Chronic Stress Effects on Prefrontal Cortical Structure and Function

Stressful life events have been implicated clinically in the pathogenesis of major depression, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of depression are associated with structural and functional abnormalities in the prefrontal cortex. In three parallel rodent and human neuroimaging studies, this project assessed the effects of chronic stress on prefrontal cortical structure and function and the behavioral correlates of these changes. The first study used fMRI to elucidate the precise computational contributions of frontoparietal circuitry to attentional control in human subjects, using a task that could be adapted for rats. The results confirmed that the contributions of dorsolateral frontoparietal areas to visual attentional shifts could be dissociated from the regulatory influences of more ventrolateral areas on stimulus/response mappings, in a manner consistent with studies in animal models. They also indicated that anterior cingulate and posterior parietal cortex may act in concert to detect dissociable forms of information processing conflicts and signal to dorsolateral prefrontal cortex the need for increased attentional control. Stress-induced alterations in these regions and in the connections between them may therefore contribute to attentional impairments. The second study tested this hypothesis in rats by examining whether chronic stress effects on medial prefrontal (mPFC) and orbitofrontal (OFC) dendritic morphology underlie impairments in the behaviors that they subserve. Chronic stress induced a selective impairment in attentional control and a corresponding retraction of apical dendritic arbors in mPFC. By contrast, stress did not adversely affect reversal learning or OFC dendritic arborization. These results suggest that prefrontal dendritic remodeling may underlie the attentional deficits that are symptomatic of stress-related mental illness. The third study was designed to extend these findings to human subjects, using the techniques developed in Study 1. Accordingly, chronic stress predicted selective attentional impairments and alterations in prefrontal functional coupling that were reversible after four weeks. Together, these studies outline in broad strokes a mechanistic model by which chronic stress may predispose susceptible persons to the attentional impairments that are characteristic of major depression. Future studies will assess the roles of serotonin and neurotrophins in mediating these changes

Glucocorticoid mechanisms of functional connectivity changes in stress-related neuropsychiatric disorders

AbstractStress—especially chronic, uncontrollable stress—is an important risk factor for many neuropsychiatric disorders. The underlying mechanisms are complex and multifactorial, but they involve correlated changes in structural and functional measures of neuronal connectivity within cortical microcircuits and across neuroanatomically distributed brain networks. Here, we review evidence from animal models and human neuroimaging studies implicating stress-associated changes in functional connectivity in the pathogenesis of PTSD, depression, and other neuropsychiatric conditions. Changes in fMRI measures of corticocortical connectivity across distributed networks may be caused by specific structural alterations that have been observed in the prefrontal cortex, hippocampus, and other vulnerable brain regions. These effects are mediated in part by glucocorticoids, which are released from the adrenal gland in response to a stressor and also oscillate in synchrony with diurnal rhythms. Recent work indicates that circadian glucocorticoid oscillations act to balance synapse formation and pruning after learning and during development, and chronic stress disrupts this balance. We conclude by considering how disrupted glucocorticoid oscillations may contribute to the pathophysiology of depression and PTSD in vulnerable individuals, and how circadian rhythm disturbances may affect non-psychiatric populations, including frequent travelers, shift workers, and patients undergoing treatment for autoimmune disorders

Changes in Functional Connectivity Following Treatment With Emotion Regulation Therapy

