextual fear conditioning , a memory model largely used in laboratory rodents, hippocampal lesions produce PLOS Computational Biology | https://doi.org/10.
Rationale Pavlovian conditioned responses to cues that signal threat are rapidly acquired and ten... more Rationale Pavlovian conditioned responses to cues that signal threat are rapidly acquired and tend to persist over time. However, recent research suggests that the ability to actively avoid or exert control over an anticipated threat can diminish the subsequent expression of Pavlovian responses. Studies in animal models suggest that active avoidance behavior and its consequences may be mediated by dopaminergic function. In the present study, we sought to replicate the finding that active control over threat can attenuate subsequent Pavlovian responding in humans and conducted exploratory analyses testing whether individual differences in blink rate, a putative index of dopaminergic function, might modulate this effect. Methods Participants underwent Pavlovian aversive conditioning, followed immediately by one of two conditions. In the active avoidance condition, participants had the opportunity to actively prevent the occurrence of an anticipated shock, whereas in a yoked extinction condition, participants passively observed the cessation of shocks, but with no ability to influence their occurrence. The following day, the conditioned stimuli were presented without shock, but both groups of participants had no opportunity to employ active instrumental responses. Blink rate was measured throughout the task, and skin conductance responses served as our index of Pavlovian conditioned responding. Results Consistent with our previous findings, we observed that the group that could actively avoid the shock on day 1 exhibited attenuated recovery of Pavlovian conditioned responses. Further, we found that individuals in the active avoidance group with higher blink rates exhibited a more robust attenuation of spontaneous recovery. Conclusion This finding suggests that individual variation in dopaminergic function may modulate the efficacy with which active avoidance strategies can attenuate reactive Pavlovian responses.
Social cognitive and affective neuroscience, Jan 22, 2016
Flexibility of associative learning can be revealed by establishing and then reversing cue-outcom... more Flexibility of associative learning can be revealed by establishing and then reversing cue-outcome discriminations. Here, we used functional MRI to examine whether neurobehavioral correlates of reversal-learning are impaired in White and Asian volunteers when initial learning involves fear-conditioning to a racial out-group. For one group, the picture of a Black male was initially paired with shock (threat) and a White male was unpaired (safe). For another group, the White male was a threat and the Black male was safe. These associations reversed midway through the task. Both groups initially discriminated threat from safety, as expressed through skin conductance responses (SCR) and activity in the insula, thalamus, midbrain, and striatum. After reversal, the group initially conditioned to a Black male exhibited impaired reversal of SCRs to the new threat stimulus (White male), and impaired reversals in the striatum, anterior cingulate cortex, midbrain, and thalamus. In contrast, th...
Sleep loss in infants may have a negative effect on the functional and structural development of ... more Sleep loss in infants may have a negative effect on the functional and structural development of the nociceptive system. We tested the hypothesis that neonatal sleep restriction induces a long-term increase of pain-related behaviors in mice and that this hypersensitivity occurs due to changes in the neuronal activity of nociceptive pathways. We aim to investigate the effects of sleep loss in neonatal mice on pain behaviors of adolescent and adult mice in a sex-dependent manner. We also analyzed neuroanatomical and functional changes in pain pathways associated with behavioral changes. An experimental animal study. A basic sleep research laboratory at Universidade Federal de São Paulo in Brazil. Neonatal mice at postnatal day (PND) 12 were randomly assigned to either control (CTRL), maternal separation (MS), or sleep restriction (SR) groups. MS and SR were performed 2 hours a day for 10 days (PND 12 until PND 21). The gentle handling method was used to prevent sleep. At PND 21, PND 3...
