Prefrontal-amygdala Circuits Research Articles

Role of stress and early-life stress in the pathogeny of inflammatory bowel disease.

Numerous preclinical and clinical studies have shown that stress is one of the main environmental factor playing a significant role in the pathogeny and life-course of bowel diseases. However, stressful events that occur early in life, even during the fetal life, leave different traces within the central nervous system, in area involved in stress response and autonomic network but also in emotion, cognition and memory regulation. Early-life stress can disrupt the prefrontal-amygdala circuit thus favoring an imbalance of the autonomic nervous system and the hypothalamic-pituitary adrenal axis, resulting in anxiety-like behaviors. The down regulation of vagus nerve and cholinergic anti-inflammatory pathway favors pro-inflammatory conditions. Recent data suggest that emotional abuse at early life are aggravating risk factors in inflammatory bowel disease. This review aims to unravel the mechanisms that explain the consequences of early life events and stress in the pathophysiology of inflammatory bowel disease and their mental co-morbidities. A review of therapeutic potential will also be covered.

Transdiagnostic depression severity and its relationship to global and prefrontal-amygdala structural properties in people with major depression and post-traumatic stress disorder.

While some studies have used a transdiagnostic approach to relate depression to metabolic or functional brain alterations, the structural substrate of depression across clinical diagnostic categories is underexplored. In a cross-sectional study of 52 patients with major depressive disorder and 51 with post-traumatic stress disorder, drug-naïve, and spanning mild to severe depression severity, we examined transdiagnostic depressive correlates with regional gray matter volume and the topological properties of gray matter-based networks. Locally, transdiagnostic depression severity correlated positively with gray matter volume in the right middle frontal gyrus and negatively with nodal topological properties of gray matter-based networks in the right amygdala. Globally, transdiagnostic depression severity correlated positively with normalized characteristic path length, a measure implying brain integration ability. Compared with 62 healthy control participants, both major depressive disorder and post-traumatic stress disorder patients showed altered nodal properties in regions of the fronto-limbic-striatal circuit, and global topological organization in major depressive disorder in particular was characterized by decreased integration and segregation. These findings provide evidence for a gray matter-based structural substrate underpinning depression, with the prefrontal-amygdala circuit a potential predictive marker for depressive symptoms across clinical diagnostic categories.

Developmental shift in testosterone influence on prefrontal emotion control.

A paradox of testosterone effects is seen in adolescents versus adults in social emotional approach-avoidance behavior. During adolescence, high testosterone levels are associated with increased anterior prefrontal (aPFC) involvement in emotion control, whereas during adulthood this neuro-endocrine relation is reversed. Rodent work shows that, during puberty, testosterone transitions from a neuro-developmental to a social-sexual activating hormone. In this study, we explored whether this functional transition is also present in human adolescents and young adults. Using a prospective longitudinal design, we investigated the role of testosterone on neural control of social emotional behavior during the transitions from middle to late adolescence and into young adulthood. Seventy-one individuals (tested at ages 14, 17, and 20 years) performed an fMRI-adapted approach-avoidance (AA) task involving automatic and controlled actions in response to social emotional stimuli. In line with predictions from animal models, the effect of testosterone on aPFC engagement decreased between middle and late adolescence, and shifted into an activational role by young adulthood-impeding neural control of emotions. This change in testosterone function was accompanied by increased testosterone-modulated amygdala reactivity. These findings qualify the testosterone-dependent maturation of the prefrontal-amygdala circuit supporting emotion control during the transition from middle adolescence into young adulthood.

