Hannah Clarke - Academia.edu (original) (raw)

Papers by Hannah Clarke

Research paper thumbnail of To be confirmed

To be confirmedThis record is embargoed until publication.This is a placeholder record, which wil... more To be confirmedThis record is embargoed until publication.This is a placeholder record, which will be updated.This work was supported by the MRC [grant number RG62920]

Research paper thumbnail of Prefrontal serotonin and serial reversal learning The effects of serotonin depletion and serotonin 1A receptor manipulation

Behavioural Pharmacology 14(Suppl, Jun 29, 2003

Research paper thumbnail of To be confirmed

Research paper thumbnail of Understanding them to understand ourselves: The importance of NHP research for translational neuroscience

Current Research in Neurobiology

Research paper thumbnail of Hippocampal Interaction With Area 25, but not Area 32, Regulates Marmoset Approach–Avoidance Behavior

Cerebral Cortex, 2019

Affective disorders are associated with increased sensitivity to negative feedback that influence... more Affective disorders are associated with increased sensitivity to negative feedback that influences approach–avoidance decision making. Although neuroimaging studies of these disorders reveal dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp), the causal involvement of these structures and their interaction in the primate brain is unknown. We therefore investigated the effects of localized pharmacological manipulations of areas 25 and 32 and/or the aHipp of the marmoset monkey on performance of an anxiolytic-sensitive instrumental decision-making task in which an approach–avoidance conflict is created by pairing a response with reward and punishment. During control infusions animals avoided punishment, but this bias was reduced by increasing glutamate release within the aHipp or area 32, and inactivation or 5-HT1a antagonism within area 25. Conversely, increasing glutamate release in area 25 enhanced punishment avoidance but, in contrast to previo...

Research paper thumbnail of Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making

Proceedings of the National Academy of Sciences, 2015

Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety... more Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety and mood disorders, but the specific contributions of each region are unknown, including how they gate the impact of threat on decision making. To address this, the effects of GABAergic inactivation of these regions were studied in marmoset monkeys performing an instrumental approach–avoidance decision-making task that is sensitive to changes in anxiety. Inactivation of either region induced a negative bias away from punishment that could be ameliorated with anxiolytic treatment. However, whereas the effects of ventrolateral prefrontal cortex inactivation on punishment avoidance were seen immediately, those of orbitofrontal cortex inactivation were delayed and their expression was dependent upon an amygdala–anterior hippocampal circuit. We propose that these negative biases result from deficits in attentional control and punishment prediction, respectively, and that they provide the bas...

Research paper thumbnail of Serotonergic, Brain Volume and Attentional Correlates of Trait Anxiety in Primates

Neuropsychopharmacology, 2014

Trait anxiety is a risk factor for the development and maintenance of affective disorders, and in... more Trait anxiety is a risk factor for the development and maintenance of affective disorders, and insights into the underlying brain mechanisms are vital for improving treatment and prevention strategies. Translational studies in non-human primates, where targeted neurochemical and genetic manipulations can be made, are critical in view of their close neuroanatomical similarity to humans in brain regions implicated in trait anxiety. Thus, we characterised the serotonergic and regional brain volume correlates of trait-like anxiety in the marmoset monkey. Low-and high-anxious animals were identified by behavioral responses to a human intruder that are known to be sensitive to anxiolytic drug treatment. Extracellular serotonin levels within the amygdala were measured with in vivo microdialysis, at baseline and in response to challenge with the selective serotonin reuptake inhibitor, citalopram. Regional brain volume was assessed by structural magnetic resonance imaging. Anxious individuals showed persistent, long-term fearful responses to both a human intruder and a model snake, alongside sustained attention (vigilance) to novel cues in a context associated with unpredictable threat. Neurally, high-anxious marmosets showed reduced amygdala serotonin levels, and smaller volumes in a closely connected prefrontal region, the dorsal anterior cingulate cortex. These findings highlight behavioral and neural similarities between trait-like anxiety in marmosets and humans, and set the stage for further investigation of the processes contributing to vulnerability and resilience to affective disorders.

