A key question in the analysis of hippocampal memory relates to how attention modulates the encod... more A key question in the analysis of hippocampal memory relates to how attention modulates the encoding and long-term retrieval of spatial and nonspatial representations in this region. To address this question, we recorded from single cells over a period of 5 days in the CA1 region of the dorsal hippocampus while mice acquired one of two goal-oriented tasks. These tasks required the animals to find a hidden food reward by attending to either the visuospatial environment or a particular odor presented in shifting spatial locations. Attention to the visuospatial environment increased the stability of visuospatial representations and phase locking to gamma oscillations-a form of neuronal synchronization thought to underlie the attentional mechanism necessary for processing task-relevant information. Attention to a spatially shifting olfactory cue compromised the stability of place fields and increased the stability of reward-associated odor representations, which were most consistently retrieved during periods of sniffing and digging when animals were restricted to the cup locations. Together, these results suggest that attention selectively modulates the encoding and retrieval of hippocampal representations by enhancing physiological responses to task-relevant information.
There has been a dramatic rise in gene x environment studies of human behavior over the past deca... more There has been a dramatic rise in gene x environment studies of human behavior over the past decade that has moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.
Moderate non-progressive cognitive impairment is a consistent feature of Duchenne muscular dystro... more Moderate non-progressive cognitive impairment is a consistent feature of Duchenne muscular dystrophy (DMD), although few central nervous system abnormalities have yet been identified. A model for DMD is provided by the mdx mouse which fails to produce full length dystrophin in muscle and brain. In this study we have compared performances in a hippocampal-dependent spatial learning task, the Morris water maze, in mdx mice and in age-matched normal (C57BL/10) mice. There was no difference in acquisition rates or in retention between the two groups. We also found no difference in the magnitude of long-term potentiation (LTP) between the two groups, either in the dentate gyrus or in area CAl. These experiments demonstrate that neither spatial learning nor hippocampal synaptic plasticity are significantly affected by the lack of full-length dystrophin.
Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive co... more Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive conditioning. NAcc core lesions had no effect on discrete-cue or contextual conditioned freezing during acquisition. During retention testing, neither pre- nor posttraining lesions had any effect on conditioned freezing to the discrete cue. However, pretraining lesions resulted in a profound impairment of contextual conditioned freezing in a retention test, and posttraining lesions resulted in a smaller impairment. NAcc core lesions had no effect on sensory or motor processes, as measured by shock reactivity and spontaneous locomotor activity. These results suggest that during acquisition, processes independent of the NAcc core mediate contextual conditioned freezing, but that the NAcc is implicated in the retention of this aversive memory.
An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both ince... more An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both incentive reward processes and in adaptive responses to conditioned and unconditioned aversive stimuli. Yet, it has been argued that NAcc activation to aversive stimuli may be a consequence of the rewarding effects of their termination, i.e., relief. To address this question we used fMRI to delineate brain response to the onset and offset of unpleasant and pleasant auditory stimuli in the absence of learning or motor response. Increased NAcc activity was seen for the onset of both pleasant and unpleasant stimuli. Our results support the expanded bivalent view of NAcc function and call for expansion of current models of NAcc function that are solely focused on reward.
