13 research outputs found
The posterior auditory field is the chief generator of prediction error signals in the auditory cortex
The auditory cortex (AC) encompasses distinct fields subserving partly different aspects of sound processing. One essential function of the AC is the detection of unpredicted sounds, as revealed by differential neural activity to predictable and unpredictable sounds. According to the predictive coding framework, this effect can be explained by repetition suppression and/or prediction error signaling. The present study investigates functional specialization of the rat AC fields in repetition suppression and prediction error by combining a tone frequency oddball paradigm (involving high-probable standard and low-probable deviant tones) with two different control sequences (many-standards and cascade). Tones in the control sequences were comparable to deviant events with respect to neural adaptation but were not violating a regularity. Therefore, a difference in the neural activity between deviant and control tones indicates a prediction error effect, whereas a difference between control and standard tones indicates a repetition suppression effect. Single-unit recordings revealed by far the largest prediction error effects for the posterior auditory field, while the primary auditory cortex, the anterior auditory field, the ventral auditory field, and the suprarhinal auditory field were dominated by repetition suppression effects. Statistically significant repetition suppression effects occurred in all AC fields, whereas prediction error effects were less robust in the primary auditory cortex and the anterior auditory field. Results indicate that the non-lemniscal, posterior auditory field is more engaged in context-dependent processing underlying deviance-detection than the other AC fields, which are more sensitive to stimulus-dependent effects underlying differential degrees of neural adaptation
In vivo whole-cell recordings of stimulus-specific adaptation in the inferior colliculus
The inferior colliculus is an auditory structure where inputs from multiple lower centers converge,
allowing the emergence of complex coding properties of auditory information such as stimulus-specific
adaptation. Stimulus-specific adaptation is the adaptation of neuronal responses to a specific repeated
stimulus, which does not entirely generalize to other new stimuli. This phenomenon provides a mechanism to emphasize saliency and potentially informative sensory inputs. Stimulus-specific adaptation has
been traditionally studied analyzing the somatic spiking output. However, studies that correlate within
the same inferior colliculus neurons their intrinsic properties, subthreshold responses and the level of
acoustic stimulus-specific adaptation are still pending. For this, we recorded in vivo whole-cell patchclamp neurons in the mouse inferior colliculus while stimulating with current injections or the classic
auditory oddball paradigm.
Our data based on cases of ten neuron, suggest that although passive properties were similar, intrinsic
properties differed between adapting and non-adapting neurons. Non-adapting neurons showed a
sustained-regular firing pattern that corresponded to central nucleus neurons and adapting neurons at
the inferior colliculus cortices showed variable firing patterns. Our current results suggest that synaptic
stimulus-specific adaptation was variable and could not be used to predict the presence of spiking
stimulus-specific adaptation. We also observed a small trend towards hyperpolarized membrane potentials in adapting neurons and increased synaptic inhibition with consecutive stimulus repetitions in
all neurons. This finding indicates a more simple type of adaptation, potentially related to potassium
conductances. Hence, these data represent a modest first step in the intracellular study of stimulusspecific adaptation in inferior colliculus neurons in vivo that will need to be expanded with pharmacological manipulations to disentangle specific ionic channels participatio
Prediction error signaling explains neuronal mismatch responses in the medial prefrontal cortex
The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought
to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the
prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance.
However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory
oddball paradigms along with “no-repetition” controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch
responses in the auditory system are mainly induced by stimulus-dependent effects, we
found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch
responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited
or amplified downstream from the auditory system. Conversely, it is more plausible for the
PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent
predictive processing, capable of suppressing redundant input more efficiently than the AC.
Remarkably, the time course of the mismatch responses we observed in the spiking activity
and local field potentials of the AC and the PFC combined coincided with the time course of
the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic,
mesoscopic, and macroscopic levels of automatic deviance detectio
Prediction error signaling explains neuronal mismatch responses in the medial prefrontal cortex
The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regulari- ties and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underly- ing this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with “no-repetition” controls to record mismatch responses in neu- ronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding con- text-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically dif- ferent composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection
Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study
Summary
Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally.
Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies
have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of
the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income
countries globally, and identified factors associated with mortality.
Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to
hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis,
exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a
minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical
status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary
intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause,
in-hospital mortality for all conditions combined and each condition individually, stratified by country income status.
We did a complete case analysis.
Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital
diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal
malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome
countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male.
Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3).
Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income
countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups).
Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome
countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries;
p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients
combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11],
p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20
[1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention
(ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety
checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed
(ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of
parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65
[0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality.
Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome,
middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will
be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger
than 5 years by 2030
Functional Mechanisms of Neuronal Mismatch in the Auditory Midbrain and the Medial Prefrontal Cortex
Tesis por compendio de publicaciones[EN] Context in the environment around us highly influences our perceptions and the neural
processing of sensory information. This doctoral thesis studies the mechanisms that shape
the neural representations of sounds depending on the context in which they occur.
Neurons in all sensory systems adapt rapidly, preserving energy while simultaneously
enabling stimuli with potential survival or behavioral relevance to use additional
processing resources. Stimulus-specific adaptation (SSA) is a special type of neuronal
adaptation, specific to repeated and predictable stimuli, while preserving responsiveness to
other different, unexpected, and probably more informative input.
