Special Issue "The Multi-Dimensional Contributions of Prefrontal Circuits to Emotion Regulation during Adulthood and Critical Stages of Development"

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Systems Neuroscience".

Deadline for manuscript submissions: closed (30 April 2019)

Special Issue Editor

Guest Editor
Prof. Angela Roberts

Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge, England
Website | E-Mail
Interests: Emotion regulation, Prefrontal cortex, Neuromodulation

Special Issue Information

Dear Colleagues,

The prefrontal cortex (PFC) plays a pivotal role in regulating our emotions as shown by the marked alterations in activity within prefrontal circuits that accompany mood and anxiety disorders. The importance of ventromedial regions in emotion regulation, including the ventral sector of the medial PFC, the medial sector of the orbital cortex and subgenual cingulate cortex, have been recognized for a long time. However, it is increasingly apparent that lateral and dorsal regions of the PFC, as well as neighbouring dorsal anterior cingulate cortex, also play a role. Defining the underlying psychological mechanisms by which these functionally distinct regions modulate positive and negative emotions and the nature and extent of their interactions, is a critical step towards better stratification of the symptoms of mood and anxiety disorders, that will ultimately lead to more effective, individualised treatment strategies. Since many disorders of emotion regulation have their onset during childhood and adolescence it is also important to extend our understanding of these prefrontal circuits in development. Specifically, to determine whether they exhibit differential sensitivity to perturbations by known risk factors e.g. stress and inflammation, at distinct developmental epochs. This special issue aims to bring together the most recent research in humans and other animals that addresses these important issues and in doing so, to highlight the value of the translational  approach.

Prof. Angela Roberts
Guest Editor

Manuscript Submission Information

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Keywords

  • Emotion regulation
  • Prefrontal circuits
  • Translational Neuroscience
  • Developmental models of psychiatric symptoms

Published Papers (10 papers)