Research paper thumbnail of Prefrontal Serotonin Depletion Affects Reversal Learning But Not Attentional Set Shifting

Journal of Neuroscience, 2005

Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the m... more Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the marmoset monkey impairs performance on a serial discrimination reversal (SDR) task, resulting in perseverative responding to the previously correct stimulus (Clarke et al., 2004). This pattern of impairment is just one example of inflexible responding seen after damage to the PFC, with performance on the SDR task being dependent on the integrity of the orbitofrontal cortex. However, the contribution of 5-HT to other forms of flexible responding, such as attentional set shifting, an ability dependent on lateral PFC (Dias et al., 1996a), is unknown. The present study addresses this issue by examining the effects of 5,7-dihydroxytryptamine-induced PFC 5-HT depletions on the ability to shift attention between two perceptual dimensions of a compound visual stimulus (extradimensional shift). Monkeys with selective PFC 5-HT lesions, despite being impaired in their ability to reverse a stimulus-reward association, were unimpaired in their ability to make an extradimensional shift when compared with sham-operated controls. These findings suggest that 5-HT is critical for flexible responding at the level of changing stimulus-reward contingencies but is not essential for the higher-order shifting of attentional set. Thus, psychological functions dependent on different loci within the PFC are differentially sensitive to serotonergic modulation, a finding of relevance to our understanding of cognitive inflexibility apparent in disorders such as obsessivecompulsive disorder and schizophrenia.

Research paper thumbnail of Role of Central Serotonin in Anticipation of Rewarding and Punishing Outcomes: Effects of Selective Amygdala or Orbitofrontal 5-HT Depletion

Understanding the role of serotonin (or 5-hydroxytryptamine, 5-HT) in aversive processing has bee... more Understanding the role of serotonin (or 5-hydroxytryptamine, 5-HT) in aversive processing has been hampered by the contradictory find-ings, across studies, of increased sensitivity to punishment in terms of subsequent response choice but decreased sensitivity to punish-ment-induced response suppression following gross depletion of central 5-HT. To address this apparent discrepancy, the present study determined whether both effects could be found in the same animals by performing localized 5-HT depletions in the amygdala or orbitofrontal cortex (OFC) of a New World monkey, the common mar-moset. 5-HT depletion in the amygdala impaired response choice on a probabilistic visual discrimination task by increasing the effective-ness of misleading, or false, punishment and reward, and decreased response suppression in a variable interval test of punishment sensi-tivity that employed the same reward and punisher. 5-HT depletion in the OFC also disrupted probabilistic discrimination learning ...

Research paper thumbnail of Differential effects of the inactivation of anterior and posterior orbitofrontal cortex on affective responses to proximal and distal threat, and reward anticipation in the common marmoset

Structural and functional abnormalities of the orbitofrontal cortex (OFC) have been implicated in... more Structural and functional abnormalities of the orbitofrontal cortex (OFC) have been implicated in affective disorders that manifest anxiety-related symptoms. However, research into the functions of primate OFC has predominantly focused on reward-oriented rather than threat-oriented responses. To redress this imbalance, the present study performed a comprehensive analysis of the independent role of 2 distinct subregions of the central OFC (anterior area 11; aOFC and posterior area 13; pOFC) in the processing of distal and proximal threat. Temporary inactivation of both aOFC and pOFC heightened responses to distal threat in the form of an unknown human, but not to proximal threat assessed in a discriminative Pavlovian conditioning task. Inactivation of the aOFC, however, did unexpectedly blunt conditioned threat responses, although the effect was not valence-specific, as conditioned appetitive responses were similarly blunted and appeared restricted to a discriminative version of the task (when both CS- and CS+ are present within a session). Inactivation of the pOFC did not affect conditioned responses to either proximal threat or reward and basal cardiovascular activity was unaffected by manipulations of activity in either subregion. The results highlight the contribution of aOFC and pOFC to regulation of responses to more distal uncertain but not proximal, certain threat and reveal their opposing contribution to that of the immediately adjacent medial OFC, area 14.