A comparative study of gray matter volumetric alterations in adults with attention deficit hyperactivity disorder and bipolar disorder type I

BackgroundAttention deficit hyperactivity disorder (ADHD) and bipolar disorder type I (BD-Ι) share great overlapping symptoms and are highly comorbid. We aimed to compare and obtain the common and distinct gray matter volume (GMV) patterns in adult patients. MethodWe searched four databases to include whole-brain voxel-based morphometry studies and compared the GMV patterns between ADHD and healthy controls (HCs), between BD-I and HCs, and between ADHD and BD-I using anisotropic effect-size signed differential mapping software. ResultsWe included 677 ADHD and 452 BD-Ι patients. Compared with HCs, ADHD patients showed smaller GMV in the anterior cingulate cortex (ACC) and supramarginal gyrus but a larger caudate nucleus. Compared with HCs, BD-Ι patients showed smaller GMV in the orbitofrontal cortex, parahippocampal gyrus, and amygdala. No common GMV alterations were found, whereas ADHD showed the smaller ACC and larger amygdala relative to BD-Ι. Subgroup analyses revealed the larger insula in manic patients, which was positively associated with the Young Mania Rating Scale. The decreased median cingulate cortex (MCC) was positively associated with the ages in ADHD, whereas the MCC was negatively associated with the ages in BD-Ι. LimitationsAll included data were cross-sectional; Potential effects of medication and disease course were not analyzed due to the limited data. ConclusionsADHD showed altered GMV in the frontal-striatal frontal-parietal circuits, and BD-Ι showed altered GMV in the prefrontal-amygdala circuit. These findings could contribute to a better understanding of the neuropathology of the two disorders.

The antidepressant effect of cognitive reappraisal training on individuals cognitively vulnerable to depression: Could cognitive bias be modified through the prefrontal-amygdala circuits?

Cognitive reappraisal (CR) is one of the core treatment components of cognitive behavioral therapy (CBT) and is the gold standard treatment for major depressive disorders. Accumulating evidence indicates that cognitive reappraisal could function as a protective factor of cognitive vulnerability to depression. However, the neural mechanism by which CR training reduces cognitive vulnerability to depression is unclear. There is ample evidence that the prefrontal–amygdala circuit is involved in CR. This study proposes a novel cognitive bias model of CR training which hypothesizes that CR training may improve the generation ability of CR with altered prefrontal–amygdala functional activation/connectivity, thus reducing negative cognitive bias (negative attention bias, negative memory bias, negative interpretation bias, and/or negative rumination bias) and alleviating depressive symptoms. This study aims to (1) explore whether there is abnormal CR strategy generation ability in individuals who are cognitively vulnerable to depression; (2) test the hypothesis that CR training alleviates depressive symptoms through the mediators of cognitive bias (interpretation bias and/or rumination bias); (3) explore the neural mechanism by which CR training may enhance the ability of CR strategy generation; and (4) examine the short- and long-term effects of CR training on the reduction in depressive symptoms in individuals who are cognitively vulnerable to depression following intervention and 6 months later. The study is promising, providing theoretical and practical evidence for the early intervention of depression-vulnerable individuals.

Selective Prefrontal-Amygdala Circuit Interactions Underlie Social and Nonsocial Valuation in Rhesus Macaques.

Lesion studies in macaques suggest dissociable functions of the orbitofrontal cortex (OFC) and medial frontal cortex (MFC), with OFC being essential for goal-directed decision-making and MFC supporting social cognition. Bilateral amygdala damage results in impairments in both of these domains. There are extensive reciprocal connections between these prefrontal areas and the amygdala; however, it is not known whether the dissociable roles of OFC and MFC depend on functional interactions with the amygdala. To test this possibility, we compared the performance of male rhesus macaques (Macaca mulatta) with crossed surgical disconnection of the amygdala and either MFC (MFC × AMY, n = 4) or OFC (OFC × AMY, n = 4) to a group of unoperated controls (CON, n = 5). All monkeys were assessed for their performance on two tasks to measure the following: (1) food-retrieval latencies while viewing videos of social and nonsocial stimuli in a test of social interest and (2) object choices based on current food value using reinforcer devaluation in a test of goal-directed decision-making. Compared with the CON group, the MFC × AMY group, but not the OFC × AMY group, showed significantly reduced food-retrieval latencies while viewing videos of conspecifics, indicating reduced social valuation and/or interest. By contrast, on the devaluation task, group OFC × AMY, but not group MFC × AMY, displayed deficits on object choices following changes in food value. These data indicate that the MFC and OFC must functionally interact with the amygdala to support normative social and nonsocial valuation, respectively.SIGNIFICANCE STATEMENT Ascribing value to conspecifics (social) versus objects (nonsocial) may be supported by distinct but overlapping brain networks. Here, we test whether two nonoverlapping regions of the prefrontal cortex, the medial frontal cortex and the orbitofrontal cortex, must causally interact with the amygdala to sustain social valuation and goal-directed decision-making, respectively. We found that these prefrontal-amygdala circuits are functionally dissociable, lending support for the idea that medial frontal and orbital frontal cortex make independent contributions to cognitive appraisals of the environment. These data provide a neural framework for distinct value assignment processes and may enhance our understanding of the cognitive deficits observed following brain injury or in the development of mental health disorders.