Emotion regulation therapy (ERT) is an efficacious treatment for distress disorders (i.e., depression and anxiety), predicated on a conceptual model wherein difficult to treat distress arises from intense emotionality (e.g., neuroticism, dispositional negativity) and is prolonged by negative self-referentiality (e.g., worry, rumination). Individuals with distress disorders exhibit disruptions in two corresponding brain networks including the salience network (SN) reflecting emotion/motivation and the default mode network (DMN) reflecting self-referentiality. Using resting-state functional connectivity (rsFC) analyses, seeded with primary regions in each of these networks, we investigated whether ERT was associated with theoretically consistent changes across nodes of these networks and whether these changes related to improvements in clinical outcomes. This study examined 21 generalized anxiety disorder (GAD) patients [with and without major depressive disorder (MDD)] drawn from a larger intervention trial (Renna et al., 2018a), who completed resting state fMRI scans before and after receiving 16 sessions of ERT. We utilized seed-based connectivity analysis with seeds in the posterior cingulate cortex (PCC), right anterior insula, and right posterior insula, to investigate whether ERT was associated with changes in connectivity of nodes of the DMN and SN networks to regions across the brain. Findings revealed statistically significant treatment linked changes in both the DMN and SN network nodes, and these changes were associated with clinical improvement corresponding to medium effect sizes. The results are discussed in light of a nuanced understanding of the role of connectivity changes in GAD and MDD, and begin to provide neural network support for the hypothesized treatment model predicated by ERT

GABA-modulating bacteria of the human gut microbiota.

The gut microbiota affects many important host functions, including the immune response and the nervous system1. However, while substantial progress has been made in growing diverse microorganisms of the microbiota2, 23-65% of species residing in the human gut remain uncultured3,4, which is an obstacle for understanding their biological roles. A likely reason for this unculturability is the absence in artificial media of key growth factors that are provided by neighbouring bacteria in situ5,6. In the present study, we used co-culture to isolate KLE1738, which required the presence of Bacteroides fragilis to grow. Bioassay-driven purification of B. fragilis supernatant led to the isolation of the growth factor, which, surprisingly, is the major inhibitory neurotransmitter GABA (γ-aminobutyric acid). GABA was the only tested nutrient that supported the growth of KLE1738, and a genome analysis supported a GABA-dependent metabolism mechanism. Using growth of KLE1738 as an indicator, we isolated a variety of GABA-producing bacteria, and found that Bacteroides ssp. produced large quantities of GABA. Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA. A transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides, Parabacteroides and Escherichia species. By coupling 16S ribosmal RNA sequencing with functional magentic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression

An automated platform for Assessing Working Memory and prefrontal circuit function

Working memory is a process for actively maintaining and updating task-relevant information, despite interference from competing inputs, and is supported in part by sustained activity in prefrontal cortical pyramidal neurons and coordinated interactions with inhibitory interneurons, which may serve to regulate interference. Chronic stress has potent effects on working memory performance, possibly by interfering with these interactions or by disrupting long-range inputs from key upstream brain regions. Still, the mechanisms by which chronic stress disrupts working memory are not well understood, due in part to a need for scalable, easy-to-implement behavioral assays that are compatible with two-photon calcium imaging and other tools for recording from large populations of neurons. Here, we describe the development and validation of a platform that was designed specifically for automated, high-throughput assessments of working memory and simultaneous two-photon imaging in chronic stress studies. This platform is relatively inexpensive and easy to build; fully automated and scalable such that one investigator can test relatively large cohorts of animals concurrently; fully compatible with two-photon imaging, yet also designed to mitigate head-fixation stress; and can be easily adapted for other behavioral paradigms. Our validation data confirm that mice could be trained to perform a delayed response working memory task with relatively high-fidelity over the course of ∼15 days. Two-photon imaging data validate the feasibility of recording from large populations of cells during working memory tasks performance and characterizing their functional properties. Activity patterns in >70% of medial prefrontal cortical neurons were modulated by at least one task feature, and a majority of cells were engaged by multiple task features. We conclude with a brief literature review of the circuit mechanisms supporting working memory and their disruption in chronic stress states—highlighting directions for future research enabled by this platform

Frontostriatal microstructure modulates efficient recruitment of cognitive control

