Perceptual learning deficits mediated by somatostatin releasing inhibitory interneurons of olfactory bulb in an early life stress mouse model.

Early life adversity (ELA) causes aberrant functioning of neural circuits affecting the health of an individual. While ELA-induced behavioural disorders resulting from sensory and cognitive disabilities can be assessed clinically, the neural mechanisms need to be probed using animal models by employing multi-pronged experimental approaches. As ELA can alter sensory perception, we investigated the effect of early weaning on murine olfaction. By implementing go/no-go odour discrimination paradigm, we observed olfactory learning and memory impairments in early life stressed (ELS) male mice. As olfactory bulb (OB) circuitry plays a critical role in odour learning, we studied the plausible changes in the OB of ELS mice. Lowered c-Fos activity in the external plexiform layer and a reduction in the number of dendritic processes of somatostatin-releasing, GABAergic interneurons (SOM-INs) in the ELS mice led us to hypothesise the underlying circuit. We recorded reduced synaptic inhibitory feedback on mitral/tufted (M/T) cells, in the OB slices from ELS mice, explaining the learning deficiency caused by compromised refinement of OB output. The reduction in synaptic inhibition was nullified by the photo-activation of ChR2-expressing SOM-INs in ELS mice. The role of SOM-INs was revealed by learning-dependent refinement of Ca2+dynamics quantified by GCaMP6f signals, which was absent in ELS mice. Further, the causal role of SOM-INs involving circuitry was investigated by optogenetic modulation during the odour discrimination learning. Photo-activating these neurons rescued the ELA-induced learning deficits. Conversely, photo-inhibition caused learning deficiency in control animals, while it completely abolished the learning in ELS mice, confirming the adverse effects mediated by SOM-INs. Our results thus establish the role of specific inhibitory circuit in pre-cortical sensory area in orchestrating ELA-dependent changes.

Measurement of the major ignored burden of multiple myeloma, pernicious anaemia and of other haematological conditions on partners and family members: A cross-sectional study.

BACKGROUND: Having a haematological condition can adversely affect the quality of life (QoL) of family members/partners of patients. It is important to measure this often ignored burden in order to implement appropriate supportive interventions. OBJECTIVE: To measure current impact of haematological conditions on the QoL of family members/partners of patients, using the Family Reported Outcome Measure-16 (FROM-16). METHODS: A cross-sectional study, recruited online through patient support groups, involved UK family members/partners of people with haematological conditions completing the FROM-16. RESULTS: 183 family members/partners (mean age = 60.5 years, SD = 13.2; females = 62.8%) of patients (mean age = 64.1, SD = 12.8; females = 46.4%) with 12 haematological conditions completed the FROM-16. The FROM-16 mean total score was 14.0 (SD = 7.2), meaning 'a moderate effect on QoL'. The mean FROM-16 scores of family members of people with multiple myeloma (mean = 15.8, SD = 6.3, n = 99) and other haematological malignancies (mean = 13.9, SD = 7.8, n = 29) were higher than of people with pernicious anaemia (mean = 10.7, SD = 7.5, n = 47) and other non-malignant conditions (mean = 11, SD = 7.4, n = 56, p < .01). Over one third (36.1%, n = 183) of family members experienced a 'very large effect' (FROM-16 score>16) on their quality of life. CONCLUSIONS: Haematological conditions, in particular those of malignant type, impact the QoL of family members/partners of patients. Healthcare professionals can now, using FROM-16, identify those most affected and should consider how to provide appropriate holistic support within routine practice.

Sulfation of Heparan and Chondroitin Sulfate Ligands Enables Cell-Specific Homing of Nanoprobes.

Demystifying the sulfation code of glycosaminoglycans (GAGs) to induce precise homing of nanoparticles in tumor cells or neurons influences the development of a potential drug- or gene-delivery system. However, GAGs, particularly heparan sulfate (HS) and chondroitin sulfate (CS), are structurally highly heterogeneous, and synthesizing well-defined HS/CS composed nanoparticles is challenging. Here, we decipher how specific sulfation patterns on HS and CS regulate receptor-mediated homing of nanoprobes in primary and secondary cells. We discovered that aggressive cancer cells such as MDA-MB-231 displayed a strong uptake of GAG-nanoprobes compared to mild or moderately aggressive cancer cells. However, there was no selectivity towards the GAG sequences, thus indicating the presence of more than one form of receptor-mediated uptake. However, U87 cells, olfactory bulb, and hippocampal primary neurons showed selective or preferential uptake of CS-E-coated nanoprobes compared to other GAG-nanoprobes. Furthermore, mechanistic studies revealed that the 4,6-O-disulfated-CS nanoprobe used the CD44 and caveolin-dependent endocytosis pathway for uptake. These results could lead to new opportunities to use GAG nanoprobes in nanomedicine.

