Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.     

Deep Artificial Neural Networks Reveal a Distributed Cortical Network Encoding Propositional Sentence-Level Meaning

Understanding how and where in the brain sentence-level meaning is constructed from words presents a major scientific challenge. Recent advances have begun to explain brain activation elicited by sentences using vector models of word meaning derived from patterns of word co-occurrence in text corpora. These studies have helped map out semantic representation across a distributed brain network spanning temporal, parietal, and frontal cortex. However, it remains unclear whether activation patterns within regions reflect unified representations of sentence-level meaning, as opposed to superpositions of context-independent component words. This is because models have typically represented sentences as “bags-of-words” that neglect sentence-level structure. To address this issue, we interrogated fMRI activation elicited as 240 sentences were read by 14 participants (9 female, 5 male), using sentences encoded by a recurrent deep artificial neural-network trained on a sentence inference task (InferSent). Recurrent connections and nonlinear filters enable InferSent to transform sequences of word vectors into unified “propositional” sentence representations suitable for evaluating intersentence entailment relations. Using voxelwise encoding modeling, we demonstrate that InferSent predicts elements of fMRI activation that cannot be predicted by bag-of-words models and sentence models using grammatical rules to assemble word vectors. This effect occurs throughout a distributed network, which suggests that propositional sentence-level meaning is represented within and across multiple cortical regions rather than at any single site. In follow-up analyses, we place results in the context of other deep network approaches (ELMo and BERT) and estimate the degree of unpredicted neural signal using an “experiential” semantic model and cross-participant encoding.SIGNIFICANCE STATEMENT A modern-day scientific challenge is to understand how the human brain transforms word sequences into representations of sentence meaning. A recent approach, emerging from advances in functional neuroimaging, big data, and machine learning, is to computationally model meaning, and use models to predict brain activity. Such models have helped map a cortical semantic information-processing network. However, how unified sentence-level information, as opposed to word-level units, is represented throughout this network remains unclear. This is because models have typically represented sentences as unordered “bags-of-words.” Using a deep artificial neural network that recurrently and nonlinearly combines word representations into unified propositional sentence representations, we provide evidence that sentence-level information is encoded throughout a cortical network, rather than in a single region.     

Neurological comorbidity and severity of COVID-19

Journal of Neurology - Neurological symptoms of COVID-19 patients have been recently described. However, no comprehensive data have been reported on pre-existing neurological comorbidities and...     

Stroke care in Italy at the time of the COVID-19 pandemic: a lesson to learn

Journal of Neurology - From March to May 2020, the Italian health care system, as many others, was almost entirely devoted to the fight against the COVID-19 pandemic. In this context, a number of...     

Cognitive and behavioral manifestations in SARS-CoV-2 infection: not specific or distinctive features?

Neurological Sciences - Patients with COVID-19 are increasingly reported to suffer from a wide range of neurological complications, affecting both the central and peripheral nervous system. Among...     

Description of fecal shedding of Cryptosporidium parvum oocysts in experimentally challenged dairy calves

The objective was to describe the probability of Cryptosporidium parvum fecal oocyst shedding at different magnitudes of exposure, the pattern of fecal shedding over time, and factors affecting fecal shedding in dairy calves. Within the first 24 h of life, 36 calves were experimentally challenged with C. parvum oocysts at one of four possible magnitudes of oral exposure (1?×?10³, 1?×?10⁴, 1?×?10⁵, and 1?×?10⁶ oocysts), and 7 control calves were sham dosed. Fecal shedding occurred in 33 (91.7 %) experimentally challenged calves and in none of the control calves. There was a difference in the log-total number of oocysts counted per gram of feces dry weight among the four exposure groups; calves with the lowest magnitude of exposure (1?×?10³ oocysts) shed less than the other three groups. At higher magnitudes of exposure, there was more variability in the range of fecal oocyst shedding. There was an inverse relationship between the log-total amount of oocysts counted per gram of feces dry weight and the number of days to the onset of fecal shedding per calf, i.e., the more time that elapsed to the onset of fecal shedding, the fewer oocysts that were shed. The pattern of fecal shedding over time for all calves shedding oocysts was curvilinear; the number of oocysts increased with time, reached a peak, and declined. Therefore, the dynamics of oocyst shedding can be influenced in part by limiting exposure among calves and delaying the onset of fecal oocyst shedding.     