Research paper thumbnail of Differential Contribution of Anterior and Posterior Midcingulate Subregions to Distal and Proximal Threat Reactivity in Marmosets

Cerebral Cortex

The midcingulate cortex (MCC) is associated with cognition and emotion regulation. Structural and... more The midcingulate cortex (MCC) is associated with cognition and emotion regulation. Structural and correlational functional evidence suggests that rather than being homogenous, the MCC may have dissociable functions that can be mapped onto distinct subregions. In this study, we use the marmoset monkey to causally investigate the contributions of two proposed subregions of the MCC: the anterior and posterior midcingulate cortices (aMCC and pMCC) to behavioral and cardiovascular correlates of threat processing relevant to anxiety disorders. Transient inactivation of the aMCC decreased anxiety-like responses to a postencounter distal threat, namely an unfamiliar human intruder, while inactivation of the pMCC showed a mild but opposing effect. Furthermore, although inactivation of neither MCC subregions had any effect on basal cardiovascular activity, aMCC inactivation blunted the expression of both cardiovascular and behavioral conditioned responses to a predictable proximal threat (a r...

Research paper thumbnail of Why we need nonhuman primates to study the role of ventromedial prefrontal cortex in the regulation of threat- and reward-elicited responses

Proceedings of the National Academy of Sciences

The ventromedial prefrontal cortex (vmPFC) is consistently implicated in the cognitive and emotio... more The ventromedial prefrontal cortex (vmPFC) is consistently implicated in the cognitive and emotional symptoms of many psychiatric disorders, but the causal mechanisms of its involvement remain unknown. In part, this is because of the poor characterization of the disorders and their symptoms, and the focus of experimental studies in animals on subcortical (rather than cortical) dysregulation. Moreover, even in those experimental studies that have focused on the vmPFC, the preferred animal model for such research has been the rodent, in which there are marked differences in the organization of this region to that seen in humans, and thus the extent of functional homology is unclear. There is also a paucity of well-defined behavioral paradigms suitable for translating disorder-relevant findings across species. With these considerations in mind, we discuss the value of nonhuman primates (NHPs) in bridging the translational gap between human and rodent studies. We focus on recent investi...

Research paper thumbnail of Glutamate within the marmoset anterior hippocampus interacts with area 25 to regulate the behavioral and cardiovascular correlates of high-trait anxiety

The Journal of Neuroscience

High-trait anxiety is a risk factor for the development of affective disorders and has been assoc... more High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studiesofhigh-traitanxietyrevealsdysregulationinprimatecingulateareas25and32andtheanteriorhippocampus(aHipp)androdentstudies revealtheimportanceofaHippglutamatergichypofunction,thecausalinvolvementofaHippglutamateanditsinteractionwiththeseareasinthe primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety.

Research paper thumbnail of Reversal learning in fronto-striatal circuits: a functional, autonomic, and neurochemical analysis

Decision Making, Affect, and Learning: …, 2011

... and a variety of anxiety disorders, including obsessive-compulsive disorder (OCD; Saxena and ... more ... and a variety of anxiety disorders, including obsessive-compulsive disorder (OCD; Saxena and Rauch, 2000; Drevets, 2007; Milad and Rauch ... et al.(2008) and Chudasama and Robbins (2003) with Boulougouris et al.(2007), Kim and Ragozzino (2005) and Ghods-Sharifi et al ...

Research paper thumbnail of A29 Serotonin and Reversal Learning: A Psychological and Neurochemical Analysis

Behavioural Pharmacology, 2005

Research paper thumbnail of Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat

Nature Communications

Stress-related disorders such as depression and anxiety are characterized by enhanced negative em... more Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat.18F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threat contrary to the beneficial effects we have previously demonstrated on over-activation induced re...

Research paper thumbnail of Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates

Proceedings of the National Academy of Sciences

Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to ... more Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset SLC6A4 repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT2A). Thus, we correlated 5HT2A binding potential (BP) and RNA gene expression in 16 SLC6A4 genotyped marmosets with responsivity to 5HT2A antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT2A BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an anxiogenic, dose-dependent response to the human intru...