Many studies have linked activity in a frontostriatal network with the capacity to suppress inappropriate thoughts and actions, but relatively few have examined the role of connectivity between these structures. Here, we use diffusion tensor imaging to assess frontostriatal connectivity in 21 subjects (ages 7--31 years). Fifteen subjects were tested on a go/no-go task, where they responded with a button press to a visual stimulus and inhibited a response to a second infrequent stimulus. An automated fiber tracking algorithm was used to delineate white matter fibers adjacent to ventral prefrontal cortex and the striatum, and the corticospinal tract, which was not expected to contribute to control per se. Diffusion in frontostriatal and corticospinal tracts became more restricted with age. This shift was paralleled by an increase in efficiency of task performance. Frontostriatal radial diffusivities predicted faster reaction times, independent of age and accuracy, and this correlation grew stronger for trials expected to require greater control. This was not observed in the corticospinal tract. On trials matched for speed of task performance, adults were significantly more accurate, and accuracies were correlated with frontostriatal, but not corticospinal, diffusivities. These findings suggest that frontostriatal connectivity may contribute to developmental and individual differences in the efficient recruitment of cognitive control

Molecular and network-level mechanisms explaining individual differences in autism spectrum disorder.

The mechanisms underlying phenotypic heterogeneity in autism spectrum disorder (ASD) are not well understood. Using a large neuroimaging dataset, we identified three latent dimensions of functional brain network connectivity that predicted individual differences in ASD behaviors and were stable in cross-validation. Clustering along these three dimensions revealed four reproducible ASD subgroups with distinct functional connectivity alterations in ASD-related networks and clinical symptom profiles that were reproducible in an independent sample. By integrating neuroimaging data with normative gene expression data from two independent transcriptomic atlases, we found that within each subgroup, ASD-related functional connectivity was explained by regional differences in the expression of distinct ASD-related gene sets. These gene sets were differentially associated with distinct molecular signaling pathways involving immune and synapse function, G-protein-coupled receptor signaling, protein synthesis and other processes. Collectively, our findings delineate atypical connectivity patterns underlying different forms of ASD that implicate distinct molecular signaling mechanisms

Distinct Functional Connectivities Predict Clinical Response with Emotion Regulation Therapy

Despite the success of available medical and psychosocial treatments, a sizable subgroup of individuals with commonly co-occurring disorders, generalized anxiety disorder (GAD) and major depressive disorder (MDD), fail to make sufficient treatment gains thereby prolonging their deficits in life functioning and satisfaction. Clinically, these patients often display temperamental features reflecting heightened sensitivity to underlying motivational systems related to threat/safety and reward/loss (e.g., somatic anxiety) as well as inordinate negative self-referential processing (e.g., worry, rumination). This profile may reflect disruption in two important neural networks associated with emotional/motivational salience (e.g., salience network) and self-referentiality (e.g., default network, DN). Emotion Regulation Therapy (ERT) was developed to target this hypothesized profile and its neurobehavioral markers. In the present study, 22 GAD patients (with and without MDD) completed resting state MRI scans before receiving 16 sessions of ERT. To test study these hypotheses, we examined the associations between baseline patterns of intrinsic functional connectivity (iFC) of the insula and of hubs within the DN (anterior and dorsal medial prefrontal cortex [MPFC] and posterior cingulate cortex [PCC]) and treatment-related changes in worry, somatic anxiety symptoms and decentering. Results suggest that greater treatment linked reductions in worry were associated with iFC clusters in both the insular and parietal cortices. Greater treatment linked gains in decentering, a metacognitive process that involves the capacity to observe items that arise in the mind with healthy psychological distance that is targeted by ERT, was associated with iFC clusters in the anterior and posterior DN. The current study adds to the growing body of research implicating disruptions in the default and salience networks as promising targets of treatment for GAD with and without co-occurring MDD.CUNY Collaborative Incentive Research Grant (CIRG) [2054]; PSC-CUNY Enhanced Research Award [65797-0043]; National Institutes of Health (NIH) MBRS-RISE Program at Hunter College [GM060665]; Doctoral Student Research Grant, City University of New York, Graduate Center; NIH [1R01HL119977-01, 1P30NR015326-01]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]