Prefrontal–amygdala circuits in social decision-making

An increasing amount of research effort is being directed toward investigating the neural bases of social cognition from a systems neuroscience perspective. Evidence from multiple animal species is beginning to provide a mechanistic understanding of the substrates of social behaviors at multiple levels of neurobiology, ranging from those underlying high-level social constructs in humans and their more rudimentary underpinnings in monkeys to circuit-level and cell-type-specific instantiations of social behaviors in rodents. Here we review literature examining the neural mechanisms of social decision-making in humans, non-human primates and rodents, focusing on the amygdala and the medial and orbital prefrontal cortical regions and their functional interactions. We also discuss how the neuropeptide oxytocin impacts these circuits and their downstream effects on social behaviors. Overall, we conclude that regulated interactions of neuronal activity in the prefrontal-amygdala pathways critically contribute to social decision-making in the brains of primates and rodents.

New Insights from 22-kHz Ultrasonic Vocalizations to Characterize Fear Responses: Relationship with Respiration and Brain Oscillatory Dynamics.

Fear behavior depends on interactions between the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), and the expression of fear involves synchronized activity in θ and γ oscillatory activities. In addition, freezing, the most classical measure of fear response in rodents, temporally coincides with the development of sustained 4-Hz oscillations in prefrontal-amygdala circuits. Interestingly, these oscillations were recently shown to depend on the animal's respiratory rhythm, supporting the growing body of evidence pinpointing the influence of nasal breathing on brain rhythms. During fearful states, rats also emit 22-kHz ultrasonic vocalizations (USVs) which drastically affect respiratory rhythm. However, the relationship between 22-kHz USV, respiration, and brain oscillatory activities is still unknown. Yet such information is crucial for a comprehensive understanding of how the different components of fear response collectively modulate rat's brain neural dynamics. Here, we trained male rats in an odor fear conditioning task, while recording simultaneously local field potentials (LFPs) in BLA, mPFC, and olfactory piriform cortex (PIR), together with USV calls and respiration. We show that USV calls coincide with an increase in delta and gamma power and a decrease in theta power. In addition, during USV emission in contrast to silent freezing, there is no coupling between respiratory rate and delta frequency, and the modulation of fast oscillations amplitude relative to the phase of respiration is modified. We propose that sequences of USV calls could result in a differential gating of information within the network of structures sustaining fear behavior, thus potentially modulating fear expression/memory.