Research paper thumbnail of A Focus on the Functions of Area 25

Brain Sciences

Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but ... more Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but activity in this area is emerging as a crucial correlate of mood and affective disorder symptomatology. The cortical and subcortical connectivity of area 25 suggests it may act as an interface between the bioregulatory and emotional states that are aberrant in disorders such as depression. However, evidence for such a role is limited because of uncertainty over the functional homologue of area 25 in rodents, which hinders cross-species translation. This emphasizes the need for causal manipulations in monkeys in which area 25, and the prefrontal and cingulate regions in which it is embedded, resemble those of humans more than rodents. In this review, we consider physiological and behavioral evidence from non-pathological and pathological studies in humans and from manipulations of area 25 in monkeys and its putative homologue, the infralimbic cortex (IL), in rodents. We highlight the simi...

Research paper thumbnail of Fractionating Blunted Reward Processing Characteristic of Anhedonia by Over-Activating Primate Subgenual Anterior Cingulate Cortex

Research paper thumbnail of Opposing roles of primate areas 25 and 32 and their putative rodent homologs in the regulation of negative emotion

Proceedings of the National Academy of Sciences of the United States of America, Jan 16, 2017

Disorders of dysregulated negative emotion such as depression and anxiety also feature increased ... more Disorders of dysregulated negative emotion such as depression and anxiety also feature increased cardiovascular mortality and decreased heart-rate variability (HRV). These disorders are correlated with dysfunction within areas 25 and 32 of the ventromedial prefrontal cortex (vmPFC), but a causal relationship between dysregulation of these areas and such symptoms has not been demonstrated. Furthermore, cross-species translation is limited by inconsistent findings between rodent fear extinction and human neuroimaging studies of negative emotion. To reconcile these literatures, we applied an investigative approach to the brain-body interactions at the core of negative emotional dysregulation. We show that, in marmoset monkeys (a nonhuman primate that has far greater vmPFC homology to humans than rodents), areas 25 and 32 have causal yet opposing roles in regulating the cardiovascular and behavioral correlates of negative emotion. In novel Pavlovian fear conditioning and extinction para...

Research paper thumbnail of To be confirmed

To be confirmedThis record is embargoed until publication.This is a placeholder record, which wil... more To be confirmedThis record is embargoed until publication.This is a placeholder record, which will be updated.This work was supported by the MRC [grant number RG62920]

Research paper thumbnail of Prefrontal serotonin and serial reversal learning The effects of serotonin depletion and serotonin 1A receptor manipulation

Behavioural Pharmacology 14(Suppl, Jun 29, 2003

Research paper thumbnail of To be confirmed

Research paper thumbnail of Understanding them to understand ourselves: The importance of NHP research for translational neuroscience

Current Research in Neurobiology

Research paper thumbnail of Hippocampal Interaction With Area 25, but not Area 32, Regulates Marmoset Approach–Avoidance Behavior

Cerebral Cortex, 2019

Affective disorders are associated with increased sensitivity to negative feedback that influence... more Affective disorders are associated with increased sensitivity to negative feedback that influences approach–avoidance decision making. Although neuroimaging studies of these disorders reveal dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp), the causal involvement of these structures and their interaction in the primate brain is unknown. We therefore investigated the effects of localized pharmacological manipulations of areas 25 and 32 and/or the aHipp of the marmoset monkey on performance of an anxiolytic-sensitive instrumental decision-making task in which an approach–avoidance conflict is created by pairing a response with reward and punishment. During control infusions animals avoided punishment, but this bias was reduced by increasing glutamate release within the aHipp or area 32, and inactivation or 5-HT1a antagonism within area 25. Conversely, increasing glutamate release in area 25 enhanced punishment avoidance but, in contrast to previo...