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Research

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Open AccessArticle
Impaired Fear Extinction Recall in Serotonin Transporter Knockout Rats Is Transiently Alleviated during Adolescence
Brain Sci. 2019, 9(5), 118; https://doi.org/10.3390/brainsci9050118
Received: 27 March 2019 / Revised: 21 May 2019 / Accepted: 21 May 2019 / Published: 22 May 2019
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Abstract
Adolescence is a developmental phase characterized by emotional turmoil and coincides with the emergence of affective disorders. Inherited serotonin transporter (5-HTT) downregulation in humans increases sensitivity to these disorders. To reveal whether and how 5-HTT gene variance affects fear-driven behavior in adolescence, we [...] Read more.
Adolescence is a developmental phase characterized by emotional turmoil and coincides with the emergence of affective disorders. Inherited serotonin transporter (5-HTT) downregulation in humans increases sensitivity to these disorders. To reveal whether and how 5-HTT gene variance affects fear-driven behavior in adolescence, we tested wildtype and serotonin transporter knockout (5-HTT−/−) rats of preadolescent, adolescent, and adult age for cued fear extinction and extinction recall. To analyze neural circuit function, we quantified inhibitory synaptic contacts and, through RT-PCR, the expression of c-Fos, brain-derived neurotrophic factor (BDNF), and NDMA receptor subunits, in the medial prefrontal cortex (mPFC) and amygdala. Remarkably, the impaired recall of conditioned fear that characterizes preadolescent and adult 5-HTT−/− rats was transiently normalized during adolescence. This did not relate to altered inhibitory neurotransmission, since mPFC inhibitory immunoreactivity was reduced in 5-HTT−/− rats across all ages and unaffected in the amygdala. Rather, since mPFC (but not amygdala) c-Fos expression and NMDA receptor subunit 1 expression were reduced in 5-HTT−/− rats during adolescence, and since PFC c-Fos correlated negatively with fear extinction recall, the temporary normalization of fear extinction during adolescence could relate to altered plasticity in the developing mPFC. Full article
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Open AccessArticle
Reliability of Fronto–Amygdala Coupling during Emotional Face Processing
Brain Sci. 2019, 9(4), 89; https://doi.org/10.3390/brainsci9040089
Received: 28 March 2019 / Revised: 4 April 2019 / Accepted: 9 April 2019 / Published: 19 April 2019
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Abstract
One of the most exciting translational prospects for brain imaging research is the potential use of functional magnetic resonance imaging (fMRI) ‘biomarkers’ to predict an individual’s risk of developing a neuropsychiatric disorder or the likelihood of responding to a particular intervention. This proposal [...] Read more.
One of the most exciting translational prospects for brain imaging research is the potential use of functional magnetic resonance imaging (fMRI) ‘biomarkers’ to predict an individual’s risk of developing a neuropsychiatric disorder or the likelihood of responding to a particular intervention. This proposal depends critically on reliable measurements at the level of the individual. Several previous studies have reported relatively poor reliability of amygdala activation during emotional face processing, a key putative fMRI ‘biomarker’. However, the reliability of amygdala connectivity measures is much less well understood. Here, we assessed the reliability of task-modulated coupling between three seed regions (left and right amygdala and the subgenual anterior cingulate cortex) and the dorsomedial frontal/cingulate cortex (DMFC), measured using a psychophysiological interaction analysis in 29 healthy individuals scanned approximately two weeks apart. We performed two runs on each day of three different emotional face-processing tasks: emotion identification, emotion matching, and gender classification. We tested both between-day reliability and within-day (between-run) reliability. We found good-to-excellent within-subject reliability of amygdala–DMFC coupling, both between days (in two tasks), and within day (in one task). This suggests that disorder-relevant regional coupling may be sufficiently reliable to be used as a predictor of treatment response or clinical risk in future clinical studies. Full article
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Open AccessArticle
Loss of Hierarchical Control by Occasion Setters Following Lesions of the Prelimbic and Infralimbic Medial Prefrontal Cortex in Rats
Brain Sci. 2019, 9(3), 48; https://doi.org/10.3390/brainsci9030048
Received: 31 January 2019 / Revised: 21 February 2019 / Accepted: 26 February 2019 / Published: 26 February 2019
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Abstract
Recent work suggests complementary roles of the prelimbic and infralimbic regions of the rat medial prefrontal cortex in cognitive control processes, with the prelimbic cortex implicated in top-down modulation of associations and the infralimbic cortex playing a role in the inhibition of inappropriate [...] Read more.
Recent work suggests complementary roles of the prelimbic and infralimbic regions of the rat medial prefrontal cortex in cognitive control processes, with the prelimbic cortex implicated in top-down modulation of associations and the infralimbic cortex playing a role in the inhibition of inappropriate responses. Following selective lesions made to prelimbic or infralimbic regions (or control sham-surgery) rats received simultaneous training on Pavlovian feature negative (A+, XA−) and feature positive (B−, YB+) discriminations designed to lead to hierarchical occasion-setting control by the features (X, Y) over their respective targets (A, B). Evidence for hierarchical control was assessed in a transfer test in which features and targets were swapped (YA, XB). All groups were able to learn the feature negative and feature positive discriminations. Whilst sham-lesioned animals showed no transfer of control by features to novel targets (a hallmark of hierarchical control), rats with lesions of prelimbic or infralimbic regions showed evidence of transfer from the positive feature (Y) to the negative target (A), and from the negative feature (X) to the positive target (B; although this only achieved significance in infralimbic-lesioned animals). These data indicate that damage to either of these regions disrupts hierarchical occasion-setting control, extending our knowledge of their role in cognitive control to encompass flexible behaviours dictated by discrete cues. Full article
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Open AccessArticle
Decreased Neuron Density and Increased Glia Density in the Ventromedial Prefrontal Cortex (Brodmann Area 25) in Williams Syndrome
Brain Sci. 2018, 8(12), 209; https://doi.org/10.3390/brainsci8120209
Received: 25 September 2018 / Revised: 22 November 2018 / Accepted: 27 November 2018 / Published: 29 November 2018
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Abstract
Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25–28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in [...] Read more.
Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25–28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS. Full article
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Review