Effect of Prefrontal Cortex Stimulation on Regulation of Amygdala Response to Threat in Individuals With Trait Anxiety

Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) is under clinical investigation as a treatment for major depressive disorder. However, the mechanisms of action are unclear, and there is a lack of neuroimaging evidence, particularly among individuals with affective dysfunction. Furthermore, there is no direct causal evidence among humans that the prefrontal-amygdala circuit functions as described in animal models (ie, that increasing activity in prefrontal cortical control regions inhibits amygdala response to threat). To determine whether stimulation of the prefrontal cortex reduces amygdala threat reactivity in individuals with trait anxiety. This community-based randomized clinical trial used a double-blind, within-participants design (2 imaging sessions per participant). Eighteen women with high trait anxiety (age range, 18-42 years) who scored greater than 45 on the trait measure of State-Trait Anxiety Inventory were randomized to receive active or sham tDCS of the DLPFC during the first session and the other intervention during the next session. Each intervention was followed immediately by a functional imaging scan during which participants performed an attentional task requiring them to ignore threatening face distractors. Data were collected from May 7 to October 6, 2015. Amygdala threat response, measured with functional magnetic resonance imaging. Data from 16 female participants (mean age, 23 years; range, 18-42 years), with 8 in each group, were analyzed. Compared with sham stimulation, active DLPFC stimulation significantly reduced bilateral amygdala threat reactivity (z = 3.30, P = .04) and simultaneously increased activity in cortical regions associated with attentional control (z = 3.28, P < .001). In confirmatory behavioral analyses, there was a mean improvement in task accuracy of 12.2% (95% CI, 0.30%-24.0%; mean [SD] difference in number of correct answers, 2.2 [4.5]; t15 = 1.94, P = .04) after active DLPFC stimulation. These results reveal a causal role for prefrontal regulation of amygdala function in attentional capture by threat in individuals with high trait anxiety. The finding that prefrontal stimulation acutely increases attentional control signals and reduces amygdala threat reactivity may indicate a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders. isrctn.org Identifier: ISRCTN78638425.

Post-traumatic stress disorder: review of DSM criteria and functional neuroanatomy

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for post-traumatic stress disorder (PTSD) consist of over twenty possible symptoms that can be divided into six broad categories. These categories correlate with specific brain networks that regulate emotions, behaviors, and autonomic function. Normal functioning of these networks depends on two key regions; the prefrontal cortex and the amygdala. The prefrontal cortex provides top-down executive control over amygdala, whereas the amygdala is critical for threat detection and activation of the ‘fight or flight’ response. Events that trigger extreme and/or prolonged fear can cause persisting dysregulation within the prefrontal-amygdala circuit; resulting in PTSD symptomatology. Studies indicate that effective treatment of PTSD, either psychotherapy or medications, reverses this prefrontal-amygdala dysregulation. This review article summarizes current knowledge and theories available in the medical literature from NCBI’s PubMed database regarding the underlying brain networks involved in PTSD.

The Role of Motivation in Cognitive Reappraisal for Depressed Patients.

Background: People engage in emotion regulation in service of motive goals (typically, to approach a desired emotional goal or avoid an undesired emotional goal). However, how motives (goals) in emotion regulation operate to shape the regulation of emotion is rarely known. Furthermore, the modulatory role of motivation in the impaired reappraisal capacity and neural abnormalities typical of depressed patients is not clear. Our hypothesis was that (1) approach and avoidance motivation may modulate emotion regulation and the underlying neural substrates; (2) approach/avoidance motivation may modulate emotion regulation neural abnormalities in depressed patients.Methods: Twelve drug-free depressed patients and fifteen matched healthy controls reappraised emotional pictures with approach/avoidant strategies and self-rated their emotional intensities during fMRI scans. Approach/avoidance motivation was measured using Behavioral Inhibition System and Behavioral Activation System (BIS/BAS) Scale. We conducted whole-brain analyses and correlation analyses of regions of interest to identify alterations in regulatory prefrontal-amygdala circuits which were modulated by motivation.Results: Depressed patients had a higher level of BIS and lower levels of BAS-reward responsiveness and BAS-drive. BIS scores were positively correlated with depressive severity. We found the main effect of motivation as well as the interactive effect of motivation and group on the neural correlates of emotion regulation. Specifically, hypoactivation of IFG underlying the group differences in the motivation-related neural correlates during reappraisal may be partially explained by the interaction between group and reappraisal. Consistent with our prediction, dlPFC and vmPFC was differentially between groups which were modulated by motivation. Specifically, the avoidance motivation of depressed patients could predict the right dlPFC activation during decreasing positive emotion, while the approach motivation of normal individuals could predict the right vmPFC activation during decreasing negative emotion. Notably, striatal regions were observed when examining the neural substrates underlying the main effect of motivation (lentiform nucleus) and the interactive effect between motivation and group (midbrain).Conclusions: Our findings highlight the modulatory role of approach and avoidance motivation in cognitive reappraisal, which is dysfunctional in depressed patients. The results could enlighten the CBT directed at modifying the motivation deficits in cognitive regulation of emotion.

