Functional and directed connectivity of the cortico-limbic network in mice in vivo

AbstractHigher cognitive processes and emotional regulation depend on densely interconnected telencephalic and limbic areas. Central structures of this cortico-limbic network are ventral hippocampus (vHC), medial prefrontal cortex (PFC), basolateral amygdala (BLA) and nucleus accumbens (NAC). Human and animal studies have revealed both anatomical and functional alterations in specific connections of this network in several psychiatric disorders. However, it is often not clear whether functional alterations within these densely interconnected brain areas are caused by modifications in the direct pathways, or alternatively through indirect interactions. We performed multi-site extracellular recordings of spontaneous activity in three different brain regions to study the functional connectivity in the BLA–NAC–PFC–vHC network of the lightly anesthetized mouse in vivo. We show that BLA, NAC, PFC and vHC are functionally connected in distinct frequency bands and determined the influence of a third brain region on this connectivity. In addition to describing mutual synchronicity, we determined the strength of functional connectivity for each region in the BLA–NAC–PFC–vHC network. We find a region-specificity in the strength of feedforward and feedback connections for each region in its interaction with other areas in the network. Our results provide insights into functional and directed connectivity in the cortico-limbic network of adult wild-type mice, which may be helpful to further elucidate the pathophysiological changes of this network in psychiatric disorders and to develop target-specific therapeutic interventions.

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Oxytocin enhances basolateral amygdala activation and functional connectivity in autistic women while processing emotional faces

10.31219/osf.io/yjpe9 ◽

2021 ◽

Author(s):

Tanya Procyshyn ◽

MIchael Lombardo ◽

Meng-Chuan Lai ◽

Bonnie Auyeung ◽

Sarah Crockford ◽

...

Keyword(s):

Functional Connectivity ◽

Basolateral Amygdala ◽

Brain Regions ◽

Placebo Condition ◽

Emotional Faces ◽

Amygdala Activation ◽

Within Subjects ◽

Emotional Information Processing ◽

Face Stimuli ◽

The Right

Background: Oxytocin is hypothesized to promote positive social interactions by enhancing the salience of social stimuli, which may be reflected by altered amygdala activation. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to emotional face stimuli in autistic men, effects in autistic women remain unclear. Methods: The influence of intranasal oxytocin on neural response to emotional faces vs. shapes were tested in 16 autistic and 21 non-autistic women by fMRI in a placebo-controlled, within-subjects, cross-over design. Effects of group (autistic vs. non-autistic) and drug condition (oxytocin vs. placebo) on the activation and functional connectivity of the basolateral amygdala, the brain’s “salience detector”, were assessed. Relationships between individual differences in autistic-like traits, social anxiety, salivary oxytocin levels, and amygdala activation were also explored.Results: Autistic and non-autistic women showed minimal activation differences in the placebo condition. Significant drug × group interactions were observed for both amygdala activation and functional connectivity. Oxytocin increased left basolateral amygdala activation among autistic women (35 voxel cluster, MNI coordinates of peak voxel = -22 -10 -28; mean change=+0.079%, t=3.159, ptukey=0.0166), but not non-autistic women (mean change =+0.003%, t=0.153, ptukey=0.999). Furthermore, oxytocin increased functional connectivity of the right basolateral amygdala with brain regions associated with socio-emotional information processing in autistic women, but not non-autistic women, thereby attenuating group connectivity differences observed in the placebo condition. Conclusions: This work demonstrates that intranasal oxytocin increases basolateral amygdala activation and connectivity in autistic women while processing emotional faces, which extends and specifies previous findings in autistic men.

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Assessment of 18F-PBR-111 in the Cuprizone Mouse Model of Multiple Sclerosis

Diagnostics ◽

10.3390/diagnostics11050786 ◽

2021 ◽

Vol 11 (5) ◽

pp. 786

Author(s):

