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 investigations into the involvement in reward and threat processing of 2 major regions of the vmPFC, areas 25 and 32 in NHPs and their anatomical homologs, the infralimbic and prelimbic cortex, in rodents. We highlight potential similarities, but also differences between species, and consider them in light of the extent to which anatomical homology reflects functional homology, the expansion of the PFC in human and NHPs, and most importantly how they can guide future studies to improve the translatability of findings from preclinical animal studies into the clinic.
INTRODUCTIONThis study was aimed to compare fracture prevalence in oligoamenorrheic athletes (AA), eumenorrheic athletes (EA), and nonathletes (NA) and determine relationships with bone density, ...structure, and strength estimates.
METHODSOne hundred seventy-five females (100 AA, 35 EA, and 40 NA) 14–25 yr old were studied. Lifetime fracture history was obtained through participant interviews. Areal bone mineral density (BMD) was assessed by DXA at the spine, hip, and whole body (WB). Bone structure was assessed by HRpQCT at the radius and tibia, and strength by finite element analysis.
RESULTSAA, EA, and NA did not differ in age, sexual maturity, or height. AA had lower BMI, and older menarchal age than EA and NA (P ≤ 0.001). Bone mineral density Z-scores were lower in AA versus EA at the total hip, femoral neck, spine, and whole body (P ≤ 0.001). Lifetime fracture risk was higher in AA than EA and NA (47%, 25.7%, 12.5%; P ≤ 0.001), largely driven by stress fractures in AA versus EA and NA (32% vs 5.9% vs 0%). In AA, those who fractured had lower lumbar and WB BMD Z-scores, volumetric BMD (vBMD) of outer trabecular region in radius and tibia, and trabecular thickness of the radius (P ≤ 0.05). In AA, those who had two or more stress fractures had lower lumbar and WB BMD Z-scores, total cross-sectional area, trabecular vBMD, stiffness, and failure load at radius; and lower stiffness and failure load at tibia versus those with fewer than two stress fractures (P ≤ 0.05).
CONCLUSIONWeight-bearing athletic activity increases BMD but may increase stress fracture risk in those with menstrual dysfunction. Bone microarchitecture and strength differences are more pronounced in AA with multiple stress fractures. This is the first study to examine fractures in relation to bone structure in adolescent female athletes.
Anhedonia is a core symptom of depression, but the underlying neurobiological mechanisms are unknown. Correlative neuroimaging studies implicate dysfunction within ventromedial prefrontal cortex, but ...the causal roles of specific subregions remain unidentified. We addressed these issues by combining intracerebral microinfusions with cardiovascular and behavioral monitoring in marmoset monkeys to show that over-activation of primate subgenual anterior cingulate cortex (sgACC, area 25) blunts appetitive anticipatory, but not consummatory, arousal, whereas manipulations of adjacent perigenual ACC (pgACC, area 32) have no effect. sgACC/25 over-activation also reduces the willingness to work for reward. 18F-FDG PET imaging reveals over-activation induced metabolic changes in circuits involved in reward processing and interoception. Ketamine treatment ameliorates the blunted anticipatory arousal and reverses associated metabolic changes. These results demonstrate a causal role for primate sgACC/25 over-activity in selective aspects of impaired reward processing translationally relevant to anhedonia, and ketamine’s modulation of an affective network to exert its action.
•Primate sgACC/25 over-activation blunts reward anticipation, but not consumption•Over-activation of sgACC/25 also blunts willingness to work for reward•Anticipatory blunting involves metabolic changes in reward-related circuits•Acute ketamine reverses blunted anticipatory arousal and metabolic changes
Using intracerebral microinfusions in marmosets, Alexander et al. demonstrate a causal role for sgACC/25 over-activity in specific aspects of impaired reward processing associated with anhedonia. Ketamine successfully ameliorates related impairments by modulating activity within a dysfunctional neural circuit involved in reward processing and interoception.
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.
F-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 reward blunting, illustrating the symptom-specificity of its actions.
