Structure of human GABAB receptor in an inactive state.

The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2-6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9-14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

Author Correction: Structure of human GABAB receptor in an inactive state.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evolving membrane-associated accessory protein variants for improved adeno-associated virus production.

Manufacturing sufficient adeno-associated virus (AAV) to meet current and projected clinical needs is a significant hurdle to the growing gene therapy industry. The recently discovered membrane-associated accessory protein (MAAP) is encoded by an alternative open reading frame in the AAV cap gene that is found in all presently reported natural serotypes. Recent evidence has emerged supporting a functional role of MAAP in AAV egress, although the underlying mechanisms of MAAP function remain unknown. Here, we show that inactivation of MAAP from AAV2 by a single point mutation that is silent in the VP1 open reading frame (ORF) (AAV2-ΔMAAP) decreased exosome-associated and secreted vector genome production. We hypothesized that novel MAAP variants could be evolved to increase AAV production and thus subjected a library encoding over 1 × 106 MAAP protein variants to five rounds of packaging selection into the AAV2-ΔMAAP capsid. Between each successive packaging round, we observed a progressive increase in both overall titer and ratio of secreted vector genomes conferred by the bulk-selected MAAP library population. Next-generation sequencing uncovered enriched mutational features, and a resulting selected MAAP variant containing missense mutations and a frameshifted C-terminal domain increased overall GFP transgene packaging in AAV2, AAV6, and AAV9 capsids.

Outcomes of Patients Receiving Thrombolysis in a Mobile Stroke Unit: A 4-Year Retrospective, Observational, Single-Center Study.

BACKGROUND AND PURPOSE: Patients with acute ischemic stroke (AIS) eligible for thrombolysis benefit when thrombolysis is administered quickly, and mobile stroke units (MSU) can facilitate timely thrombolysis. We sought to compare time metrics and clinical outcomes of AIS patients receiving thrombolysis in an MSU compared with patients arriving via local emergency medical services (EMS). METHODS: We performed a retrospective, non-randomized, cohort study comparing MSU-arriving to EMS-arriving AIS patients from January 20, 2017 through November 30, 2020. The primary outcome was rate of return to baseline functional status as measured by the modified Rankin Score (mRS) 90 days after thrombolysis. Secondary outcomes included evaluation and treatment intervals from last known well, treatment rate in the first hour of symptoms, hospital length of stay, and mortality. Chi square and Student's t-test were used to compare groups. RESULTS: Of 1752 total patients with prehospital suspected stroke, 975 (55.7%) were transported via MSU, of whom 431 (44.2%) were diagnosed with stroke, including 368 (85.4%) with AIS, and 69 AIS patients (18.8%) received thrombolysis. Of 777 (44.3%) EMS-arriving patients, 373 (48%) were diagnosed with stroke, including 305 (81.8%) with AIS, and 74 (24.3%) received thrombolysis. Though not statistically significant, point estimates of the proportion of AIS patients treated with thrombolysis returning to baseline functional status were more commonly observed for MSU than for EMS transports when the baseline mRS was 0-2 (45.8% vs 33.3%), 0-3 (41.9% vs 33.3%), and 4-5 (71.4% vs 20.0%). MSU patients were more likely to receive thrombolysis in the first 60 minutes of symptom onset (31.9% vs 12.2%, p = 0.006). Overall mortality rates regardless of baseline mRS were similar between groups. CONCLUSIONS: AIS patients received thrombolysis faster in the MSU compared with EMS and more frequently within 60 minutes of stroke onset. Point estimates for 90-day clinical outcomes of AIS patients treated with thrombolysis favored MSU without a statistically significant difference.

Osteocyte-Derived CaMKK2 Regulates Osteoclasts and Bone Mass in a Sex-Dependent Manner through Secreted Calpastatin.

Calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) regulates bone remodeling through its effects on osteoblasts and osteoclasts. However, its role in osteocytes, the most abundant bone cell type and the master regulator of bone remodeling, remains unknown. Here we report that the conditional deletion of CaMKK2 from osteocytes using Dentine matrix protein 1 (Dmp1)-8kb-Cre mice led to enhanced bone mass only in female mice owing to a suppression of osteoclasts. Conditioned media isolated from female CaMKK2-deficient osteocytes inhibited osteoclast formation and function in in vitro assays, indicating a role for osteocyte-secreted factors. Proteomics analysis revealed significantly higher levels of extracellular calpastatin, a specific inhibitor of calcium-dependent cysteine proteases calpains, in female CaMKK2 null osteocyte conditioned media, compared to media from female control osteocytes. Further, exogenously added non-cell permeable recombinant calpastatin domain I elicited a marked, dose-dependent inhibition of female wild-type osteoclasts and depletion of calpastatin from female CaMKK2-deficient osteocyte conditioned media reversed the inhibition of matrix resorption by osteoclasts. Our findings reveal a novel role for extracellular calpastatin in regulating female osteoclast function and unravel a novel CaMKK2-mediated paracrine mechanism of osteoclast regulation by female osteocytes.

A meta-analytic investigation of grey matter differences in anorexia nervosa and autism spectrum disorder.

Recent research reports Anorexia Nervosa (AN) to be highly dependent upon neurobiological function. Some behaviours, particularly concerning food selectivity are found in populations with both Autism Spectrum Disorder (ASD) and AN, and there is a proportionally elevated number of anorexic patients exhibiting symptoms of ASD. We performed a systematic review of structural MRI literature with the aim of identifying common structural neural correlates common to both AN and ASD. Across 46 ASD publications, a meta-analysis of volumetric differences between ASD and healthy controls revealed no consistently affected brain regions. Meta-analysis of 23 AN publications revealed increased volume within the orbitofrontal cortex and medial temporal lobe, and adult-only AN literature revealed differences within the genu of the anterior cingulate cortex. The changes are consistent with alterations in flexible reward-related learning and episodic memory reported in neuropsychological studies. There was no structural overlap between ASD and AN. Findings suggest no consistent neuroanatomical abnormality associated with ASD, and evidence is lacking to suggest that reported behavioural similarities between those with AN and ASD are due to neuroanatomical structural similarities.

Sequence analysis of the Petunia inflata S-locus region containing 17 S-Locus F-Box genes and the S-RNase gene involved in self-incompatibility.

Self-incompatibility in Petunia is controlled by the polymorphic S-locus, which contains S-RNase encoding the pistil determinant and 16-20 S-locus F-box (SLF) genes collectively encoding the pollen determinant. Here we sequenced and assembled approximately 3.1 Mb of the S2 -haplotype of the S-locus in Petunia inflata using bacterial artificial chromosome clones collectively containing all 17 SLF genes, SLFLike1, and S-RNase. Two SLF pseudogenes and 28 potential protein-coding genes were identified, 20 of which were also found at the S-loci of both the S6a -haplotype of P. inflata and the SN -haplotype of self-compatible Petunia axillaris, but not in the S-locus remnants of self-compatible potato (Solanum tuberosum) and tomato (Solanum lycopersicum). Comparative analyses of S-locus sequences of these three S-haplotypes revealed potential genetic exchange in the flanking regions of SLF genes, resulting in highly similar flanking regions between different types of SLF and between alleles of the same type of SLF of different S-haplotypes. The high degree of sequence similarity in the flanking regions could often be explained by the presence of similar long terminal repeat retroelements, which were enriched at the S-loci of all three S-haplotypes and in the flanking regions of all S-locus genes examined. We also found evidence of the association of transposable elements with SLF pseudogenes. Based on the hypothesis that SLF genes were derived by retrotransposition, we identified 10 F-box genes as putative SLF parent genes. Our results shed light on the importance of non-coding sequences in the evolution of the S-locus, and on possible evolutionary mechanisms of generation, proliferation, and deletion of SLF genes.

S-Locus F-Box Proteins Are Solely Responsible for S-RNase-Based Self-Incompatibility of Petunia Pollen.