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Open AccessReview
A Focus on the Functions of Area 25
Brain Sci. 2019, 9(6), 129; https://doi.org/10.3390/brainsci9060129
Received: 18 March 2019 / Revised: 24 May 2019 / Accepted: 29 May 2019 / Published: 3 June 2019
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Abstract
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 [...] Read 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 similarities between area 25 function in monkeys and IL function in rodents with respect to the regulation of reward-driven responses, but also the apparent inconsistencies in the regulation of threat responses, not only between the rodent and monkey literatures, but also within the rodent literature. Overall, we provide evidence for a causal role of area 25 in both the enhanced negative affect and decreased positive affect that is characteristic of affective disorders, and the cardiovascular and endocrine perturbations that accompany these mood changes. We end with a brief consideration of how future studies should be tailored to best translate these findings into the clinic. Full article
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Open AccessReview
Loss of Prefrontal Cortical Higher Cognition with Uncontrollable Stress: Molecular Mechanisms, Changes with Age, and Relevance to Treatment
Brain Sci. 2019, 9(5), 113; https://doi.org/10.3390/brainsci9050113
Received: 17 April 2019 / Revised: 13 May 2019 / Accepted: 13 May 2019 / Published: 17 May 2019
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Abstract
The newly evolved prefrontal cortex (PFC) generates goals for “top-down” control of behavior, thought, and emotion. However, these circuits are especially vulnerable to uncontrollable stress, with powerful, intracellular mechanisms that rapidly take the PFC “off-line.” High levels of norepinephrine and dopamine released during [...] Read more.
The newly evolved prefrontal cortex (PFC) generates goals for “top-down” control of behavior, thought, and emotion. However, these circuits are especially vulnerable to uncontrollable stress, with powerful, intracellular mechanisms that rapidly take the PFC “off-line.” High levels of norepinephrine and dopamine released during stress engage α1-AR and D1R, which activate feedforward calcium-cAMP signaling pathways that open nearby potassium channels to weaken connectivity and reduce PFC cell firing. Sustained weakening with chronic stress leads to atrophy of dendrites and spines. Understanding these signaling events helps to explain the increased susceptibility of the PFC to stress pathology during adolescence, when dopamine expression is increased in the PFC, and with advanced age, when the molecular “brakes” on stress signaling are diminished by loss of phosphodiesterases. These mechanisms have also led to pharmacological treatments for stress-related disorders, including guanfacine treatment of childhood trauma, and prazosin treatment of veterans and civilians with post-traumatic stress disorder. Full article
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Open AccessReview
Positive and Negative Emotion Regulation in Adolescence: Links to Anxiety and Depression
Brain Sci. 2019, 9(4), 76; https://doi.org/10.3390/brainsci9040076
Received: 11 February 2019 / Revised: 15 March 2019 / Accepted: 26 March 2019 / Published: 29 March 2019
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Abstract
Emotion regulation skills develop substantially across adolescence, a period characterized by emotional challenges and developing regulatory neural circuitry. Adolescence is also a risk period for the new onset of anxiety and depressive disorders, psychopathologies which have long been associated with disruptions in regulation [...] Read more.
Emotion regulation skills develop substantially across adolescence, a period characterized by emotional challenges and developing regulatory neural circuitry. Adolescence is also a risk period for the new onset of anxiety and depressive disorders, psychopathologies which have long been associated with disruptions in regulation of positive and negative emotions. This paper reviews the current understanding of the role of disrupted emotion regulation in adolescent anxiety and depression, describing findings from self-report, behavioral, peripheral psychophysiological, and neural measures. Self-report studies robustly identified associations between emotion dysregulation and adolescent anxiety and depression. Findings from behavioral and psychophysiological studies are mixed, with some suggestion of specific impairments in reappraisal in anxiety. Results from neuroimaging studies broadly implicate altered functioning of amygdala-prefrontal cortical circuitries, although again, findings are mixed regarding specific patterns of altered neural functioning. Future work may benefit from focusing on designs that contrast effects of specific regulatory strategies, and isolate changes in emotional regulation from emotional reactivity. Approaches to improve treatments based on empirical evidence of disrupted emotion regulation in adolescents are also discussed. Future intervention studies might consider training and measurement of specific strategies in adolescents to better understand the role of emotion regulation as a treatment mechanism. Full article
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Open AccessReview
Sketching the Power of Machine Learning to Decrypt a Neural Systems Model of Behavior
Brain Sci. 2019, 9(3), 67; https://doi.org/10.3390/brainsci9030067
Received: 30 January 2019 / Revised: 27 February 2019 / Accepted: 14 March 2019 / Published: 20 March 2019
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Abstract
Uncovering brain-behavior mechanisms is the ultimate goal of neuroscience. A formidable amount of discoveries has been made in the past 50 years, but the very essence of brain-behavior mechanisms still escapes us. The recent exploitation of machine learning (ML) tools in neuroscience opens [...] Read more.
Uncovering brain-behavior mechanisms is the ultimate goal of neuroscience. A formidable amount of discoveries has been made in the past 50 years, but the very essence of brain-behavior mechanisms still escapes us. The recent exploitation of machine learning (ML) tools in neuroscience opens new avenues for illuminating these mechanisms. A key advantage of ML is to enable the treatment of large data, combing highly complex processes. This essay provides a glimpse of how ML tools could test a heuristic neural systems model of motivated behavior, the triadic neural systems model, which was designed to understand behavioral transitions in adolescence. This essay previews analytic strategies, using fictitious examples, to demonstrate the potential power of ML to decrypt the neural networks of motivated behavior, generically and across development. Of note, our intent is not to provide a tutorial for these analyses nor a pipeline. The ultimate objective is to relate, as simply as possible, how complex neuroscience constructs can benefit from ML methods for validation and further discovery. By extension, the present work provides a guide that can serve to query the mechanisms underlying the contributions of prefrontal circuits to emotion regulation. The target audience concerns mainly clinical neuroscientists. As a caveat, this broad approach leaves gaps, for which references to comprehensive publications are provided. Full article
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Open AccessReview
Maturational Changes in Prefrontal and Amygdala Circuits in Adolescence: Implications for Understanding Fear Inhibition during a Vulnerable Period of Development
Brain Sci. 2019, 9(3), 65; https://doi.org/10.3390/brainsci9030065
Received: 6 February 2019 / Revised: 13 March 2019 / Accepted: 14 March 2019 / Published: 18 March 2019
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Abstract
Anxiety disorders that develop in adolescence represent a significant burden and are particularly challenging to treat, due in no small part to the high occurrence of relapse in this age group following exposure therapy. This pattern of persistent fear is preserved across species; [...] Read more.
Anxiety disorders that develop in adolescence represent a significant burden and are particularly challenging to treat, due in no small part to the high occurrence of relapse in this age group following exposure therapy. This pattern of persistent fear is preserved across species; relative to those younger and older, adolescents consistently show poorer extinction, a key process underpinning exposure therapy. This suggests that the neural processes underlying fear extinction are temporarily but profoundly compromised during adolescence. The formation, retrieval, and modification of fear- and extinction-associated memories are regulated by a forebrain network consisting of the prefrontal cortex (PFC), the amygdala, and the hippocampus. These regions undergo robust maturational changes in early life, with unique alterations in structure and function occurring throughout adolescence. In this review, we focus primarily on two of these regions—the PFC and the amygdala—and discuss how changes in plasticity, synaptic transmission, inhibition/excitation, and connectivity (including modulation by hippocampal afferents to the PFC) may contribute to transient deficits in extinction retention. We end with a brief consideration of how exposure to stress during this adolescent window of vulnerability can permanently disrupt neurodevelopment, leading to lasting impairments in pathways of emotional regulation. Full article
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Other