Heart failure (HF) is characterized by a reduced tolerance to exercise due to early fatigue and d... more Heart failure (HF) is characterized by a reduced tolerance to exercise due to early fatigue and dyspnea; this may be due in part to skeletal muscle myopathy with a shift from slow to fast fibers and loss of muscle mass. Muscle wasting does not occur similarly in all types of muscle fiber, thus we tested the hypothesis that HF induces skeletal muscle atrophy in a fiber type-specific manner altering the expression of atrogin-1 and MuRF1 in a fast muscle of rats with monocrotaline-induced heart failure. We studied extensor digitorum longus (EDL) muscle from both HF and control Wistar rats. Atrogin-1 and MuRF1 mRNA content were determined using Real-Time RT-qPCR while muscle fiber cross-sectional area (CSA) from sections stained histochemically for myofibrillar ATPase were used as an index of type-specific fiber atrophy. The measurement of gene expression by RT-qPCR revealed that EDL muscle mRNA expression of MuRF1 and atrogin-1 was significantly increased in the HF group. Muscle fiber type IIB CSA decreased in the HF group compared to the CT group; there was no significant difference in muscle fiber types I and IIA/D CSA between the HF and CT groups. In conclusion, we showed that HF induces fiber type IIB specific atrophy, up-regulating atrogin-1 and MuRF1 mRNA expression in EDL muscle of monocrotaline treated rats.
Hippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear ... more Hippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear conditioning (CFC). Although the content learned in the latter have been discussed, alternative regions supporting CFC learning were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using inter-regional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belongi...
Fear-related behaviors are prone to relapse following extinction. We tested in humans a compound ... more Fear-related behaviors are prone to relapse following extinction. We tested in humans a compound extinction design ("deepened extinction") shown in animal studies to reduce post-extinction fear recovery. Adult subjects underwent fear conditioning to a visual and an auditory conditioned stimulus (CSA and CSB, respectively) separately paired with an electric shock. The target CS (CSA) was extinguished alone followed by compound presentations of the extinguished CSA and nonextinguished CSB. Recovery of conditioned skin conductance responses to CSA was reduced 24 h after compound extinction, as compared with a group who received an equal number of extinction trials to the CSA alone.
Hippocampal damage results in profound retrograde, but no anterograde amnesia in con-textual fear... more Hippocampal damage results in profound retrograde, but no anterograde amnesia in con-textual fear conditioning (CFC). Although the content learned in the latter have been discussed , alternative regions supporting CFC learning were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using interregional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belonging to the SHAM network. These results suggest that dHPC network engaged in CFC learning is partially different, and engage alternative hubs. We next tested if pre-training lesions of dHPC and one of the new dHPC network hubs (peri-rhinal, Per; or disgranular retrosplenial, RSC, cortices) would impair CFC. Only dHPC-RSC, but not dHPC-Per, impaired CFC. Interestingly, only RSC showed a consistently higher cen-trality in the dHPC network, suggesting that the increased centrality reflects an increased functional dependence on RSC. Our results provide evidence that, without hippocampus, the RSC, an anatomically central region in the medial temporal lobe memory system might support CFC learning and memory. Author summary When determined cognitive performances are not affected by brain lesions of regions generally involved in that performance, the interpretation is that the remaining regions can promote function despite of (or compensate) the damaged one. In contextual fear conditioning , a memory model largely used in laboratory rodents, hippocampal lesions produce PLOS Computational Biology | https://doi.org/10.
Rationale Pavlovian conditioned responses to cues that signal threat are rapidly acquired and ten... more Rationale Pavlovian conditioned responses to cues that signal threat are rapidly acquired and tend to persist over time. However, recent research suggests that the ability to actively avoid or exert control over an anticipated threat can diminish the subsequent expression of Pavlovian responses. Studies in animal models suggest that active avoidance behavior and its consequences may be mediated by dopaminergic function. In the present study, we sought to replicate the finding that active control over threat can attenuate subsequent Pavlovian responding in humans and conducted exploratory analyses testing whether individual differences in blink rate, a putative index of dopaminergic function, might modulate this effect. Methods Participants underwent Pavlovian aversive conditioning, followed immediately by one of two conditions. In the active avoidance condition, participants had the opportunity to actively prevent the occurrence of an anticipated shock, whereas in a yoked extinction condition, participants passively observed the cessation of shocks, but with no ability to influence their occurrence. The following day, the conditioned stimuli were presented without shock, but both groups of participants had no opportunity to employ active instrumental responses. Blink rate was measured throughout the task, and skin conductance responses served as our index of Pavlovian conditioned responding. Results Consistent with our previous findings, we observed that the group that could actively avoid the shock on day 1 exhibited attenuated recovery of Pavlovian conditioned responses. Further, we found that individuals in the active avoidance group with higher blink rates exhibited a more robust attenuation of spontaneous recovery. Conclusion This finding suggests that individual variation in dopaminergic function may modulate the efficacy with which active avoidance strategies can attenuate reactive Pavlovian responses.