Valerie L. Jewells ◽

Hong Yuan ◽

Joseph R. Merrill ◽

Jonathan E. Frank ◽

Akhil Patel ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mouse Model ◽

Animal Studies ◽

Therapy Response ◽

Internal Capsule ◽

Structural Data ◽

Brain Regions ◽

Immunofluorescence Staining ◽

In Vivo Evaluation

The study aims to assess site assessment of the performance of 18F-PBR-111 as a neuroinflammation marker in the cuprizone mouse model of multiple sclerosis (MS). 18F-PBR-111 PET imaging has not been well evaluated in multiple sclerosis applications both in preclinical and clinical research. This study will help establish the potential utility of 18F-PBR-111 PET in preclinical MS research and future animal and future human applications.18F-PBR-111 PET/CT was conducted at 3.5 weeks (n = 7) and 5.0 weeks (n = 7) after cuprizone treatment or sham control (n = 3) in the mouse model. A subgroup of mice underwent autoradiography with cryosectioned brain tissue. T2 weighted MRI was performed to obtain the brain structural data of each mouse. 18F-PBR-111 uptake was assessed in multiple brain regions with PET and autoradiography images. The correlation between autoradiography and immunofluorescence staining of neuroinflammation (F4/80 and CD11b) was measured. Compared to control mice, significant 18F-PBR-111 uptake in the corpus callosum (p < 0.001), striatum (caudate and internal capsule, p < 0.001), and hippocampus (p < 0.05) was identified with PET images at both 3.5 weeks and 5.0 weeks, and validated with autoradiography. No significant uptake differences were detected between 3.5 weeks and 5.0 weeks assessing these regions as a whole, although there was a trend of increased uptake at 5.0 weeks compared to 3.5 weeks in the CC. High 18F-PBR-111 uptake regions correlated with microglial/ macrophage locations by immunofluorescence staining with F4/80 and CD11b antibodies. 18F-PBR-111 uptake in anatomic locations correlated with activated microglia at histology in the cuprizone mouse model of MS suggests that 18F-PBR-111 has potential for in vivo evaluation of therapy response and potential for use in MS patients and animal studies.

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Hyperconnectivity Between The Posterior Cingulate and Middle Frontal and Temporal Gyrus in Depression: Based On Functional Connectivity Meta-Analyses.

10.21203/rs.3.rs-633328/v1 ◽

2021 ◽

Author(s):

Ziqing Zhu ◽

You Wang ◽

Way Lau ◽

Xinhua Wei ◽

Yingjun Liu ◽

...

Keyword(s):

Functional Connectivity ◽

Cognitive Control ◽

Emotional Regulation ◽

Meta Analysis ◽

Brain Regions ◽

Structural Basis ◽

Middle Temporal Gyrus ◽

Resting State Functional Connectivity ◽

Posterior Cingulate ◽

The Right

Abstract BackgroundDisrupted whole-brain resting-state functional connectivity (RSFC) of the posterior cingulate (PCC) has been highlighted to associate with cognitive and affective dysfunction in major depressive disorder (MDD). However, prior findings showed certain inconsistency about the RSFC of the PCC in MDD. This study aims to investigate the aberrant RSFC of the PCC in MDD using anisotropic effect-size version of seed-based d mapping (AES-SDM). MethodsWeb of Science and PubMed were searched for studies investigating PCC-based RSFC in MDD. A total of 17 studies, involving 804 patients and 724 healthy controls (HCs), fit our selection criteria. Additionally, to seek for the link between functional and structural differences, we did a meta-analysis on the studies in conjunction with Voxel-based morphology (VBM) analysis. ResultsThe PCC showed higher RSFC with the left middle temporal gyrus (MTG) and the right middle frontal gyrus (MFG), and lower RSFC with the left superior frontal gyrus (SFG) and the left precuneus in patients with MDD than HCs. Notably, the left MTG and the left MFG were the overlapped regions of aberrant VBM and RSFC results.ConclusionsOur results indicated that the aberrant RSFC between the PCC and brain regions sub-serving cognitive control and emotional regulation in patients with MDD. And such functional alterations may have structural basis. These findings may underlie the mechanisms of deficits in cognitive control and emotional regulation of MDD.

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Developmental outcomes of early adverse care on amygdala functional connectivity in nonhuman primates

Development and Psychopathology ◽

10.1017/s0954579420001133 ◽

2020 ◽

Vol 32 (5) ◽

pp. 1579-1596

Author(s):

Elyse L. Morin ◽

Brittany R. Howell ◽

Eric Feczko ◽

Eric Earl ◽

Melanie Pincus ◽

...

Keyword(s):

Functional Connectivity ◽

Childhood Maltreatment ◽

Emotional Regulation ◽

Region Of Interest ◽

Brain Regions ◽

Adverse Experience ◽

Juvenile Period ◽

Macaque Model ◽

Prenatal Factors ◽

Magnetic Resonance Imaging Mri

AbstractDespite the strong link between childhood maltreatment and psychopathology, the underlying neurodevelopmental mechanisms are poorly understood and difficult to disentangle from heritable and prenatal factors. This study used a translational macaque model of infant maltreatment in which the adverse experience occurs in the first months of life, during intense maturation of amygdala circuits important for stress and emotional regulation. Thus, we examined the developmental impact of maltreatment on amygdala functional connectivity (FC) longitudinally, from infancy through the juvenile period. Using resting state functional magnetic resonance imaging (MRI) we performed amygdala–prefrontal cortex (PFC) region-of-interest and exploratory whole-brain amygdala FC analyses. The latter showed (a) developmental increases in amygdala FC with many regions, likely supporting increased processing of socioemotional-relevant stimuli with age; and (b) maltreatment effects on amygdala coupling with arousal and stress brain regions (locus coeruleus, laterodorsal tegmental area) that emerged with age. Maltreated juveniles showed weaker FC than controls, which was negatively associated with infant hair cortisol concentrations. Findings from the region-of-interest analysis also showed weaker amygdala FC with PFC regions in maltreated animals than controls since infancy, whereas bilateral amygdala FC was stronger in maltreated animals. These effects on amygdala FC development may underlie the poor behavioral outcomes associated with this adverse experience.