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Open AccessPerspective
What Role Does the Prefrontal Cortex Play in the Processing of Negative and Positive Stimuli in Adolescent Depression?
Brain Sci. 2019, 9(5), 104; https://doi.org/10.3390/brainsci9050104
Received: 27 March 2019 / Revised: 30 April 2019 / Accepted: 3 May 2019 / Published: 7 May 2019
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Abstract
This perspective describes the contribution of the prefrontal cortex to the symptoms of depression in adolescents and specifically the processing of positive and negative information. We also discuss how the prefrontal cortex (PFC) activity and connectivity during tasks and at rest might be [...] Read more.
This perspective describes the contribution of the prefrontal cortex to the symptoms of depression in adolescents and specifically the processing of positive and negative information. We also discuss how the prefrontal cortex (PFC) activity and connectivity during tasks and at rest might be a biomarker for risk for depression onset in adolescents. We include some of our recent work examining not only the anticipation and consummation of positive and negative stimuli, but also effort to gain positive and avoid negative stimuli in adolescents with depression. We find, using region of interest analyses, that the PFC is blunted in those with depression compared to controls across the different phases but in a larger sample the PFC is blunted in the anticipatory phase of the study only. Taken together, in adolescents with depression there is evidence for dysfunctional PFC activity across different studies and tasks. However, the data are limited with small sample sizes and inconsistent findings. Larger longitudinal studies with more detailed assessments of symptoms across the spectrum are needed to further evaluate the role of the PFC in adolescent depression. Full article
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