Research paper thumbnail of Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making

Proceedings of the National Academy of Sciences, 2015

Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety... more Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety and mood disorders, but the specific contributions of each region are unknown, including how they gate the impact of threat on decision making. To address this, the effects of GABAergic inactivation of these regions were studied in marmoset monkeys performing an instrumental approach–avoidance decision-making task that is sensitive to changes in anxiety. Inactivation of either region induced a negative bias away from punishment that could be ameliorated with anxiolytic treatment. However, whereas the effects of ventrolateral prefrontal cortex inactivation on punishment avoidance were seen immediately, those of orbitofrontal cortex inactivation were delayed and their expression was dependent upon an amygdala–anterior hippocampal circuit. We propose that these negative biases result from deficits in attentional control and punishment prediction, respectively, and that they provide the bas...

Research paper thumbnail of Serotonergic, Brain Volume and Attentional Correlates of Trait Anxiety in Primates

Neuropsychopharmacology, 2014

Trait anxiety is a risk factor for the development and maintenance of affective disorders, and in... more Trait anxiety is a risk factor for the development and maintenance of affective disorders, and insights into the underlying brain mechanisms are vital for improving treatment and prevention strategies. Translational studies in non-human primates, where targeted neurochemical and genetic manipulations can be made, are critical in view of their close neuroanatomical similarity to humans in brain regions implicated in trait anxiety. Thus, we characterised the serotonergic and regional brain volume correlates of trait-like anxiety in the marmoset monkey. Low-and high-anxious animals were identified by behavioral responses to a human intruder that are known to be sensitive to anxiolytic drug treatment. Extracellular serotonin levels within the amygdala were measured with in vivo microdialysis, at baseline and in response to challenge with the selective serotonin reuptake inhibitor, citalopram. Regional brain volume was assessed by structural magnetic resonance imaging. Anxious individuals showed persistent, long-term fearful responses to both a human intruder and a model snake, alongside sustained attention (vigilance) to novel cues in a context associated with unpredictable threat. Neurally, high-anxious marmosets showed reduced amygdala serotonin levels, and smaller volumes in a closely connected prefrontal region, the dorsal anterior cingulate cortex. These findings highlight behavioral and neural similarities between trait-like anxiety in marmosets and humans, and set the stage for further investigation of the processes contributing to vulnerability and resilience to affective disorders.

Research paper thumbnail of Prefrontal Serotonin Depletion Affects Reversal Learning But Not Attentional Set Shifting

Journal of Neuroscience, 2005

Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the m... more Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the marmoset monkey impairs performance on a serial discrimination reversal (SDR) task, resulting in perseverative responding to the previously correct stimulus (Clarke et al., 2004). This pattern of impairment is just one example of inflexible responding seen after damage to the PFC, with performance on the SDR task being dependent on the integrity of the orbitofrontal cortex. However, the contribution of 5-HT to other forms of flexible responding, such as attentional set shifting, an ability dependent on lateral PFC (Dias et al., 1996a), is unknown. The present study addresses this issue by examining the effects of 5,7-dihydroxytryptamine-induced PFC 5-HT depletions on the ability to shift attention between two perceptual dimensions of a compound visual stimulus (extradimensional shift). Monkeys with selective PFC 5-HT lesions, despite being impaired in their ability to reverse a stimulus-reward association, were unimpaired in their ability to make an extradimensional shift when compared with sham-operated controls. These findings suggest that 5-HT is critical for flexible responding at the level of changing stimulus-reward contingencies but is not essential for the higher-order shifting of attentional set. Thus, psychological functions dependent on different loci within the PFC are differentially sensitive to serotonergic modulation, a finding of relevance to our understanding of cognitive inflexibility apparent in disorders such as obsessivecompulsive disorder and schizophrenia.

Research paper thumbnail of Role of Central Serotonin in Anticipation of Rewarding and Punishing Outcomes: Effects of Selective Amygdala or Orbitofrontal 5-HT Depletion

Understanding the role of serotonin (or 5-hydroxytryptamine, 5-HT) in aversive processing has bee... more Understanding the role of serotonin (or 5-hydroxytryptamine, 5-HT) in aversive processing has been hampered by the contradictory find-ings, across studies, of increased sensitivity to punishment in terms of subsequent response choice but decreased sensitivity to punish-ment-induced response suppression following gross depletion of central 5-HT. To address this apparent discrepancy, the present study determined whether both effects could be found in the same animals by performing localized 5-HT depletions in the amygdala or orbitofrontal cortex (OFC) of a New World monkey, the common mar-moset. 5-HT depletion in the amygdala impaired response choice on a probabilistic visual discrimination task by increasing the effective-ness of misleading, or false, punishment and reward, and decreased response suppression in a variable interval test of punishment sensi-tivity that employed the same reward and punisher. 5-HT depletion in the OFC also disrupted probabilistic discrimination learning ...

