The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.
Copyright © 2019 Elsevier Inc. All rights reserved.
Infancy is marked by rapid neural and emotional development. The relation between brain function and emotion in infancy, however, is not well understood. Methods for measuring brain function predominantly rely on the BOLD signal; however, interpretation of the BOLD signal in infancy is challenging because the neuronal-hemodynamic relation is immature. Regional cerebral blood flow (rCBF) provides a context for the infant BOLD signal and can yield insight into the developmental maturity of brain regions that may support affective behaviors. This study aims to elucidate the relations among rCBF, age, and emotion in infancy. One hundred and seven mothers reported their infants' (infant age M ± SD = 6.14 ± 0.51 months) temperament. A subsample of infants completed MRI scans, 38 of whom produced usable perfusion MRI during natural sleep to quantify rCBF. Mother-infant dyads completed the repeated Still-Face Paradigm, from which infant affect reactivity and recovery to stress were quantified. We tested associations of infant age at scan, temperament factor scores, and observed affect reactivity and recovery with voxel-wise rCBF. Infant age was positively associated with CBF in nearly all voxels, with peaks located in sensory cortices and the ventral prefrontal cortex, supporting the formulation that rCBF is an indicator of tissue maturity. Temperamental Negative Affect and recovery of positive affect following a stressor were positively associated with rCBF in several cortical and subcortical limbic regions, including the orbitofrontal cortex and inferior frontal gyrus. This finding yields insight into the nature of affective neurodevelopment during infancy. Specifically, infants with relatively increased prefrontal cortex maturity may evidence a disposition toward greater negative affect and negative reactivity in their daily lives yet show better recovery of positive affect following a social stressor.
© 2019 John Wiley & Sons Ltd.
Highly selective, positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M receptor signaling in native systems, and it is not clear whether biased M PAMs display differences in modulating M-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M-dependent LTD in the PFC. In contrast, biased and nonbiased M PAMs acted similarly in potentiating M-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M PAMs to modulate certain central nervous system (CNS) functions and that biased M PAMs function differently in brain regions implicated in cognition.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
The left ventral occipitotemporal cortex (vOT) is a critical region in reading. According to the interactive account of reading, the vOT is an interface between the lower-level visual regions and higher-level language areas. One prediction of the interactive account is that orthographic activation in vOT should be automatically influenced by semantics and phonology. In the current study, we used functional magnetic resonance imaging (fMRI) and a masked priming paradigm with a relatively short duration (150 ms) to examine whether language information automatically influences vOT during Chinese reading. Participants were asked to perform a lexical decision task on target characters. We separately tested the phonological and semantic influence on orthographic processing in vOT. Brain activation analyses showed that the activation of vOT was modulated by semantic information. In addition, a functional connectivity analysis showed stronger connectivity between vOT and the left ventral inferior frontal gyrus was modulated by semantic information. These findings provided converging evidence for the existence of an automatic semantic influence on vOT during reading, supporting the interactive account. Our study did not show a phonological effect either in the activation of or connectivity with vOT. Taken together, these results reflect the unique processes of Chinese reading, which relies more on the mapping between orthography and semantics, as compared to the orthographic to phonology mapping.
Copyright © 2019 Elsevier Ltd. All rights reserved.
BACKGROUND - The striatum is abnormal in schizophrenia and possibly represents a common neurobiological mechanism underlying psychotic disorders. Resting-state functional magnetic resonance imaging studies have not reached a consensus regarding striatal dysconnectivity in schizophrenia, although these studies generally find impaired frontoparietal and salience network connectivity. The goal of the current study was to clarify the pattern of corticostriatal connectivity, including whether corticostriatal dysconnectivity is transdiagnostic and extends into psychotic bipolar disorder.
METHODS - We examined corticostriatal functional connectivity in 60 healthy subjects and 117 individuals with psychosis, including 77 with a schizophrenia spectrum illness and 40 with psychotic bipolar disorder. We conducted a cortical seed-based region-of-interest analysis with follow-up voxelwise analysis for any significant results. Further, a striatum seed-based analysis was conducted to examine group differences in connectivity between the striatum and the whole cortex.
RESULTS - Cortical region-of-interest analysis indicated that overall connectivity of the salience network with the striatum was reduced in psychotic disorders, which follow-up voxelwise analysis localized to the left putamen. Striatum seed-based analyses showed reduced ventral rostral putamen connectivity with the salience network portion of the medial prefrontal cortex in both schizophrenia and psychotic bipolar disorder.