The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system ar... more The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system are believed to modulate behavioral responses to stressful and/or anxiogenic stimuli. However, although the BNST AL receives heavy serotonergic innervation, the functional significance of this input is not known. Data obtained from in vitro whole-cell patch clamp recording in the rat BNST slice show that exogenous application of 5-hydroxytryptamine (5-HT) evoked a heterogeneous response in BNST AL neurons. The principal action of 5-HT in this region was inhibitory, evoking a membrane hyperpolarization (5-HT Hyp ) and a concomitant reduction in input resistance in the majority of neurons tested. The broad-spectrum 5-HT 1 agonist, 5-carboxamindotryptamine (5-CT), but not R(؎)8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), mimicked the 5-HT Hyp response in the BNST. Moreover, the outward current mediating 5-HT Hyp was inwardly rectifying and sensitive to the G protein activated inwardly rectifying K ؉ (G IRK ) channel blocker, tertiapin-Q. In the CNS 5-HT 1A receptors are thought to couple to G IRK channels, suggesting that 5-HT Hyp in BNST AL neurons was mediated by activation of 5-HT 1A-like receptors. This was confirmed by the blockade of both 5-HT Hyp and 5-CT Hyp by the specific 5-HT 1A receptor antagonist N-[2-[4-(2methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635 200nM). Furthermore, an in vivo examination of the functional consequences of 5-HT 1A-like induced inhibition of BNST neurons revealed that infusion of 5-CT into the BNST significantly reduced the acoustic startle response, without affecting the general motor activity of the animals. These data point to the possibility that 5-HT 1A mediated inhibition of the BNST AL could contribute to an anxiolytic action. Hence, we propose that in response to stressful stimuli, enhanced levels of 5-HT in the BNST AL plays a critical homeostatic role in feedback inhibition of the anxiogenic response to these stimuli. (D. Rainnie). Abbreviations: ACSF, artificial cerebrospinal fluid; BNST, bed nucleus of the stria terminalis; BNST AL , anteriorlateral bed nucleus of the stria terminalis; CGP 52432, 3-[[3,4-dichlorophenyl)methyl]amino]propyl] diethoxymethyl)phosphinic acid; DAB, 3,3=-diaminobenzidine; E 5-HT , reversal potential of 5-HT; G IRK , G protein-activated inwardly rectifying K ϩ channels; ISI, interstimulus interval; LTDg, lateral tegmental nucleus; PnC, nucleus reticularis pontis caudalis; PPTg, pedunculopontine tegmental nucleus; Rm, input resistance; TTX, tetrodotoxin; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt; 5-CT, 5-carboxamidotryptamine; 5-CT Hyp , 5-CT-evoked membrane hyperpolarization; 5-HT, 5-hydroxytryptamine; 5-HT Dep , 5-HT-evoked membrane depolarization; 5-HT Hyp , 5-HT-evoked membrane hyperpolarization; 5-HT Hyp-Dep , 5-HT-evoked membrane hyperpolarization followed by depolarization; 8-OH-DPAT, R(Ϯ)8-hydroxydipropylaminotetralin hydrobromide.
Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a nu... more Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia. #
Mouse models are useful for studying genes involved in behavior, but whether they are relevant fo... more Mouse models are useful for studying genes involved in behavior, but whether they are relevant for human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat, and in the efficacy of treatments that rely on extinction mechanisms such as exposure therapy.
A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learni... more A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learning is supported by a large body of evidence, which has challenged the view that the NAcc is solely involved in mediating appetitive processes. Unfortunately, due to conflicting findings in the aversive conditioning literature the role of the NAcc in aversive conditioning remains unclear. This review focuses on the results of recent in vivo microdialysis studies that have examined the release of NAcc DA during Pavlovian aversive conditioning. In addition, we present additional new findings, which re-examine the involvement of NAcc DA in aversive conditioning. DA release was measured in the NAcc core using in vivo microdialysis during discrete cue Pavlovian aversive conditioning in four experiments. In all cases no change in DA levels was observed either during training or in response to the CS presentations despite robust behavioural evidence of discrete cue Pavlovian aversive conditioning. These findings contrast with some previous studies that show that primary and conditioned aversive stimuli increase DA release in the NAcc. We suggest that the inconsistencies in the literature might be due to procedural differences in the measurement of aversive conditioning, and the precise location of the probe in the NAcc region. Hence, rather than discount an involvement of NAcc DA in affective processes, we propose that functionally dissociable sub-regions of the NAcc may contribute to different aspects of Pavlovian aversive learning. #
Optimization of cognitive processing may depend on specific and distinct functions of the cortica... more Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradrenergic systems. This investigation dissociates functions of cortical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional performance. The five-choice serial reaction time task was used to provide a continuous assessment of visuospatial attention. Previous studies using this task have established a critical role for the cortical cholinergic system in the detection of visual targets. However, selective lesions of the locus coeruleus noradrenergic system impair performance only when additional attentional demands are placed on the subject by distractors or temporally unpredictable targets. To test the hypothesis that the cortical noradrenergic system is particularly sensitive to novel task contingencies, we also assessed NA and ACh efflux in rats that been trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished. Cortical ACh efflux showed a robust and task-related increase during established contingent performance. This response was significantly attenuated in noncontingent subjects, although it still exceeded pretask values. In contrast, NA efflux only increased transiently in contingent subjects after task onset but showed sustained elevations in noncontingent subjects on the first day when contingencies were changed. These data also implicate cortical ACh in aspects of attentional functioning but highlight a specific involvement of the cortical noradrenergic system in detecting shifts in the predictive relationship between instrumental action and reinforcement.