Social cognitive and affective neuroscience, Jan 22, 2016
Flexibility of associative learning can be revealed by establishing and then reversing cue-outcom... more Flexibility of associative learning can be revealed by establishing and then reversing cue-outcome discriminations. Here, we used functional MRI to examine whether neurobehavioral correlates of reversal-learning are impaired in White and Asian volunteers when initial learning involves fear-conditioning to a racial out-group. For one group, the picture of a Black male was initially paired with shock (threat) and a White male was unpaired (safe). For another group, the White male was a threat and the Black male was safe. These associations reversed midway through the task. Both groups initially discriminated threat from safety, as expressed through skin conductance responses (SCR) and activity in the insula, thalamus, midbrain, and striatum. After reversal, the group initially conditioned to a Black male exhibited impaired reversal of SCRs to the new threat stimulus (White male), and impaired reversals in the striatum, anterior cingulate cortex, midbrain, and thalamus. In contrast, th...
Sleep loss in infants may have a negative effect on the functional and structural development of ... more Sleep loss in infants may have a negative effect on the functional and structural development of the nociceptive system. We tested the hypothesis that neonatal sleep restriction induces a long-term increase of pain-related behaviors in mice and that this hypersensitivity occurs due to changes in the neuronal activity of nociceptive pathways. We aim to investigate the effects of sleep loss in neonatal mice on pain behaviors of adolescent and adult mice in a sex-dependent manner. We also analyzed neuroanatomical and functional changes in pain pathways associated with behavioral changes. An experimental animal study. A basic sleep research laboratory at Universidade Federal de São Paulo in Brazil. Neonatal mice at postnatal day (PND) 12 were randomly assigned to either control (CTRL), maternal separation (MS), or sleep restriction (SR) groups. MS and SR were performed 2 hours a day for 10 days (PND 12 until PND 21). The gentle handling method was used to prevent sleep. At PND 21, PND 3...
Heart failure (HF) is characterized by a reduced tolerance to exercise due to early fatigue and d... more Heart failure (HF) is characterized by a reduced tolerance to exercise due to early fatigue and dyspnea; this may be due in part to skeletal muscle myopathy with a shift from slow to fast fibers and loss of muscle mass. Muscle wasting does not occur similarly in all types of muscle fiber, thus we tested the hypothesis that HF induces skeletal muscle atrophy in a fiber type-specific manner altering the expression of atrogin-1 and MuRF1 in a fast muscle of rats with monocrotaline-induced heart failure. We studied extensor digitorum longus (EDL) muscle from both HF and control Wistar rats. Atrogin-1 and MuRF1 mRNA content were determined using Real-Time RT-qPCR while muscle fiber cross-sectional area (CSA) from sections stained histochemically for myofibrillar ATPase were used as an index of type-specific fiber atrophy. The measurement of gene expression by RT-qPCR revealed that EDL muscle mRNA expression of MuRF1 and atrogin-1 was significantly increased in the HF group. Muscle fiber type IIB CSA decreased in the HF group compared to the CT group; there was no significant difference in muscle fiber types I and IIA/D CSA between the HF and CT groups. In conclusion, we showed that HF induces fiber type IIB specific atrophy, up-regulating atrogin-1 and MuRF1 mRNA expression in EDL muscle of monocrotaline treated rats.
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