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IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria: guidelines of the EU-CARDIOPROTECTION COST Action

Basic Research in Cardiology ◽

10.1007/s00395-021-00893-5 ◽

2021 ◽

Vol 116 (1) ◽

Cited By ~ 1

Author(s):

Sandrine Lecour ◽

Ioanna Andreadou ◽

Hans Erik Bøtker ◽

Sean M. Davidson ◽

Gerd Heusch ◽

...

Keyword(s):

Animal Studies ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Therapeutic Interventions ◽

Acute Ischemia ◽

Myocardial Infarct Size ◽

Patient Benefit ◽

The Eu

AbstractAcute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.

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Kynurenines Increase MRS Metabolites in Basal Ganglia and Decrease Resting State Connectivity in Frontostriatal Reward Circuitry in Depression

10.1101/2021.05.16.21257295 ◽

2021 ◽

Author(s):

Xiangchuan Chen ◽

Diana J Beltran ◽

Valeriya D Tsygankova ◽

Bobbi J Woolwine ◽

Trusharth Patel ◽

...

Keyword(s):

Depressive Symptoms ◽

Basal Ganglia ◽

Magnetic Resonance ◽

Functional Connectivity ◽

Resting State ◽

Animal Studies ◽

Brain Regions ◽

Kynurenine Pathway ◽

Resonance Spectroscopy ◽

The Brain

Inflammation is associated with depressive symptoms including anhedonia in patients with major depression. Nevertheless, the mechanisms by which peripheral inflammatory signals are communicated to the brain to influence central nervous system (CNS) function has yet to be fully elucidated. Based on laboratory animal studies, molecules of the kynurenine pathway (KP), which is activated by inflammation, can readily enter the brain, and generate metabolites that can alter neuronal and glial function, leading to behavioral changes. We therefore examined the relationship between KP metabolites in the plasma and cerebrospinal fluid (CSF) and brain chemistry and neural network function using multi-modal neuroimaging in 49 unmedicated, depressed subjects. CNS measures included 1) biochemical markers of glial dysfunction including glutamate (Glu) and myo-inositol (mI) in the left basal ganglia (LBG) using magnetic resonance spectroscopy (MRS); 2) local activity coherence (regional homogeneity, ReHo) and functional connectivity using resting-state functional magnetic resonance imaging; and 3) anhedonia from the Inventory for Depressive Symptoms-Self Reported. Plasma quinolinic acid (QA) was associated with increases and kynurenic acid (KYNA) and KYNA/QA with decreases in LBG Glu. Plasma kynurenine/tryptophan and CSF 3-hydroxy kynurenine (3HK) were associated with increases in LBG mI. Plasma and CSF KP were associated with decreases in ReHo in LBG and dorsomedial prefrontal cortex (DMPFC), and impaired functional connectivity between these two brain regions. DMPFC-BG connectivity mediated the effect of plasma and CSF KP metabolites on anhedonia. These findings highlight the contribution of KP metabolites to glial and neuronal dysfunction and ultimately behavior in depression.

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Depressive symptoms following traumatic brain injury are associated with resting-state functional connectivity

Psychological Medicine ◽

10.1017/s0033291721004724 ◽

2021 ◽

pp. 1-8

Author(s):

Lizhu Luo ◽

Christelle Langley ◽

Laura Moreno-Lopez ◽

Keith Kendrick ◽

David K. Menon ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Depressive Symptoms ◽