A key question in the analysis of hippocampal memory relates to how attention modulates the encod... more A key question in the analysis of hippocampal memory relates to how attention modulates the encoding and long-term retrieval of spatial and nonspatial representations in this region. To address this question, we recorded from single cells over a period of 5 days in the CA1 region of the dorsal hippocampus while mice acquired one of two goal-oriented tasks. These tasks required the animals to find a hidden food reward by attending to either the visuospatial environment or a particular odor presented in shifting spatial locations. Attention to the visuospatial environment increased the stability of visuospatial representations and phase locking to gamma oscillations-a form of neuronal synchronization thought to underlie the attentional mechanism necessary for processing task-relevant information. Attention to a spatially shifting olfactory cue compromised the stability of place fields and increased the stability of reward-associated odor representations, which were most consistently retrieved during periods of sniffing and digging when animals were restricted to the cup locations. Together, these results suggest that attention selectively modulates the encoding and retrieval of hippocampal representations by enhancing physiological responses to task-relevant information.
There has been a dramatic rise in gene x environment studies of human behavior over the past deca... more There has been a dramatic rise in gene x environment studies of human behavior over the past decade that has moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.
Moderate non-progressive cognitive impairment is a consistent feature of Duchenne muscular dystro... more Moderate non-progressive cognitive impairment is a consistent feature of Duchenne muscular dystrophy (DMD), although few central nervous system abnormalities have yet been identified. A model for DMD is provided by the mdx mouse which fails to produce full length dystrophin in muscle and brain. In this study we have compared performances in a hippocampal-dependent spatial learning task, the Morris water maze, in mdx mice and in age-matched normal (C57BL/10) mice. There was no difference in acquisition rates or in retention between the two groups. We also found no difference in the magnitude of long-term potentiation (LTP) between the two groups, either in the dentate gyrus or in area CAl. These experiments demonstrate that neither spatial learning nor hippocampal synaptic plasticity are significantly affected by the lack of full-length dystrophin.
Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive co... more Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive conditioning. NAcc core lesions had no effect on discrete-cue or contextual conditioned freezing during acquisition. During retention testing, neither pre- nor posttraining lesions had any effect on conditioned freezing to the discrete cue. However, pretraining lesions resulted in a profound impairment of contextual conditioned freezing in a retention test, and posttraining lesions resulted in a smaller impairment. NAcc core lesions had no effect on sensory or motor processes, as measured by shock reactivity and spontaneous locomotor activity. These results suggest that during acquisition, processes independent of the NAcc core mediate contextual conditioned freezing, but that the NAcc is implicated in the retention of this aversive memory.
An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both ince... more An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both incentive reward processes and in adaptive responses to conditioned and unconditioned aversive stimuli. Yet, it has been argued that NAcc activation to aversive stimuli may be a consequence of the rewarding effects of their termination, i.e., relief. To address this question we used fMRI to delineate brain response to the onset and offset of unpleasant and pleasant auditory stimuli in the absence of learning or motor response. Increased NAcc activity was seen for the onset of both pleasant and unpleasant stimuli. Our results support the expanded bivalent view of NAcc function and call for expansion of current models of NAcc function that are solely focused on reward.