Multimodal learning of pheromone locations.

Memorizing pheromonal locations is critical for many mammalian species as it involves finding mates and avoiding competitors. In rodents, pheromonal information is perceived by the main and accessory olfactory systems. However, the role of somatosensation in context-dependent learning and memorizing of pheromone locations remains unexplored. We addressed this problem by training female mice on a multimodal task to locate pheromones by sampling volatiles emanating from male urine through the orifices of varying dimensions or shapes that are sensed by their vibrissae. In this novel pheromone location assay, female mice' preference toward male urine scent decayed over time when they were permitted to explore pheromones vs neutral stimuli, water. On training them for the associations involving olfactory and whisker systems, it was established that they were able to memorize the location of opposite sex pheromones, when tested 15 days later. This memory was not formed either when the somatosensory inputs through whisker pad were blocked or when the pheromonal cues were replaced with that of same sex. The association between olfactory and somatosensory systems was further confirmed by the enhanced expression of the activity-regulated cytoskeleton protein. Furthermore, the activation of main olfactory bulb circuitry by pheromone volatiles did not cause any modulation in learning and memorizing non-pheromonal volatiles. Our study thus provides the evidence for associations formed between different sensory modalities facilitating the long-term memory formation relevant to social and reproductive behaviors.

Intraoperative pyloric botulinum toxin injection during Ivor-Lewis gastroesophagectomy to prevent delayed gastric emptying.

Delayed gastric emptying (DGE) is a common morbidity that affects 10%-50% of Ivor-Lewis gastroesophagectomy (ILGO) patients. DGE management is variable with no gold standard prevention or treatment. We conducted a study to assess the effectiveness of intraoperative pyloric botulinum toxin injection in preventing DGE. All patients undergoing an ILGO for curative intent, semi-mechanical anastomosis, and enhanced recovery between 1st December 2011 and 30th June 2017 were included. Patients with pyloroplasties were excluded and botulinum toxin was routinely given from the 2nd April 2016. We compared botulinum toxin injection (BOTOX) against no intervention (NONE) for patient demographics, adjuvant therapy, surgical approach, DGE incidence, length of stay (LOS), and complications. Additionally, we compared pneumonia risk, anastomotic leak rate, and LOS in DGE versus non-DGE patients. DGE was defined using nasogastric tube input/output differences and chest X-ray appearance according to an algorithm adopted in our unit, which were retrospectively applied. There were 228 patients: 65 (28.5%) received botulinum toxin and 163 (71.5%) received no intervention. One hundred twenty-four (54.4%) operations were performed laparoscopically, of which 11 (4.8%) were converted to open procedures, and 104 (45.6%) were open operations. DGE incidence was 11 (16.9%) in BOTOX and 29 (17.8%) in NONE, P = 0.13. Medical management was required in 14 of 228 (6.1%) cases: 3 (4.6%) in BOTOX and 11 (4.8%) in NONE. Pyloric dilatation was required in 26 of 228 (11.4%): 8 of 65 (12.3%) in the BOTOX and 18 of 163 (11.0%) in NONE. There were no significant differences between groups and requirement for intervention, P = 0.881. Overall median LOS was 10 (6.0-75.0) days: 9 (7.0-75.0) in BOTOX and 10 (6.0-70.0) in NONE, P = 0.516. In non-DGE versus DGE patients, median LOS was 9 (6-57) versus 14 (7-75) days (P < 0.0001), pneumonia incidence of 27.7% versus 30.0% (P = 0.478), and anastomotic leak rate of 2.1% versus 10.0% (P = 0.014). Overall leak rate was 3.5%. Overall complication rate was 67.1%, including minor/mild complications. There were 43 of 65 (66.2%) in BOTOX and 110 of 163 (67.5%) in NONE, P = 0.482. In-hospital mortality was 1 (0.44%), 30-day mortality was 2 (0.88%), 90-day mortality was 5 (2.2%), and there were no 30-day readmissions. Intraoperative pyloric botulinum toxin injections were ineffective in preventing DGE (BOTOX vs. NONE: 16.9% vs. 17.8%) or reducing postoperative complications. DGE was relatively common (17.5%) with 11.4% of patients requiring postoperative balloon dilatation. DGE also resulted in prolonged LOS (increase from 9 to 14 days) and significant increase in leak rate from 2.1% to 10.0%. A better understanding of DGE will guide assessment, investigation, and management of the condition.