Brain Injury ◽

Functional Connectivity ◽

Resting State ◽

Emotional Regulation ◽

Positive Association ◽

Structural Mri ◽

Brain Regions ◽

Resting State Functional Connectivity

Abstract Background To determine whether depressive symptoms in traumatic brain injury (TBI) patients were associated with altered resting-state functional connectivity (rs-fc) or voxel-based morphology in brain regions involved in emotional regulation and associated with depression. Methods In the present study, we examined 79 patients (57 males; age range = 17–70 years, M ± s.d. = 38 ± 16.13; BDI-II, M ± s.d. = 9.84 ± 8.67) with TBI. We used structural MRI and resting-state fMRI to examine whether there was a relationship between depression, as measured with the Beck Depression Inventory (BDI-II), and the voxel-based morphology or functional connectivity in regions previously identified as involved in emotional regulation in patients following TBI. Patients were at least 4 months post-TBI (M ± s.d. = 15.13 ± 11.67 months) and the severity of the injury included mild to severe cases [Glasgow Coma Scale (GCS), M ± s.d. = 6.87 ± 3.31]. Results Our results showed that BDI-II scores were unrelated to voxel-based morphology in the examined regions. We found a positive association between depression scores and rs-fc between limbic regions and cognitive control regions. Conversely, there was a negative association between depression scores and rs-fc between limbic and frontal regions involved in emotion regulation. Conclusion These findings lead to a better understanding of the exact mechanisms that contribute to depression following TBI and better inform treatment decisions.

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The connectome predicts resting state functional connectivity across the Drosophila brain

10.1101/2020.12.11.422105 ◽

2020 ◽

Cited By ~ 1

Author(s):

Maxwell H Turner ◽

Kevin Mann ◽

Thomas R. Clandinin

Keyword(s):

Functional Connectivity ◽

Large Scale ◽

Neural Circuit ◽

Brain Networks ◽

Brain Regions ◽

Central Complex ◽

Resting State Functional Connectivity ◽

Brain Structure And Function ◽

And Function

Connectomic datasets have emerged as invaluable tools for understanding neural circuits in many systems. What constraints does the connectome place on information processing and routing in a large scale neural circuit? For mesoscale brain networks, the relationship between cell and synaptic level connectivity and brain function is not well understood. Here, we use data from the Drosophila connectome in conjunction with whole-brain in vivo imaging to relate structural and functional connectivity in the central brain. We find that functional connectivity is strongly associated with the strength of both direct and indirect anatomical pathways. We also show that some brain regions, including the mushroom body and central complex, show considerably higher functional connectivity to other brain regions than is predicted based on their direct anatomical connections. We find several key topological similarities between mesoscale brain networks in flies and mammals, revealing conserved principles relating brain structure and function.

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Biomimetic Microfluidic Platforms for the Assessment of Breast Cancer Metastasis

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.633671 ◽

2021 ◽

Vol 9 ◽

Author(s):

Indira Sigdel ◽

Niraj Gupta ◽

Fairuz Faizee ◽

Vishwa M. Khare ◽

Amit K. Tiwari ◽

...

Keyword(s):

Breast Cancer ◽

Animal Studies ◽

Cancer Metastasis ◽

Three Dimensional ◽

Breast Cancer Metastasis ◽

Therapeutic Interventions ◽

Special Focus ◽

Cellular Interactions

Of around half a million women dying of breast cancer each year, more than 90% die due to metastasis. Models necessary to understand the metastatic process, particularly breast cancer cell extravasation and colonization, are currently limited and urgently needed to develop therapeutic interventions necessary to prevent breast cancer metastasis. Microfluidic approaches aim to reconstitute functional units of organs that cannot be modeled easily in traditional cell culture or animal studies by reproducing vascular networks and parenchyma on a chip in a three-dimensional, physiologically relevantin vitrosystem. In recent years, microfluidics models utilizing innovative biomaterials and micro-engineering technologies have shown great potential in our effort of mechanistic understanding of the breast cancer metastasis cascade by providing 3D constructs that can mimicin vivocellular microenvironment and the ability to visualize and monitor cellular interactions in real-time. In this review, we will provide readers with a detailed discussion on the application of the most up-to-date, state-of-the-art microfluidics-based breast cancer models, with a special focus on their application in the engineering approaches to recapitulate the metastasis process, including invasion, intravasation, extravasation, breast cancer metastasis organotropism, and metastasis niche formation.

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In Vivo Circuit Analysis

10.1093/med/9780190681425.003.0007 ◽

2017 ◽

Author(s):

Ryan Bowman ◽

Hannah Schwennesen ◽

Kafui Dzirasa ◽

Rainbo Hultman

Keyword(s):

Side Effects ◽

Animal Models ◽

Psychiatric Disorders ◽

Neural Circuit ◽

Brain Regions ◽

Therapeutic Strategies ◽

Dynamic Activity ◽

Wide Range

Breakthroughs in understanding neural circuit activity hold much promise for developing next generation therapeutics for psychiatric disorders. Determination of how dynamic activity is coordinated across brain regions to effect specific behavioral function (or dysfunction) enables the development of therapeutics with increased specificity and fewer side effects. This chapter discusses methodologies for measuring neural circuit activity in humans and in animal models, and describes a bidirectional research pipeline whereby studies in humans are followed by tightly controlled studies in animal models that can then be applied back to humans. Targeted neural circuit manipulations from these studies are already being applied to a wide range of therapeutic strategies.

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