Pro-caspase-3 is constitutively expressed in luteinized granulosa cells from women undergoing controlled ovarian stimulation for in vitro fertilization

Apoptosis regulation in luteinized granulosa cells (LGC) during assisted reproduction procedures is still controversial. Caspase-3 is a major apoptosis mediator encoded by CASP3 and formed through cleavage of its precursor pro-caspase-3. The aim of this study was to investigate the expression patterns of pro-caspase-3 (mRNA and protein) and cleaved caspase-3 in human LGC. Thirty-five women undergoing controlled ovarian stimulation for in vitro fertilization were prospectively enrolled in the study. LGC were isolated from follicular fluid during oocyte pickup and evaluated by immunocytochemistry for pro-caspase-3 and cleaved caspase-3, and by real-time PCR for CASP3 mRNA expression. We found a positive staining of pro-caspase-3 in 77 % of the LGC (95 % confidence interval [CI] 60%–84%), whereas cleaved caspase-3 was found in only 4% of the cells (95 % CI 3%–6%). The abundance of cells expressing pro-caspase-3 was independent from CASP3 mRNA levels (r = 0.24, p = 0.255) and did not correlate with the amount of cleaved caspase-3 (r = -0.24, p = 0.186). Multivariable logistic regression showed that pro-caspase-3 positivity was not influenced by clinical characteristics such as age, cause or length of infertility, antral follicle count or hormonal drugs used to induce ovulation. These findings suggest that pro-caspase-3 is constitutively expressed in LGC, allowing quick cleavage into active caspase-3 and apoptosis triggering whenever needed in the course of gonadotropin-induced follicular development.     

Development and validation of two new image receptor-holding devices for overlapping reduction of proximal surfaces in bitewing radiography: a preclinical study

Objective:To create and validate two new Image Receptor-Holding devices (IRHDs) to reduce proximal surfaces overlapping in bitewing radiography in comparison to a regular well-established and commercially available IRHD.Methods:Two IRHDs for bitewing radiographs with a wedge on the biting surface were designed and 3D-printed. These IRHDs, with a large wedge (Pr-Lw) and small wedge (Pr-Sw), were compared with a regular commercially available IRHD (Rinn XCP^®) during image acquisition of bitewing radiographs of four posterior regions (one upper region and three lower regions) in two dry skulls and mandibles. A total of 156 interproximal regions on bitewing radiographs were radiographed by 13 oral radiology graduate students and independently assessed by two oral radiologists (10 years of experience). IRHDs were compared by Cochran’s Q test regarding the number of overlapped proximal surfaces in the acquired radiographs with a significance level of 5%.Results:The observers were in perfect agreement (κ = 1.0) to classify the proximal surfaces overlapping. The Pr-Lw IRHD presented the lowest number of surfaces overlapping (19.2%) followed by the Pr-Sw IRHD (48.1%) and the XCP^®IRHD with the highest surfaces overlapping (71.2%). The Pr-Lw IRHD surfaces overlapping was statistically different from the XCP IRHD (p < 0.001), and the Pr-Sw IRHD (p = 0.014).Conclusions:The Pr-Lw IRHD demonstrated the most efficient performance in overlapping surfaces reduction, compared with the Pr-Sw IRHD and the XCP^® IRHD in adult dry skulls and mandibles.     

Tooth loss in complying and non-complying periodontitis patients with different periodontal risk levels during supportive periodontal care

Clinical Oral Investigations - To evaluate yearly tooth loss rate (TLR) in periodontitis patients with different periodontal risk levels who had complied or not complied with supportive periodontal...