The ability to switch responding between two visual stimuli based on their changing relationship with reward is dependent on the orbitofrontal cortex (OFC). OFC lesions in humans, monkeys, and rats ...disrupt performance on a common test of this ability, the visual serial discrimination reversal task. This finding is of particular significance to our understanding of psychiatric disorders such as obsessive-compulsive disorder (OCD) and schizophrenia, in which behavioral inflexibility is a prominent symptom. Although OFC dysfunction can occur in these disorders, there is considerable evidence for more widespread dysfunction within frontostriatal and frontoamygdalar circuitry. Because the contribution of these subcortical structures to behavioral flexibility is poorly understood, the present study compared the effects of excitotoxic lesions of the medial striatum (MS), amygdala, and OFC in the marmoset monkey on performance of the serial reversal task. All monkeys were able to learn a novel stimulus-reward association but, compared with both control and amygdala-lesioned monkeys, those with MS or OFC lesions showed a perseverative impairment in their ability to reverse this association. However, whereas both MS and OFC groups showed insensitivity to negative feedback, only OFC-lesioned monkeys showed insensitivity to positive feedback. These findings suggest that, for different reasons, both the MS and OFC support behavioral flexibility after changes in reward contingencies, and are consistent with the hypothesis that striatal and OFC dysfunction can contribute to pathological perseveration.
A Focus on the Functions of Area 25 Alexander, Laith; Clarke, Hannah F; Roberts, Angela C
Brain sciences,
06/2019, Letnik:
9, Številka:
6
Journal Article
Recenzirano
Odprti dostop
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.
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 paradigms, pharmacological inactivation of area 25 decreased the autonomic and behavioral correlates of negative emotion expectation, whereas inactivation of area 32 increased them via generalization. Area 25 inactivation also increased resting HRV. These findings are inconsistent with current theories of rodent/primate prefrontal functional similarity, and provide insight into the role of these brain regions in affective disorders. They demonstrate that area 32 hypoactivity causes behavioral generalization relevant to anxiety, and that area 25 is a causal node governing the emotional and cardiovascular symptomatology relevant to anxiety and depression.
Culture plays an important role in communities' abilities to adapt to environmental change and crises. The emerging field of resilience thinking has made several efforts to better integrate social ...and cultural factors into the systems-level approach to understanding social-ecological resilience. However, attempts to integrate culture into structural models often fail to account for the agentic processes that influence recovery at the individual and community levels, overshadowing the potential for agency and variation in community response. Using empirical data on the 2010 BP oil spill's impact on a small, natural-resource-dependent community, we propose an alternative approach emphasizing culture's ability to operate as a resource that contributes to social, or community, resilience. We refer to this more explicit articulation of culture's role in resilience as cultural resilience. Our findings reveal that not all cultural resources that define resilience in reference to certain disasters provided successful mitigation, adaptation, or recovery from the BP spill.
The discrimination reversal paradigm is commonly used to measure a subject's ability to adapt their behavior according to changes in stimulus-reward contingencies. Human functional neuroimaging ...studies have demonstrated activations in the lateral orbitofrontal cortex (OFC) and the inferior frontal gyrus (IFG) in subjects performing this task. Excitotoxic lesions of analogous regions in marmosets have revealed, however, that although the OFC is indeed critical for reversal learning, ventrolateral prefrontal cortex (VLPFC) (analogous to IFG) is not, contributing instead to higher order processing, such as that required in attentional set-shifting and strategy transfer. One major difference between the marmoset and human studies has been the level of training subjects received in reversal learning, being far greater in the latter. Since exposure to repeated contingency changes, as occurs in serial reversal learning, is likely to trigger the development of higher order, rule-based strategies, we hypothesized a critical role of the marmoset VLPFC in performance of a serial reversal learning paradigm. After extensive training in reversal learning, marmosets received an excitotoxic lesion of the VLPFC, OFC, or a sham control procedure. In agreement with our prediction, postsurgery, VLPFC lesioned animals were impaired in performing a series of discrimination reversals, but only when novel visual stimuli were introduced. In contrast, OFC lesioned animals were impaired regardless of whether the visual stimuli were the same or different from those used during presurgery training. Together, these data demonstrate the heterogeneous but interrelated involvement of primate OFC and VLPFC in the performance of serial reversal learning.
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 basis for understanding how distinct regional prefrontal dysregulation contributes to the heterogeneity of anxiety disorders with implications for cognitive-behavioral treatment strategies.
Significance Fear of negative outcomes has a powerful adverse influence on decision making in anxiety disorders. Although neuroimaging studies of patients with anxiety disorders have revealed dysregulation in numerous frontal brain regions including the orbitofrontal and ventrolateral prefrontal cortex, the causal involvement of this dysregulation is unknown. Here we demonstrate that in the marmoset monkey, inactivation of anterior orbitofrontal or ventrolateral prefrontal cortex increases negative bias in decision making via two distinct cognitive mechanisms—elevated uncertainty and attentional disruption, respectively. These findings provide, to our knowledge, the first direct evidence that dysregulation of distinct neurocognitive mechanisms within the prefrontal cortex may underlie the mixed etiology of anxiety disorders. Such insight will allow the development of more precise diagnostics and individually tailored therapeutic approaches.
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