P.4.b.015 - The prefrontal-amygdala circuit in trait anxiety and generalized anxiety disorder. Testing the boundaries between healthy and pathological worries

P.4.b.015 - The prefrontal-amygdala circuit in trait anxiety and generalized anxiety disorder. Testing the boundaries between healthy and pathological worries

Paradoxical Prefrontal-Amygdala Recruitment to Angry and Happy Expressions in Pediatric Posttraumatic Stress Disorder.

The neural substrates of pediatric posttraumatic stress disorder (PTSD) remain incompletely understood, but likely involve abnormal function and development of emotion processing circuitry. Valence-specific and age-related abnormalities during emotion processing have not been elucidated. We examined implicit emotional face processing in pediatric PTSD, predicting abnormalities specific to threat-related emotion. Youth (ages 8-18 years) with PTSD (n=25) and healthy youth (n=28) completed a dynamic emotional face task during fMRI, viewing faces changing from neutral to angry or happy, or changing shape control. Group and cross-sectional age-related differences in activation and functional connectivity were examined in amygdala/hippocampus, medial prefrontal cortex (mPFC), and whole-brain analyses. The post hoc analyses examined the relationship of neural abnormalities with symptom measures of PTSD, anxiety, and depression. Compared with decreased activation with age in healthy youth, PTSD youth showed increased amygdala activation to emotional faces with age. In a group by emotion interaction, PTSD youth showed dorsal (d)ACC hyperactivation to happy faces relative to healthy youth, with no difference for angry faces. Connectivity analyses revealed paradoxical coupling in prefrontal-amygdala circuits, including dACC-dorsomedial (dm)PFC, amygdala-dmPFC, and amygdala-ventrolateral (vl)PFC. In each case, PTSD youth showed reduced connectivity to angry faces, but increased connectivity to happy faces, the reverse of healthy youth. Valence-abnormal recruitment was associated with greater symptom severity, implicating a role in trauma-related psychopathology in youth. Notably, impaired recruitment during angry faces and heightened recruitment to happy faces may reflect increased salience and ambiguity of positive emotional expressions in pediatric PTSD. Finally, age-related findings suggest a developmental sensitization of the amygdala across emotional expressions in youth with PTSD. These findings provide novel insights into the underlying pathophysiology of pediatric PTSD, extending beyond abnormal neural responses to canonical threat.

4-Hz oscillations synchronize prefrontal–amygdala circuits during fear behavior

Fear expression relies on the coordinated activity of prefrontal and amygdala circuits, yet the mechanisms allowing long-range network synchronization during fear remain unknown. Using a combination of extracellular recordings, pharmacological, and optogenetic manipulations we report that freezing, a behavioural expression of fear, temporally coincides with the development of sustained, internally generated 4 Hz oscillations within prefrontal-amygdala circuits. 4 Hz oscillations predict freezing onset and offset and synchronize prefrontal-amygdala circuits. Optogenetic induction of prefrontal 4 Hz oscillations coordinates prefrontal-amygdala activity and elicits fear behaviour. These results unravel a novel sustained oscillatory mechanism mediating prefrontal-amygdala coupling during fear behaviour.