The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system ar... more The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system are believed to modulate behavioral responses to stressful and/or anxiogenic stimuli. However, although the BNST AL receives heavy serotonergic innervation, the functional significance of this input is not known. Data obtained from in vitro whole-cell patch clamp recording in the rat BNST slice show that exogenous application of 5-hydroxytryptamine (5-HT) evoked a heterogeneous response in BNST AL neurons. The principal action of 5-HT in this region was inhibitory, evoking a membrane hyperpolarization (5-HT Hyp ) and a concomitant reduction in input resistance in the majority of neurons tested. The broad-spectrum 5-HT 1 agonist, 5-carboxamindotryptamine (5-CT), but not R(؎)8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), mimicked the 5-HT Hyp response in the BNST. Moreover, the outward current mediating 5-HT Hyp was inwardly rectifying and sensitive to the G protein activated inwardly rectifying K ؉ (G IRK ) channel blocker, tertiapin-Q. In the CNS 5-HT 1A receptors are thought to couple to G IRK channels, suggesting that 5-HT Hyp in BNST AL neurons was mediated by activation of 5-HT 1A-like receptors. This was confirmed by the blockade of both 5-HT Hyp and 5-CT Hyp by the specific 5-HT 1A receptor antagonist N-[2-[4-(2methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635 200nM). Furthermore, an in vivo examination of the functional consequences of 5-HT 1A-like induced inhibition of BNST neurons revealed that infusion of 5-CT into the BNST significantly reduced the acoustic startle response, without affecting the general motor activity of the animals. These data point to the possibility that 5-HT 1A mediated inhibition of the BNST AL could contribute to an anxiolytic action. Hence, we propose that in response to stressful stimuli, enhanced levels of 5-HT in the BNST AL plays a critical homeostatic role in feedback inhibition of the anxiogenic response to these stimuli. (D. Rainnie). Abbreviations: ACSF, artificial cerebrospinal fluid; BNST, bed nucleus of the stria terminalis; BNST AL , anteriorlateral bed nucleus of the stria terminalis; CGP 52432, 3-[[3,4-dichlorophenyl)methyl]amino]propyl] diethoxymethyl)phosphinic acid; DAB, 3,3=-diaminobenzidine; E 5-HT , reversal potential of 5-HT; G IRK , G protein-activated inwardly rectifying K ϩ channels; ISI, interstimulus interval; LTDg, lateral tegmental nucleus; PnC, nucleus reticularis pontis caudalis; PPTg, pedunculopontine tegmental nucleus; Rm, input resistance; TTX, tetrodotoxin; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt; 5-CT, 5-carboxamidotryptamine; 5-CT Hyp , 5-CT-evoked membrane hyperpolarization; 5-HT, 5-hydroxytryptamine; 5-HT Dep , 5-HT-evoked membrane depolarization; 5-HT Hyp , 5-HT-evoked membrane hyperpolarization; 5-HT Hyp-Dep , 5-HT-evoked membrane hyperpolarization followed by depolarization; 8-OH-DPAT, R(Ϯ)8-hydroxydipropylaminotetralin hydrobromide.
Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a nu... more Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia. #
Mouse models are useful for studying genes involved in behavior, but whether they are relevant fo... more Mouse models are useful for studying genes involved in behavior, but whether they are relevant for human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat, and in the efficacy of treatments that rely on extinction mechanisms such as exposure therapy.
A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learni... more A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learning is supported by a large body of evidence, which has challenged the view that the NAcc is solely involved in mediating appetitive processes. Unfortunately, due to conflicting findings in the aversive conditioning literature the role of the NAcc in aversive conditioning remains unclear. This review focuses on the results of recent in vivo microdialysis studies that have examined the release of NAcc DA during Pavlovian aversive conditioning. In addition, we present additional new findings, which re-examine the involvement of NAcc DA in aversive conditioning. DA release was measured in the NAcc core using in vivo microdialysis during discrete cue Pavlovian aversive conditioning in four experiments. In all cases no change in DA levels was observed either during training or in response to the CS presentations despite robust behavioural evidence of discrete cue Pavlovian aversive conditioning. These findings contrast with some previous studies that show that primary and conditioned aversive stimuli increase DA release in the NAcc. We suggest that the inconsistencies in the literature might be due to procedural differences in the measurement of aversive conditioning, and the precise location of the probe in the NAcc region. Hence, rather than discount an involvement of NAcc DA in affective processes, we propose that functionally dissociable sub-regions of the NAcc may contribute to different aspects of Pavlovian aversive learning. #
Optimization of cognitive processing may depend on specific and distinct functions of the cortica... more Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradrenergic systems. This investigation dissociates functions of cortical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional performance. The five-choice serial reaction time task was used to provide a continuous assessment of visuospatial attention. Previous studies using this task have established a critical role for the cortical cholinergic system in the detection of visual targets. However, selective lesions of the locus coeruleus noradrenergic system impair performance only when additional attentional demands are placed on the subject by distractors or temporally unpredictable targets. To test the hypothesis that the cortical noradrenergic system is particularly sensitive to novel task contingencies, we also assessed NA and ACh efflux in rats that been trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished. Cortical ACh efflux showed a robust and task-related increase during established contingent performance. This response was significantly attenuated in noncontingent subjects, although it still exceeded pretask values. In contrast, NA efflux only increased transiently in contingent subjects after task onset but showed sustained elevations in noncontingent subjects on the first day when contingencies were changed. These data also implicate cortical ACh in aspects of attentional functioning but highlight a specific involvement of the cortical noradrenergic system in detecting shifts in the predictive relationship between instrumental action and reinforcement.
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