Research paper thumbnail of Differential effects of the inactivation of anterior and posterior orbitofrontal cortex on affective responses to proximal and distal threat, and reward anticipation in the common marmoset

Structural and functional abnormalities of the orbitofrontal cortex (OFC) have been implicated in... more Structural and functional abnormalities of the orbitofrontal cortex (OFC) have been implicated in affective disorders that manifest anxiety-related symptoms. However, research into the functions of primate OFC has predominantly focused on reward-oriented rather than threat-oriented responses. To redress this imbalance, the present study performed a comprehensive analysis of the independent role of 2 distinct subregions of the central OFC (anterior area 11; aOFC and posterior area 13; pOFC) in the processing of distal and proximal threat. Temporary inactivation of both aOFC and pOFC heightened responses to distal threat in the form of an unknown human, but not to proximal threat assessed in a discriminative Pavlovian conditioning task. Inactivation of the aOFC, however, did unexpectedly blunt conditioned threat responses, although the effect was not valence-specific, as conditioned appetitive responses were similarly blunted and appeared restricted to a discriminative version of the task (when both CS- and CS+ are present within a session). Inactivation of the pOFC did not affect conditioned responses to either proximal threat or reward and basal cardiovascular activity was unaffected by manipulations of activity in either subregion. The results highlight the contribution of aOFC and pOFC to regulation of responses to more distal uncertain but not proximal, certain threat and reveal their opposing contribution to that of the immediately adjacent medial OFC, area 14.

Research paper thumbnail of Differential Contribution of Anterior and Posterior Midcingulate Subregions to Distal and Proximal Threat Reactivity in Marmosets

Cerebral Cortex

The midcingulate cortex (MCC) is associated with cognition and emotion regulation. Structural and... more The midcingulate cortex (MCC) is associated with cognition and emotion regulation. Structural and correlational functional evidence suggests that rather than being homogenous, the MCC may have dissociable functions that can be mapped onto distinct subregions. In this study, we use the marmoset monkey to causally investigate the contributions of two proposed subregions of the MCC: the anterior and posterior midcingulate cortices (aMCC and pMCC) to behavioral and cardiovascular correlates of threat processing relevant to anxiety disorders. Transient inactivation of the aMCC decreased anxiety-like responses to a postencounter distal threat, namely an unfamiliar human intruder, while inactivation of the pMCC showed a mild but opposing effect. Furthermore, although inactivation of neither MCC subregions had any effect on basal cardiovascular activity, aMCC inactivation blunted the expression of both cardiovascular and behavioral conditioned responses to a predictable proximal threat (a r...

Research paper thumbnail of Why we need nonhuman primates to study the role of ventromedial prefrontal cortex in the regulation of threat- and reward-elicited responses

Proceedings of the National Academy of Sciences

The ventromedial prefrontal cortex (vmPFC) is consistently implicated in the cognitive and emotio... more The ventromedial prefrontal cortex (vmPFC) is consistently implicated in the cognitive and emotional symptoms of many psychiatric disorders, but the causal mechanisms of its involvement remain unknown. In part, this is because of the poor characterization of the disorders and their symptoms, and the focus of experimental studies in animals on subcortical (rather than cortical) dysregulation. Moreover, even in those experimental studies that have focused on the vmPFC, the preferred animal model for such research has been the rodent, in which there are marked differences in the organization of this region to that seen in humans, and thus the extent of functional homology is unclear. There is also a paucity of well-defined behavioral paradigms suitable for translating disorder-relevant findings across species. With these considerations in mind, we discuss the value of nonhuman primates (NHPs) in bridging the translational gap between human and rodent studies. We focus on recent investi...