Self-incompatibility (SI) in Petunia is regulated by a polymorphic S-locus. For each S-haplotype, the S-locus contains a pistil-specific S-RNase gene and multiple pollen-specific S-locus F-box (SLF) genes. Both gain-of-function and loss-of-function experiments have shown that S-RNase alone regulates pistil specificity in SI. Gain-of-function experiments on SLF genes suggest that the entire suite of encoded proteins constitute the pollen specificity determinant. However, clear-cut loss-of-function experiments must be performed to determine if SLF proteins are essential for SI of pollen. Here, we used CRISPR/Cas9 to generate two frame-shift indel alleles of S2 -SLF1 (SLF1 of S2 -haplotype) in S2S3 plants of P. inflata and examined the effect on the SI behavior of S2 pollen. In the absence of a functional S2-SLF1, S2 pollen was either rejected by or remained compatible with pistils carrying one of eight normally compatible S-haplotypes. All results are consistent with interaction relationships between the 17 SLF proteins of S2 -haplotype and these eight S-RNases that had been determined by gain-of-function experiments performed previously or in this work. Our loss-of-function results provide definitive evidence that SLF proteins are solely responsible for SI of pollen, and they reveal their diverse and complex interaction relationships with S-RNases to maintain SI while ensuring cross-compatibility.

Latent cellular analysis robustly reveals subtle diversity in large-scale single-cell RNA-seq data.

Single-cell RNA sequencing (scRNA-seq) is a powerful tool for characterizing the cell-to-cell variation and cellular dynamics in populations which appear homogeneous otherwise in basic and translational biological research. However, significant challenges arise in the analysis of scRNA-seq data, including the low signal-to-noise ratio with high data sparsity, potential batch effects, scalability problems when hundreds of thousands of cells are to be analyzed among others. The inherent complexities of scRNA-seq data and dynamic nature of cellular processes lead to suboptimal performance of many currently available algorithms, even for basic tasks such as identifying biologically meaningful heterogeneous subpopulations. In this study, we developed the Latent Cellular Analysis (LCA), a machine learning-based analytical pipeline that combines cosine-similarity measurement by latent cellular states with a graph-based clustering algorithm. LCA provides heuristic solutions for population number inference, dimension reduction, feature selection, and control of technical variations without explicit gene filtering. We show that LCA is robust, accurate, and powerful by comparison with multiple state-of-the-art computational methods when applied to large-scale real and simulated scRNA-seq data. Importantly, the ability of LCA to learn from representative subsets of the data provides scalability, thereby addressing a significant challenge posed by growing sample sizes in scRNA-seq data analysis.

Recovery and Regrowth After Nerve Repair: A Systematic Analysis of Four Repair Techniques.

BACKGROUND: Outcome assessments that evaluate post-transection nerve repair do not often correlate with one another. The aims of this study were twofold: to compare four nerve repair techniques with each other and incorporate both negative and positive control groups and to identify possible correlations between outcome assessments. MATERIALS AND METHODS: Sciatic nerve transection and repair was performed in Lewis rats using one of the following techniques: interrupted epineural, running epineural, grouped fascicular, epineural with absorbable type I collagen wrap, and high tension for incorporation of a negative control. A sham surgery group was also included as a positive control group. Outcomes were compared using assessments of functional recovery (behavior and electrophysiology) and nerve regrowth (imaging and histomorphometry). Three-dimensional printed custom electrode stabilization and imaging devices were designed and fabricated to provide standardization in assessment between subjects. RESULTS: Nerve repair was performed in 48 male Lewis rats. In all animals, functional testing was performed at week 13. The sham group (n = 7) performed the best on both behavioral assays (P < 0.001) and electrophysiology assessments (P < 0.001). The negative control group (high tension) performed poorest on multiple assessments, and there were no significant differences observed for any of the four repair types. Positive correlations were observed between behavioral and histomorphometric tests. CONCLUSIONS: There was no difference in outcome between the four types of nerve repair. High-tension nerve repair represents an ideal negative control. Not all assessment methods correlate equally, and consistent use of complimentary outcome assessments could allow for improved comparison between studies.

Modeling observations with a detection limit using a truncated normal distribution with censoring.

BACKGROUND: When data are collected subject to a detection limit, observations below the detection limit may be considered censored. In addition, the domain of such observations may be restricted; for example, values may be required to be non-negative. METHODS: We propose a method for estimating population mean and variance from censored observations that accounts for known domain restriction. The method finds maximum likelihood estimates assuming an underlying truncated normal distribution. RESULTS: We show that our method, tcensReg, has lower bias, Type I error rates, and mean squared error than other methods commonly used for data with detection limits such as Tobit regression and single imputation under a range of simulation settings from mild to heavy censoring and truncation. We further demonstrate the consistency of the maximum likelihood estimators. We apply our method to analyze vision quality data collected from ophthalmology clinical trials comparing different types of intraocular lenses implanted during cataract surgery. All of the methods yield similar conclusions regarding non-inferiority, but estimates from the tcensReg method suggest that there may be greater mean differences and overall variability. CONCLUSIONS: In the presence of detection limits, our new method tcensReg provides a way to incorporate known domain restrictions in dependent variables that substantially improves inferences.