SSA has been linked to high-order brain processing such as deviance detection and
perceptual inference. The nonlemniscal subdivisions of the inferior colliculus (IC) are the
first sites in which these multifaceted coding properties emerge in the auditory hierarchy.
Nevertheless, the molecular, cellular, and network mechanisms contributing to the
generation of SSA are controversial and a matter of debate. SSA has been classically studied
at the somatic spiking output, which results from the interaction of the synaptic inputs, its
tuning characteristics, and membrane properties. Hence, in Study I, I report the passive
properties, intrinsic properties, and auditory postsynaptic potentials under the oddball
paradigm stimulation in 10 whole-cell patch-clamp recordings in vivo in the mouse IC
(Valdés-Baizabal et al., 2020b). Although passive properties were similar, data suggest that
intrinsic properties such as the firing patterns differed between lemniscal nonadapting and
nonlemniscal adapting cells. SSA is absent at the synaptic level of the recorded neurons,
which further demonstrates that SSA emerges in the nonlemniscal IC.
Ascending along the auditory hierarchy, the encoding of the spectral properties of
sound is subsequently substituted by more abstract representations allowing the detection
of contextual changes in prefrontal regions. These high-order areas have been classically
studied for the generation of automatic deviance detection using the scalp-recorded
mismatch negativity (MMN) using similar oddball paradigms that also elicit SSA.
However, the mechanisms that generate MMN and its neuronal correlate are neither
clearly located nor understood in frontal cortices. Thus, Study II analyses the mechanisms
governing deviance detection under the oddball paradigm in the rat medial prefrontal
cortex (mPFC) within the predictive processing framework (Casado-Román et al., 2020).
My results demonstrate in all mPFC fields and cortical layers that unpredictable auditory
stimulation elicited stronger responses than the weak or even absent activity driven by
predictable sounds. The time course of prefrontal spiking and LFP activity coincides with
the large-scale MMN-like signals in the rat providing the missing link at the microscopic,
mesoscopic, and macroscopic levels of automatic deviance detection. Hence, mPFC cells
could model the possible neuronal correlate of the frontal MMN generators. Mismatch
responses in mPFC are almost purely made of prediction error signaling activity and
different in nature from those at the IC, auditory thalamus, and auditory cortex with an
important effect of repetition suppression (comparisons with a previous study in our lab
by Parras et al., 2017)
TAP tagging proteins in Saccharomyces Cerevisiae
Tandem Affinity Purification (TAP) is a technique based on attaching a tag to the N- or C- terminus of target proteins. The tagged proteins can then be used for studies of protein-protein or protein-DNA interactions. In this study TAP tags of Med7, Tfb3, Spt3, Spt15 and Gal80 were attached to the C-termini in the yeast Saccharomyces cerevisiae by transformation with PCR-generated DNA fragments which integrate into the yeast genome by homologous recombination. The TAP tags will facilitate functional studies of these proteins in transcriptional regulation of the GAL network, and their interactions
Effects of rpt1, rpt4 and rpt6 td mutants on GAL1/10 gene expression in Saccharomyces cerevisiae
The aim of this project was to study the roles of Rpt1, Rpt4 and Rpt6 in transcriptional regulation of the GAL network. Therefore, three temperature sentitive degron (td) mutants were created by integrating recombinant plasmids into Saccharomyces cerevisiae chromosomes.
Under galactose induction, degradation of Rpt4 caused a decrease in GAL1 and GAL10 mRNA levels, Rpt1 degradation did not cause any detectable effect and Rpt6 degradation caused an increase in GAL1 and GAL10 mRNA transcribed.
Furthermore, the binding of Tfb3 to the GAL1/10 promoter was studied using formaldehyde-based in vivo cross-linking and chromatin immunoprecipitation (ChIP) in conjunction with mutational and transcriptional analyses. The protein was tagged with a Tandem Affinity Purification (TAP) tag which allows its isolation using an immunoglobulin matrix for studying protein-DNA interactions. In this way, we found that Tfb3 is bound to the GAL1/10 genetic region at position 278326 to 278406 which corresponds to the start of GAL10 gene and its core promoter. We also found that this binding is negatively affected by degradation of Rpt4
Prediction error signaling explains neuronal mismatch responses in the medial prefrontal cortex.
The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with "no-repetition" controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection
Discovering HIV related information by means of association rules and machine learning
Acquired immunodeficiency syndrome (AIDS) is still one of the main health problems worldwide. It is therefore essential to keep making progress in improving the prognosis and quality of life of affected patients. One way to advance along this pathway is to uncover connections between other disorders associated with HIV/AIDS-so that they can be anticipated and possibly mitigated. We propose to achieve this by using Association Rules (ARs). They allow us to represent the dependencies between a number of diseases and other specific diseases. However, classical techniques systematically generate every AR meeting some minimal conditions on data frequency, hence generating a vast amount of uninteresting ARs, which need to be filtered out. The lack of manually annotated ARs has favored unsupervised filtering, even though they produce limited results. In this paper, we propose a semi-supervised system, able to identify relevant ARs among HIV-related diseases with a minimal amount of annotated training data. Our system has been able to extract a good number of relationships between HIV-related diseases that have been previously detected in the literature but are scattered and are often little known. Furthermore, a number of plausible new relationships have shown up which deserve further investigation by qualified medical experts