Research paper thumbnail of Glutamate within the marmoset anterior hippocampus interacts with area 25 to regulate the behavioral and cardiovascular correlates of high-trait anxiety

The Journal of Neuroscience

High-trait anxiety is a risk factor for the development of affective disorders and has been assoc... more High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studiesofhigh-traitanxietyrevealsdysregulationinprimatecingulateareas25and32andtheanteriorhippocampus(aHipp)androdentstudies revealtheimportanceofaHippglutamatergichypofunction,thecausalinvolvementofaHippglutamateanditsinteractionwiththeseareasinthe primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety.

Research paper thumbnail of Reversal learning in fronto-striatal circuits: a functional, autonomic, and neurochemical analysis

Decision Making, Affect, and Learning: …, 2011

... and a variety of anxiety disorders, including obsessive-compulsive disorder (OCD; Saxena and ... more ... and a variety of anxiety disorders, including obsessive-compulsive disorder (OCD; Saxena and Rauch, 2000; Drevets, 2007; Milad and Rauch ... et al.(2008) and Chudasama and Robbins (2003) with Boulougouris et al.(2007), Kim and Ragozzino (2005) and Ghods-Sharifi et al ...

Research paper thumbnail of A29 Serotonin and Reversal Learning: A Psychological and Neurochemical Analysis

Behavioural Pharmacology, 2005

Research paper thumbnail of Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat

Nature Communications

Stress-related disorders such as depression and anxiety are characterized by enhanced negative em... more Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat.18F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threat contrary to the beneficial effects we have previously demonstrated on over-activation induced re...

Research paper thumbnail of Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates

Proceedings of the National Academy of Sciences

Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to ... more Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset SLC6A4 repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT2A). Thus, we correlated 5HT2A binding potential (BP) and RNA gene expression in 16 SLC6A4 genotyped marmosets with responsivity to 5HT2A antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT2A BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an anxiogenic, dose-dependent response to the human intru...

Research paper thumbnail of A Focus on the Functions of Area 25

Brain Sciences

Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but ... more Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but activity in this area is emerging as a crucial correlate of mood and affective disorder symptomatology. The cortical and subcortical connectivity of area 25 suggests it may act as an interface between the bioregulatory and emotional states that are aberrant in disorders such as depression. However, evidence for such a role is limited because of uncertainty over the functional homologue of area 25 in rodents, which hinders cross-species translation. This emphasizes the need for causal manipulations in monkeys in which area 25, and the prefrontal and cingulate regions in which it is embedded, resemble those of humans more than rodents. In this review, we consider physiological and behavioral evidence from non-pathological and pathological studies in humans and from manipulations of area 25 in monkeys and its putative homologue, the infralimbic cortex (IL), in rodents. We highlight the simi...

Research paper thumbnail of Fractionating Blunted Reward Processing Characteristic of Anhedonia by Over-Activating Primate Subgenual Anterior Cingulate Cortex

Research paper thumbnail of Opposing roles of primate areas 25 and 32 and their putative rodent homologs in the regulation of negative emotion

Proceedings of the National Academy of Sciences of the United States of America, Jan 16, 2017

Disorders of dysregulated negative emotion such as depression and anxiety also feature increased ... more Disorders of dysregulated negative emotion such as depression and anxiety also feature increased cardiovascular mortality and decreased heart-rate variability (HRV). These disorders are correlated with dysfunction within areas 25 and 32 of the ventromedial prefrontal cortex (vmPFC), but a causal relationship between dysregulation of these areas and such symptoms has not been demonstrated. Furthermore, cross-species translation is limited by inconsistent findings between rodent fear extinction and human neuroimaging studies of negative emotion. To reconcile these literatures, we applied an investigative approach to the brain-body interactions at the core of negative emotional dysregulation. We show that, in marmoset monkeys (a nonhuman primate that has far greater vmPFC homology to humans than rodents), areas 25 and 32 have causal yet opposing roles in regulating the cardiovascular and behavioral correlates of negative emotion. In novel Pavlovian fear conditioning and extinction para...