The Adolescent and Caregiver Sickle Cell Disease Self-management Skills Checklist: Preliminary Reliability and Validity.

Adolescents with sickle cell disease (SCD) need assistance in developing the knowledge and skills that contribute to increased disease self-management and successful transition to adult-based health care. This study evaluated the preliminary psychometric properties of the Self-Management Skills Checklist (SMSC and SMSC-C; Adolescent and Caregiver versions), a measure of perceived SCD-specific knowledge and skills. A retrospective cohort study included 114 adolescents (mean=15.6 y) and their caregivers. We examined internal structure and reliability, score changes over time, and group differences. Cronbach coefficient alphas were 0.79 and 0.74 for caregiver-reported Skills and caregiver-reported knowledge, respectively, and 0.77 and 0.44 for adolescent-reported skills and adolescent-reported knowledge, respectively, indicating good internal consistency for 3 of the subscales. Poor reliability in the adolescent-reported knowledge summary score and factor analysis suggest an interpretation item-by-item, independent of one another. Participant group differences in age and chronic transfusion treatment existed in both summary and subscale scores of the SMSC and SMSC-C. Follow-up administrations of the scales indicated an increase in caregiver-reported skills for their adolescents from time 1 scores (M=3.72±0.83) to time 2 scores (M=3.99±0.63) (t16=2.178, P=0.045). Findings provide preliminary support for the usage of the SMSC and continued development to improve its psychometrics.

Adolescents with autism spectrum disorder and social skills groups at school: A randomized trial comparing intervention environment and peer composition.

This study used a randomized controlled trial to compare two distinct models of group social skills interventions with adolescents with autism spectrum disorder (ASD). Participants had a confirmed diagnosis of ASD, an IQ greater than or equal to 70, and were educated in the general education setting. Data from 62 adolescent participants who were randomized to one of two treatment conditions (SKILLS vs. ENGAGE) were analyzed. SKILLS participants had a diagnosis of ASD, or social difficulties. ENGAGE groups included adolescents with ASD and typically developing (TD) peer mentors. SKILLS and ENGAGE participants both improved joint engagement and reduced solitary engagement, however, SKILLS participants reported higher social stress and lower quality interpersonal relationships at exit, and increased emotional symptoms and problem behaviors at follow-up compared to the ENGAGE group. The findings suggest that within inclusive secondary school settings, it may be beneficial to include TD peers in social intervention groups.

Tuning a timing device that regulates lateral root development in rice.

Peptidyl Prolyl Isomerases (PPIases) accelerate cis-trans isomerization of prolyl peptide bonds. In rice, the PPIase LRT2 is essential for lateral root initiation. LRT2 displays in vitro isomerization of a highly conserved W-P peptide bond (104W-P105) in the natural substrate OsIAA11. OsIAA11 is a transcription repressor that, in response to the plant hormone auxin, is targeted to ubiquitin-mediated proteasomal degradation via specific recognition of the cis isomer of its 104W-P105 peptide bond. OsIAA11 controls transcription of specific genes, including its own, that are required for lateral root development. This auxin-responsive negative feedback circuit governs patterning and development of lateral roots along the primary root. The ability to tune LRT2 activity via mutagenesis is crucial for understanding and modeling the role of this bimodal switch in the auxin circuit and lateral root development. We present characterization of the thermal stability and isomerization rates of several LRT2 mutants acting on the OsIAA11 substrate. The thermally stable mutants display activities lower than that of wild-type (WT) LRT2. These include binding diminished but catalytically active P125K, binding incompetent W128A, and binding capable but catalytically incompetent H133Q mutations. Additionally, LRT2 homologs hCypA from human, TaCypA from Triticum aestivum (wheat) and PPIB from E. coli were shown to have 110, 50 and 60% of WT LRT2 activity on the OsIAA11 substrate. These studies identify several thermally stable LRT2 mutants with altered activities that will be useful for establishing relationships between cis-trans isomerization, auxin circuit dynamics, and lateral root development in rice.