CONCLUSIONS - The current study found evidence of transdiagnostic corticostriatal dysconnectivity in both schizophrenia and psychotic bipolar disorder, including reduced salience network connectivity, as well as reduced connectivity between the putamen and the medial prefrontal cortex. Overall, the current study points to the relative importance of salience network hypoconnectivity in psychotic disorders.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by semantic memory deficits with relatively preserved motor speech, syntax, and phonology. There is consistent evidence linking focal neurodegeneration of the anterior temporal lobes (ATL) to the semantic deficits observed in svPPA. Less is known about large-scale functional connectivity changes in this syndrome, particularly regarding the interplay between affected and spared language networks that leads to the unique cognitive dissociations typical of svPPA. Using whole-brain, seed-based connectivity on task-free Magnetic Resonance Imaging (MRI) data, we studied connectivity of networks anchored to three left-hemisphere regions crucially involved in svPPA symptomatology: ATL just posterior to the main atrophic area, opercular inferior frontal gyrus, and posterior inferior temporal lobe. First, in 32 healthy controls, these seeds isolated three networks: a ventral semantic network involving anterior middle temporal and angular gyri, a dorsal articulatory-phonological system involving inferior frontal and supramarginal regions, and a third functional connection between posterior inferior temporal and intraparietal regions likely involved in linking visual and linguistic processes. We then compared connectivity strength of these three networks between 16 svPPA patients and the 32 controls. In svPPA, decreased functional connectivity in the ventral semantic network correlated with weak semantic skills, while connectivity of the network seeded from the posterior inferior temporal lobe, though not significantly different between the two groups, correlated with pseudoword reading skills. Increased connectivity between the inferior frontal gyrus and the superior portion of the angular gyrus suggested possible adaptive changes. Our findings have two main implications. First, they support a functional subdivision of the left IPL based on its connectivity to specific language-related regions. Second, the unique neuroanatomical and linguistic profile observed in svPPA provides a compelling model for the functional interplay of these networks, being either up- or down- regulated in response to disease.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2 mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2 mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2 mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes. Autism Research 2019, 12: 732-743. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors.
© 2019 International Society for Autism Research, Wiley Periodicals, Inc.
Obsessive compulsive disorder (OCD) is associated with altered processing in brain regions involved in conflict resolution. However, limited research has examined the extent to which conflict from emotional distracters characterizes OCD such that responsiveness to task-irrelevant emotional stimuli is altered compared to controls. In the present study, 16 patients with OCD and 15 healthy controls underwent functional magnetic resonance imaging (fMRI) during resolution of conflict from emotional or nonemotional distracters. Results in healthy controls demonstrated that rostral anterior cingulate cortex (rACC), middle frontal gyrus (MFG), and medial superior frontal gyrus (MSFG) showed greater activation for high conflict versus low conflict. Responses in these regions differed between the emotional and nonemotional distracter tasks, with rACC and MSFG having greater activation for conflict from nonemotional distracters and anterior MFG showing greater activation for conflict from emotional distracters. Furthermore, between-group differences revealed a region in right posterior MFG in which controls similarly exhibited greater activation during high conflict versus low conflict with emotional distracters; however, OCD patients showed the opposite pattern with greater activation during low conflict compared to high conflict. These findings suggest that activity of right posterior MFG may be relevant in better understanding inefficient responding during emotional conflict in OCD.
Copyright © 2019 Elsevier B.V. All rights reserved.
Despite considerable evidence showing thalamus anatomy and connectivity abnormalities in schizophrenia, how these abnormalities are reflected in thalamus function during cognition is relatively understudied. Modulation of thalamic connectivity with the prefrontal cortex (PFC) is required for higher-order cognitive processes, which are often impaired in schizophrenia. To address this gap, we investigated how thalamus function and thalamus-PFC connectivity under different levels of cognitive demand may be disrupted in schizophrenia. Participants underwent fMRI scanning while performing an event-related two-alternative forced choice task under Single and Dual task conditions. In the Single task condition, participants responded either to a visual cue with a well-learned motor response, or an audio cue with a well-learned vocal response. In the Dual task condition, participants performed both tasks. Thalamic connectivity with task relevant regions of the PFC for each condition was measured using beta-series correlation. Individuals with schizophrenia demonstrated less modulation of both mediodorsal thalamus activation and thalamus-PFC connectivity with increased cognitive demand. In contrast, their ability to modulate PFC function during task performance was maintained. These results suggest that the pathophysiology of cognitive impairment in schizophrenia is associated with thalamus-PFC circuitry and suggests that the thalamus, along with the PFC, should be a focus of investigation.
Copyright © 2019 Elsevier B.V. All rights reserved.
OBJECTIVES - The ventrolateral prefrontal cortex (vlPFC) has been speculated to play an important role in complex processes that allow emotional factors to influence human cognition. Accumulating evidence from human neuroimaging studies, in conjunction with studies of patients with lesions and animal models, shed light on the role of the vlPFC in emotion regulation (ER). This review aims to discuss and integrate recent findings related to vlPFC's role in ER in the context of aging, drawing from diverse sources, and suggest future directions for research utilizing transcranial magnetic stimulation (TMS).
METHODS/DESIGN - We summarize findings from the existing literature investigating the neural basis of frontal-lobe mediated ER and then highlight major findings from recent studies directly comparing healthy younger and older adult groups. We conclude by pointing to unaddressed questions worth pursuing in future research.
RESULTS AND DISCUSSION - We propose future research directions utilizing TMS to answer key unaddressed questions. Moreover, we discuss the potential advantages, challenges, and limitations of using TMS as a complement to the existing neuroimaging methods in ER.
© 2018 John Wiley & Sons, Ltd.