The Role of Serotonin in Aversive Inhibition: Behavioural, Cognitive and Neural Perspectives

Serotonin has long been implicated in emotional processing, but its specific mechanism of action is unclear. In this review we briefly summarise current perspectives on the neurobiological role of serotonin at the behavioural, cognitive and neural levels. We provide a general overview of serotonergic molecular pathways before discussing behavioural research delineating a role of serotonin in aversive inhibition. We then outline recent attempts to computationally formalise this role in aversive inhibition at the cognitive level. Finally, we try to situate these effects within neural circuitry. We argue, in particular, that the computational role of serotonin in aversive inhibition may be underpinned by serotonergic inhibition of prefrontal-amygdala circuits. Working to refine and improve our understanding of the neurobiological basis of serotonergic function is critical in order to improve our ability to diagnose and treat psychiatric disorders such as depression and anxiety in which serotonin may play a central role.

Fear renewal preferentially activates ventral hippocampal neurons projecting to both amygdala and prefrontal cortex in rats.

Anxiety, trauma and stress-related disorders are often characterized by a loss of context-appropriate emotional responding. The contextual retrieval of emotional memory involves hippocampal projections to the medial prefrontal cortex and amygdala; however the relative contribution of these projections is unclear. To address this question, we characterized retrieval-induced Fos expression in ventral hippocampal (VH) neurons projecting to the prelimbic cortex (PL) and basal amygdala (BA) after the extinction of conditioned fear in rats. After extinction, freezing behavior (an index of learned fear) to the auditory conditioned stimulus was suppressed in the extinction context, but was “renewed” in another context. Hippocampal neurons projecting to either PL or BA exhibited similar degrees of context-dependent Fos expression; there were more Fos-positive neurons in each area after the renewal, as opposed, to suppression of fear. Importantly, however, VH neurons projecting to both PL and BA were more likely to express Fos during fear renewal than neurons projecting to either PL or BA alone. These data suggest that although projections from the hippocampus to PL and BA are similarly involved in the contextual retrieval of emotional memories, VH neurons with collaterals to both areas may be particularly important for synchronizing prefrontal-amygdala circuits during fear renewal.

Dopamine D1 receptor activation rescues extinction impairments in low-estrogen female rats and induces cortical layer-specific activation changes in prefrontal-amygdala circuits.

Post-traumatic stress disorder (PTSD) is twice as common in women as in men; it is a major public health problem whose neurobiological basis is unknown. In preclinical studies using fear conditioning and extinction paradigms, women and female animals with low estrogen levels exhibit impaired extinction retrieval, but the mechanisms that underlie these hormone-based discrepancies have not been identified. There is much evidence that estrogen can modulate dopaminergic transmission, and here we tested the hypothesis that dopamine-estrogen interactions drive extinction processes in females. Intact male and female rats were trained on cued fear conditioning, and received an intraperitoneal injection of a D1 agonist or vehicle before extinction learning. As reported previously, females that underwent extinction during low estrogen estrous phases (estrus/metaestrus/diestrus (EMD)) froze more during extinction retrieval than those that had been in the high-estrogen phase (proestrus; PRO). However, D1 stimulation reversed this relationship, impairing extinction retrieval in PRO and enhancing it in EMD. We also combined retrograde tracing and fluorescent immunohistochemistry to measure c-fos expression in infralimbic (IL) projections to the basolateral area of the amygdala (BLA), a neural pathway known to be critical to extinction retrieval. Again we observed diverging, estrous-dependent effects; SKF treatment induced a positive correlation between freezing and IL-BLA circuit activation in EMD animals, and a negative correlation in PRO animals. These results show for the first time that hormone-dependent extinction deficits can be overcome with non-hormone-based interventions, and suggest a circuit-specific mechanism by which these behavioral effects occur.

Fear signaling in the prelimbic-amygdala circuit: a computational modeling and recording study.