CaMKK2 Signaling in Metabolism and Skeletal Disease: a New Axis with Therapeutic Potential.

PURPOSE OF REVIEW: Age and metabolic disorders result in the accumulation of advanced glycation endproducts (AGEs), oxidative stress, and inflammation, which cumulatively cause a decline in skeletal health. Bone becomes increasingly vulnerable to fractures and its regenerative capacity diminishes under such conditions. With a rapidly aging population in the USA and the global increase in diabetes, efficacious, multi-dimensional therapies that can treat or prevent skeletal diseases associated with metabolic dysfunction and inflammatory disorders are acutely needed. RECENT FINDINGS: Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of nutrient intake, glucose metabolism, insulin production, and adipogenesis. Recent studies suggest a pivotal role for CaMKK2 in bone metabolism, fracture healing, and inflammation. Aside from rekindling previous concepts of CaMKK2 as a potent regulator of whole-body energy homeostasis, this review emphasizes CaMKK2 as a potential therapeutic target to treat skeletal diseases that underlie metabolic conditions and inflammation.

Use of Domain-Swapping to Identify Candidate Amino Acids Involved in Differential Interactions between Two Allelic Variants of Type-1 S-Locus F-Box Protein and S3-RNase in Petunia inflata.

Petunia inflata possesses a self-incompatibility (SI) mechanism, which involves S-RNase and multiple S-locus F-box (SLF) genes at the polymorphic S-locus. For a given S-haplotype, each SLF is thought to interact with some of its non-self S-RNases, but not with its self S-RNase. In this work, we studied an allelic pair of SLF1, S2-SLF1 and S3-SLF1, which differ in 44 amino acids and show differential interactions with S3-RNase. We first used an in vivo transgenic assay to determine whether four chimeric proteins of S2-SLF1 and S3-SLF1, each with one of the three functional domains swapped, interact with S3-RNase. The results narrowed the candidate amino acids for specific interaction of S2-SLF1 with S3-RNase to the 16 in domain FD3. We then examined seven additional chimeric proteins by dividing FD3 into two subdomains and four mini-domains (A, B, C and D). The results further narrowed the candidate amino acids to four in mini-domain A and four in mini-domain D. Molecular modeling of interactions between S3-RNase and S2-SLF1 revealed that three of these eight are at the interaction surface, and all three are conserved in S1-SLF1 and S6a-SLF1, both of which interact with S3-RNase based on the in vivo transgenic assay. Three of the chimeric proteins were used for the in vivo transgenic assay to determine whether FD3 alone contains the amino acids required for S2-SLF1 to interact with S7-RNase and S13-RNase. The results revealed the diversity and complexity of interactions between SLF proteins and S-RNases.

Folding, Assembly, and Persistence: The Essential Nature and Origins of Biopolymers.

Life as we know it requires three basic types of polymers: polypeptide, polynucleotide, and polysaccharide. Here we evaluate both universal and idiosyncratic characteristics of these biopolymers. We incorporate this information into a model that explains much about their origins, selection, and early evolution. We observe that all three biopolymer types are pre-organized, conditionally self-complementary, chemically unstable in aqueous media yet persistent because of kinetic trapping, with chiral monomers and directional chains. All three biopolymers are synthesized by dehydration reactions that are catalyzed by molecular motors driven by hydrolysis of phosphorylated nucleosides. All three biopolymers can access specific states that protect against hydrolysis. These protected states are folded, using self-complementary interactions among recurrent folding elements within a given biopolymer, or assembled, in associations between the same or different biopolymer types. Self-association in a hydrolytic environment achieves self-preservation. Heterogeneous association achieves partner-preservation. These universal properties support a model in which life's polymers emerged simultaneously and co-evolved in a common hydrolytic milieu where molecular persistence depended on folding and assembly. We believe that an understanding of the structure, function, and origins of any given type of biopolymer requires the context of other biopolymers.

Hitting the Target: Mathematical Attainment in Children Is Related to Interceptive-Timing Ability.