The transient manifold structure of the p53 extreme C-terminal domain: insight into disorder, recognition, and binding promiscuity by molecular dynamics simulations.

The p53 tumour suppressor is a transcription activator that signals for cell cycle arrest and apoptosis. In its active form p53 is a tetramer, with each monomer organised in domains with different degrees of structural stability, ranging from the well folded DNA-binding domain (DBD) and tetramerization domain (TET), to the intrinsically disordered transactivation domain (TAD), and extreme C-terminal domain (CTD). Compared to all other domains, the structure/function relationship of the p53-CTD within the full-length p53 tetramer is still poorly understood due to its high degree of conformational disorder. Meanwhile, the structure of p53-CTD-like peptides has been well characterized when in complex with a variety of receptors, where, as other intrinsically disordered regions (IDR), it adopts specific, while diverse, conformations. Receptor-specific folding is likely to occur upon binding, either from a random coil, or as a result of an initial recognition of a pre-formed structural motif, known as molecular recognition feature (MoRF), selected by the receptor within the conformational ensemble of the IDP in solution. In this latter case, MoRFs act as nucleation sites, favouring the initiation of the folding process within the binding site. In this work we show the results of over 20 µs of cumulative molecular dynamics (MD) simulations of a 22 residue peptide unbound in solution with sequence corresponding to the p53-CTD 367-388 section. Such extensive sampling allowed us to identify and characterize the structure of specific sets of minimal structural MoRFs within the p53-CTD peptide conformational ensemble at equilibrium. These motifs are short, involving only 3 to 4 residues, and specifically localized within the peptide sequence. Corresponding patterns of secondary structure propensity along the p53-CTD sequence are also predicted by disorder prediction calculations. Based on these findings we discuss how the structural complementarity of specific minimal structural MoRFs to the binding site of different receptors could regulate the p53-CTD binding promiscuity.

Responsiveness and minimal important change of the Family Reported Outcome Measure (FROM-16).

BACKGROUND: The FROM-16 is a generic family quality of life (QoL) instrument that measures the QoL impact of patients' disease on their family members/partners. The study aimed to assess the responsiveness of FROM-16 to change and determine Minimal Important Change (MIC). METHODS: Responsiveness and MIC for FROM-16 were assessed prospectively with patients and their family members recruited from outpatient departments of the University Hospital Wales and University Hospital Llandough, Cardiff, United Kingdom. Patients completed the EQ-5D-3L and a global severity question (GSQ) online at baseline and at 3-month follow-up. Family members completed FROM-16 at baseline and a Global Rating of Change (GRC) in addition to FROM-16 at follow-up. Responsiveness was assessed using the distribution-based (effect size-ES, standardized response mean -SRM) and anchor-based (area under the receiver operating characteristics curve ROC-AUC) approaches and by testing hypotheses on expected correlation strength between FROM-16 change score and patient assessment tools (GSQ and EQ-5D). Cohen's criteria were used for assessing ES. The AUC ≥ 0.7 was considered a good measure of responsiveness. MIC was calculated using anchor-based (ROC analysis and adjusted predictive modelling) and distribution methods based on standard deviation (SD) and standard error of the measurement (SEM). RESULTS: Eighty-three patients with 15 different health conditions and their relatives completed baseline and follow-up questionnaires and were included in the responsiveness analysis. The mean FROM-16 change over 3 months = 1.43 (SD = 4.98). The mean patient EQ-5D change over 3 months = -0.059 (SD = 0.14). The responsiveness analysis showed that the FROM-16 was responsive to change (ES = 0.2, SRM = 0.3; p < 0.01). The ES and SRM of FROM-16 change score ranged from small (ES = 0.2; SRM = 0.3) for the distribution-based method to large (ES = 0.8, SRM = 0.85) for anchor-based methods. The AUC value was above 0.7, indicating good responsiveness. There was a significant positive correlation between the FROM-16 change scores and the patient's disease severity change scores (p < 0.001). The MIC analysis was based on data from 100 family members of 100 patients. The MIC value of 4 was suggested for FROM-16. CONCLUSIONS: The results of this study confirm the longitudinal validity of FROM-16 which refers to the degree to which an instrument is able to measure change in the construct to be measured. The results yield a MIC value of 4 for FROM-16. These psychometric attributes of the FROM-16 instrument are useful in both clinical research as well as clinical practice.