The acquisition and expression of conditioned fear depends on prefrontal-amygdala circuits. Auditory fear conditioning increases the tone responses of lateral amygdala neurons, but the increase is transient, lasting only a few hundred milliseconds after tone onset. It was recently reported that that the prelimbic (PL) prefrontal cortex transforms transient lateral amygdala input into a sustained PL output, which could drive fear responses via projections to the lateral division of basal amygdala (BL). To explore the possible mechanisms involved in this transformation, we developed a large-scale biophysical model of the BL-PL network, consisting of 850 conductance-based Hodgkin-Huxley-type cells, calcium-based learning, and neuromodulator effects. The model predicts that sustained firing in PL can be derived from BL-induced release of dopamine and norepinephrine that is maintained by PL-BL interconnections. These predictions were confirmed with physiological recordings from PL neurons during fear conditioning with the selective β-blocker propranolol and by inactivation of BL with muscimol. Our model suggests that PL has a higher bandwidth than BL, due to PL's decreased internal inhibition and lower spiking thresholds. It also suggests that variations in specific microcircuits in the PL-BL interconnection can have a significant impact on the expression of fear, possibly explaining individual variability in fear responses. The human homolog of PL could thus be an effective target for anxiety disorders.

The role of serotonin in the neurocircuitry of negative affective bias: Serotonergic modulation of the dorsal medial prefrontal-amygdala ‘aversive amplification’ circuit

Serotonergic medications can mitigate the negative affective biases in disorders such as depression or anxiety, but the neural mechanism by which this occurs is largely unknown. In line with recent advances demonstrating that negative affective biases may be driven by specific medial prefrontal-amygdala circuitry, we asked whether serotonin manipulation can alter affective processing within a key dorsal medial prefrontal-amygdala circuit: the putative human homologue of the rodent prelimbic-amygdala circuit or 'aversive amplification' circuit. In a double-blind, placebo-controlled crossover pharmaco-fMRI design, subjects (N=19) performed a forced-choice face identification task with word distractors in an fMRI scanner over two separate sessions. On one session subjects received dietary depletion of the serotonin precursor tryptophan while on the other session they received a balanced placebo control diet. Results showed that dorsal medial prefrontal responding was elevated in response to fearful relative to happy faces under depletion but not placebo. This negative bias under depletion was accompanied by a corresponding increase in positive dorsal medial prefrontal-amygdala functional connectivity. We therefore conclude that serotonin depletion engages a prefrontal-amygdala circuit during the processing of fearful relative to happy face stimuli. This same 'aversive amplification' circuit is also engaged during anxiety induced by shock anticipation. As such, serotonergic projections may inhibit engagement of the 'aversive amplification' circuit and dysfunction in this projection may contribute to the negative affective bias in mood and anxiety disorders. These findings thus provide a promising explanation for the role of serotonin and serotonergic medications in the neurocircuitry of negative affective bias.

Deep brain stimulation of the ventral striatum increases BDNF in the fear extinction circuit.

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces the symptoms of treatment-resistant obsessive compulsive disorder (OCD), and improves response to extinction-based therapies. We recently reported that DBS-like stimulation of a rat homologue of VC/VS, the dorsal-VS, reduced conditioned fear and enhanced extinction memory (Rodriguez-Romaguera et al., 2012). In contrast, DBS of the ventral-VS had the opposite effects. To examine possible mechanisms of these effects, we assessed the effects of VS DBS on the expression of the neural activity marker Fos and brain-derived neurotrophic factor (BDNF), a key mediator of extinction plasticity in prefrontal-amygdala circuits. Consistent with decreased fear expression, DBS of dorsal-VS increased Fos expression in prelimbic and infralimbic prefrontal cortices and in the lateral division of the central nucleus of amygdala, an area that inhibits amygdala output. Consistent with improved extinction memory, we found that DBS of dorsal-VS, but not ventral-VS, increased neuronal BDNF expression in prelimbic and infralimbic prefrontal cortices. These rodent findings are consistent with the idea that clinical DBS of VC/VS may augment fear extinction through an increase in BDNF expression.