Interceptive timing is a fundamental ability underpinning numerous actions (e.g., ball catching), but its development and relationship with other cognitive functions remain poorly understood. Piaget suggested that children need to learn the physical rules that govern their environment before they can represent abstract concepts such as number and time. Thus, learning how objects move in space and time may underpin the development of related abstract representations (i.e., mathematics). To test this hypothesis, we captured objective measures of interceptive timing in 309 primary school children (5-11 years old), alongside scores for general motor skill and national standardized academic attainment. Bayesian estimation showed that interceptive timing (but not general motor capability) uniquely predicted mathematical ability even after we controlled for age, reading, and writing attainment. This finding demonstrates that interceptive timing is distinct from other motor skills with specificity in predicting childhood mathematical ability independently of other forms of attainment and motor capability.

All 17 S-locus F-box proteins of the S2 - and S3 -haplotypes of Petunia inflata are assembled into similar SCF complexes with a specific function in self-incompatibility.

The collaborative non-self-recognition model for S-RNase-based self-incompatibility predicts that multiple S-locus F-box proteins (SLFs) produced by pollen of a given S-haplotype collectively mediate ubiquitination and degradation of all non-self S-RNases, but not self S-RNases, in the pollen tube, thereby resulting in cross-compatible pollination but self-incompatible pollination. We had previously used pollen extracts containing GFP-fused S2 -SLF1 (SLF1 with an S2 -haplotype) of Petunia inflata for co-immunoprecipitation (Co-IP) and mass spectrometry (MS), and identified PiCUL1-P (a pollen-specific Cullin1), PiSSK1 (a pollen-specific Skp1-like protein) and PiRBX1 (a conventional Rbx1) as components of the SCF(S) (2-) (SLF) (1) complex. Using pollen extracts containing PiSSK1:FLAG:GFP for Co-IP/MS, we identified two additional SLFs (SLF4 and SLF13) that were assembled into SCF(SLF) complexes. As 17 SLF genes (SLF1 to SLF17) have been identified in S2 and S3 pollen, here we examined whether all 17 SLFs are assembled into similar complexes and, if so, whether these complexes are unique to SLFs. We modified the previous Co-IP/MS procedure, including the addition of style extracts from four different S-genotypes to pollen extracts containing PiSSK1:FLAG:GFP, to perform four separate experiments. The results taken together show that all 17 SLFs and an SLF-like protein, SLFLike1 (encoded by an S-locus-linked gene), co-immunoprecipitated with PiSSK1:FLAG:GFP. Moreover, of the 179 other F-box proteins predicted by S2 and S3 pollen transcriptomes, only a pair with 94.9% identity and another pair with 99.7% identity co-immunoprecipitated with PiSSK1:FLAG:GFP. These results suggest that SCF(SLF) complexes have evolved specifically to function in self-incompatibility.

Estimating cortical column sensory networks in rodents from micro-electrocorticograph (µECoG) recordings.

Micro-electrocorticograph (µECoG) arrays offer the flexibility to record local field potentials (LFPs) from the surface of the cortex, using high density electrodes that are sub-mm in diameter. Research to date has not provided conclusive evidence for the underlying signal generation of µECoG recorded LFPs, or if µECoG arrays can capture network activity from the cortex. We studied the pervading view of the LFP signal by exploring the spatial scale at which the LFP can be considered elemental. We investigated the underlying signal generation and ability to capture functional networks by implanting, µECoG arrays to record sensory-evoked potentials in four rats. The organization of the sensory cortex was studied by analyzing the sensory-evoked potentials with two distinct modeling techniques: (1) The volume conduction model, that models the electrode LFPs with an electrostatic representation, generated by a single cortical generator, and (2) the dynamic causal model (DCM), that models the electrode LFPs with a network model, whose activity is generated by multiple interacting cortical sources. The volume conduction approach modeled activity from electrodes separated < 1000 µm, with reasonable accuracy but a network model like DCM was required to accurately capture activity > 1500 µm. The extrinsic network component in DCM was determined to be essential for accurate modeling of observed potentials. These results all point to the presence of a sensory network, and that µECoG arrays are able to capture network activity in the neocortex. The estimated DCM network models the functional organization of the cortex, as signal generators for the µECoG recorded LFPs, and provides hypothesis-testing tools to explore the brain.