Long COVID: From olfactory dysfunctions to viral Parkinsonism.

Neurological and psychiatric complications continue to be a public health concern in long coronavirus disease 2019 (COVID-19). This varies from olfactory dysfunctions such as parosmia to cognitive and emotional challenges. Historically, the surge of neurological disorders followed the viral pandemics, for example, the emergence of Encephalitis Lethargica after the outbreak of Spanish Influenza. During and after COVID-19 infection, the problems associated with the sense of smell and the reports of affected olfactory and limbic brain areas are leading to a growing concern about the similarity with the symptoms and the pattern of degeneration observed at the onset of Parkinson's disease and Alzheimer's disease. These reports reveal the essentiality of long-term studies of olfactory and cognitive functions in the post-COVID era and the experiments using animal models to dissect the neural basis of these complications. In this manuscript, we summarize the research reporting the potential correlation between neurological disorders and viral pandemic outbreaks with a historical perspective. Further, we discuss the studies providing evidence of neurodegeneration due to severe acute respiratory syndrome coronavirus 2 infection by focusing on viral Parkinsonism.

Subtle design changes control the difference in colour reflection from the dorsal and ventral wing-membrane surfaces of the damselfly Matronoides cyaneipennis.

The hind wings of males of the damselfly Matronoides cyaneipennis exhibit iridescence that is blue dorsally and green ventrally. These structures are used semiotically in agonistic and courtship display. Transmission electron microscopy reveals these colours are due to two near-identical 5-layer distributed Bragg reflectors, one placed either side of the wing membrane. Interestingly the thicknesses of corresponding layers in each distributed Bragg reflector are very similar for all but the second layer from each outer surface. This one key difference creates the significant disparity between the reflected spectra from the distributed Bragg reflectors and the observed colours of either side of the wing. Modelling indicates that modifications to the thickness of this layer alone create a greater change in the peak reflected wavelength than is observed for similar modifications to the thickness of any other layer. This results in an optimised and highly effective pair of semiotic reflector systems, based on extremely comparable design parameters, with relatively low material and biomechanical costs.

Efficient method for controlling the spatial coherence of a laser.

An efficient method to tune the spatial coherence of a degenerate laser over a broad range with minimum variation in the total output power is presented. It is based on varying the diameter of a spatial filter inside the laser cavity. The number of lasing modes supported by the degenerate laser can be controlled from 1 to 320,000, with less than a 50% change in the total output power. We show that a degenerate laser designed for low spatial coherence can be used as an illumination source for speckle-free microscopy that is nine orders of magnitude brighter than conventional thermal light.

Coupled lasers: phase versus chaos synchronization.

The synchronization of chaotic lasers and the optical phase synchronization of light originating in multiple coupled lasers have both been extensively studied. However, the interplay between these two phenomena, especially at the network level, is unexplored. Here, we experimentally compare these phenomena by controlling the heterogeneity of the coupling delay times of two lasers. While chaotic lasers exhibit deterioration in synchronization as the time delay heterogeneity increases, phase synchronization is found to be independent of heterogeneity. The experimental results are found to be in agreement with numerical simulations for semiconductor lasers.

Persistent olfactory learning deficits during and post-COVID-19 infection.

Quantifying olfactory impairments can facilitate early detection of Coronavirus disease 2019 (COVID-19). Despite being a debated topic, many reports provide evidence for the neurotropism of SARS-CoV-2. However, a sensitive, specific, and accurate non-invasive method for quantifying persistent neurological impairments is missing to date. To quantify olfactory detectabilities and neurocognitive impairments in symptomatic COVID-19 patients during and post-infection periods, we used a custom-built olfactory-action meter (OAM) providing accurate behavioral readouts. Ten monomolecular odors were used for quantifying olfactory detectabilities and two pairs of odors were employed for olfactory matching tests. We followed cohorts of healthy subjects, symptomatic patients, and recovered subjects for probing olfactory learning deficits, before the Coronavirus Omicron variant was reported in India. Our method identifies severe and persistent olfactory dysfunctions in symptomatic patients during COVID-19 infection. Symptomatic patients and recovered subjects showed significant olfactory learning deficits during and post-infection periods, 4-18 months, in comparison to healthy subjects. On comparing olfactory fitness, we found differential odor detectabilities and olfactory function scores in symptomatic patients and asymptomatic carriers. Our results indicate probable long-term neurocognitive deficits in COVID-19 patients imploring the necessity of long-term tracking during post-infection period. Differential olfactory fitness observed in symptomatic patients and asymptomatic carriers demand probing mechanisms of potentially distinct infection routes.

Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell.

Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems' performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.

Phase locking of lasers with self-stabilized minimal coupling.

A novel configuration for phase locking two ring lasers with self-stabilized minimal exchange of power between them is presented. We show experimentally that losses introduced between the lasers are self compensated in order to maintain minimal power exchange between them. The experimental results are in good agreement with numerical results.

Enhanced coherence of weakly coupled lasers.

We present the phase-locking and coherence properties between two weakly coupled lasers. We show how the degree of coherence between the two lasers can be enhanced by nearly 1 order of magnitude after taking into account the effects of coupling on both their phases as well as their amplitudes. Specifically, correlations between synchronized spikes in the amplitude dynamics and the phase dynamics of the lasers allow for an interference pattern with a fringe visibility of 90%, even when the coupling strength is far below the critical value and they are not phase locked.

Quantitative assessment of olfactory dysfunction accurately detects asymptomatic COVID-19 carriers.

BACKGROUND: COVID-19 threatens the global community because a large fraction of infected people are asymptomatic, yet can effectively transmit SARS-CoV-2. Finding and isolating these silent carriers is a crucial step in confining the spread of the disease. A sudden loss of the sense of smell has been self-reported by COVID-19 patients across different countries, consistent with expression of the molecular factors mediating SARS-CoV-2 uptake into human olfactory epithelial supporting cells. However, precise quantification of olfactory loss in asymptomatic COVID-19 carriers is missing to date. METHODS: To quantify olfactory functions in asymptomatic COVID-19 patients, we designed an olfactory-action meter that determines detectability indices at different odor concentrations and an olfactory matching accuracy score using monomolecular odors. The optimization of test parameters allowed us to reliably and accurately assess olfactory deficits in a patient within 20 minutes. FINDINGS: Measurement of detection indices at low concentrations revealed a 50% reduction in asymptomatic COVID-19 carriers. Further, patients with better detection scores showed significantly reduced olfactory matching accuracies compared to normal healthy subjects. Our quantification of olfactory loss, considering all parameters, identified 82% of the asymptomatic SARS-CoV-2 carriers with olfactory deficits. However, on subjective evaluation, only 15% of the patients noticed a compromised ability to smell. INTERPRETATION: Compromised olfactory fitness can serve as a strong basis for identifying asymptomatic COVID-19 patients. Detailed design specifications and protocols provided here should enable the development of a sensitive, fast, and economical screening strategy that can be administered to large populations to prevent the rapid spread of COVID-19. FUNDING: This work was supported by the DBT - Wellcome Trust India Alliance intermediate grant (IA/I/14/1/501,306 to N.A.) and UGC NET Fellowship (A.B.). All the funding sources played no roles in the study.

Local Postsynaptic Signaling on Slow Time Scales in Reciprocal Olfactory Bulb Granule Cell Spines Matches Asynchronous Release.

In the vertebrate olfactory bulb (OB), axonless granule cells (GC) mediate self- and lateral inhibitory interactions between mitral/tufted cells via reciprocal dendrodendritic synapses. Locally triggered release of GABA from the large reciprocal GC spines occurs on both fast and slow time scales, possibly enabling parallel processing during olfactory perception. Here we investigate local mechanisms for asynchronous spine output. To reveal the temporal and spatial characteristics of postsynaptic ion transients, we imaged spine and adjacent dendrite Ca2 +- and Na+-signals with minimal exogenous buffering by the respective fluorescent indicator dyes upon two-photon uncaging of DNI-glutamate in OB slices from juvenile rats. Both postsynaptic fluorescence signals decayed slowly, with average half durations in the spine head of t1 / 2_Δ[Ca2 +]i ∼500 ms and t1 / 2_Δ[Na+]i ∼1,000 ms. We also analyzed the kinetics of already existing data of postsynaptic spine Ca2 +-signals in response to glomerular stimulation in OB slices from adult mice, either WT or animals with partial GC glutamate receptor deletions (NMDAR: GluN1 subunit; AMPAR: GluA2 subunit). In a large subset of spines the fluorescence signal had a protracted rise time (average time to peak ∼400 ms, range 20 to >1,000 ms). This slow rise was independent of Ca2 + entry via NMDARs, since similarly slow signals occurred in ΔGluN1 GCs. Additional Ca2 + entry in ΔGluA2 GCs (with AMPARs rendered Ca2 +-permeable), however, resulted in larger ΔF/Fs that rose yet more slowly. Thus GC spines appear to dispose of several local mechanisms to promote asynchronous GABA release, which are reflected in the time course of mitral/tufted cell recurrent inhibition.

Genetic parameters of milking frequency and milk production traits in Canadian Holsteins milked by an automated milking system.

Twice-a-day milking is currently the most frequently used milking schedule in Canadian dairy cattle. However, with an automated milking system (AMS), dairy cows can be milked more frequently. The objective of this study was to estimate genetic parameters for milking frequency and for production traits of cows milked within an AMS. Data were 141,927 daily records of 953 primiparous Holstein cows from 14 farms in Ontario and Quebec. Most cows visited the AMS 2 (46%) or 3 (37%) times a day. A 2-trait [daily (24-h) milking frequency and daily (24-h) milk yield] random regression daily animal model and a multiple-trait (milk, fat, protein yields, somatic cell score, and milking frequency) random regression test-day animal model were used for the estimation of (co)variance components. Both models included fixed effect of herd x test-date, fixed regressions on days in milk (DIM) nested within age at calving by season of calving, and random regressions for additive genetic and permanent environmental effects. Both fixed and random regressions were fitted with fourth-order Legendre polynomials on DIM. The number of cows in the multiple-trait test-day model was smaller compared with the daily animal model. Heritabilities from the daily model for daily (24-h) milking frequency and daily (24-h) milk yield ranged between 0.02 and 0.08 and 0.14 and 0.20, respectively. Genetic correlations between daily (24-h) milk yield and daily (24-h) milking frequency were largest at the end of lactation (0.80) and smallest in mid-lactation (0.27). Heritabilities from the test-day model for test-day milking frequency, milk, fat and protein yield, and somatic cell score were 0.14, 0.26, 0.20, 0.21, and 0.20, respectively. The genetic correlation was positive between test-day milking frequency and official test-day milk, fat, and protein yields, and negative between official test-day somatic cell score and test-day milking frequency.

Similarity and Strength of Glomerular Odor Representations Define a Neural Metric of Sniff-Invariant Discrimination Time.

The olfactory environment is first represented by glomerular activity patterns in the olfactory bulb. It remains unclear how these representations intersect with sampling behavior to account for the time required to discriminate odors. Using different chemical classes, we investigate glomerular representations and sniffing behavior during olfactory decision-making. Mice rapidly discriminate odorants and learn to increase sniffing frequency at a fixed latency after trial initiation, independent of odor identity. Relative to the increase in sniffing frequency, monomolecular odorants are discriminated within 10-40 ms, while binary mixtures require an additional 60-70 ms. Intrinsic imaging of glomerular activity in anesthetized and awake mice reveals that Euclidean distance between activity patterns and the time needed for discriminations are anti-correlated. Therefore, the similarity of glomerular patterns and their activation strengths, rather than sampling behavior, define the extent of neuronal processing required for odor discrimination, establishing a neural metric to predict olfactory discrimination time.

Maintaining accuracy at the expense of speed: stimulus similarity defines odor discrimination time in mice.

Odor discrimination times and their dependence on stimulus similarity were evaluated to test temporal and spatial models of odor representation in mice. In a go/no-go operant conditioning paradigm, discrimination accuracy and time were determined for simple monomolecular odors and binary mixtures of odors. Mice discriminated simple odors with an accuracy exceeding 95%. Binary mixtures evoking highly overlapping spatiotemporal patterns of activity in the olfactory bulb were discriminated equally well. However, while discriminating simple odors in less than 200 ms, mice required 70-100 ms more time to discriminate highly similar binary mixtures. We conclude that odor discrimination in mice is fast and stimulus dependent. Thus, the underlying neuronal mechanisms act on a fast timescale, requiring only a brief epoch of odor-specific spatiotemporal representations to achieve rapid discrimination of dissimilar odors. The fine discrimination of highly similar stimuli, however, requires temporal integration of activity, suggesting a tradeoff between accuracy and speed.