Composite receptive fields in the mouse auditory cortex.

A central question in sensory neuroscience is how neurons represent complex natural stimuli. This process involves multiple steps of feature extraction to obtain a condensed, categorical representation useful for classification and behaviour. It has previously been shown that central auditory neurons in the starling have composite receptive fields composed of multiple features. Whether this property is an idiosyncratic characteristic of songbirds, a group of highly specialized vocal learners or a generic property of sensory processing is unknown. To address this question, we have recorded responses from auditory cortical neurons in mice, and characterized their receptive fields using mouse ultrasonic vocalizations (USVs) as a natural and ethologically relevant stimulus and pitch-shifted starling songs as a natural but ethologically irrelevant control stimulus. We have found that these neurons display composite receptive fields with multiple excitatory and inhibitory subunits. Moreover, this was the case with either the conspecific or the heterospecific vocalizations. We then trained the sparse filtering algorithm on both classes of natural stimuli to obtain statistically optimal features, and compared the natural and artificial features using UMAP, a dimensionality-reduction algorithm previously used to analyse mouse USVs and birdsongs. We have found that the receptive-field features obtained with both types of the natural stimuli clustered together, as did the sparse-filtering features. However, the natural and artificial receptive-field features clustered mostly separately. Based on these results, our general conclusion is that composite receptive fields are not a unique characteristic of specialized vocal learners but are likely a generic property of central auditory systems. KEY POINTS: Auditory cortical neurons in the mouse have composite receptive fields with several excitatory and inhibitory features. Receptive-field features capture temporal and spectral modulations of natural stimuli. Ethological relevance of the stimulus affects the estimation of receptive-field dimensionality.

The functional role of sequentially neuromodulated synaptic plasticity in behavioural learning.

To survive, animals have to quickly modify their behaviour when the reward changes. The internal representations responsible for this are updated through synaptic weight changes, mediated by certain neuromodulators conveying feedback from the environment. In previous experiments, we discovered a form of hippocampal Spike-Timing-Dependent-Plasticity (STDP) that is sequentially modulated by acetylcholine and dopamine. Acetylcholine facilitates synaptic depression, while dopamine retroactively converts the depression into potentiation. When these experimental findings were implemented as a learning rule in a computational model, our simulations showed that cholinergic-facilitated depression is important for reversal learning. In the present study, we tested the model's prediction by optogenetically inactivating cholinergic neurons in mice during a hippocampus-dependent spatial learning task with changing rewards. We found that reversal learning, but not initial place learning, was impaired, verifying our computational prediction that acetylcholine-modulated plasticity promotes the unlearning of old reward locations. Further, differences in neuromodulator concentrations in the model captured mouse-by-mouse performance variability in the optogenetic experiments. Our line of work sheds light on how neuromodulators enable the learning of new contingencies.

Peptidase inhibitor 16 identifies a human regulatory T-cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes.

CD4+ T-cell subsets play a major role in the host response to infection, and a healthy immune system requires a fine balance between reactivity and tolerance. This balance is in part maintained by regulatory T cells (Treg), which promote tolerance, and loss of immune tolerance contributes to autoimmunity. As the T cells which drive immunity are diverse, identifying and understanding how these subsets function requires specific biomarkers. From a human CD4 Tconv/Treg cell genome wide analysis we identified peptidase inhibitor 16 (PI16) as a CD4 subset biomarker and we now show detailed analysis of its distribution, phenotype and links to Treg function in type 1 diabetes. To determine the clinical relevance of Pi16 Treg, we analysed PI16+ Treg cells from type 1 diabetes patient samples. We observed that FOXP3 expression levels declined with disease progression, suggesting loss of functional fitness in these Treg cells in Type 1 diabetes, and in particular the rate of loss of FOXP3 expression was greatest in the PI16+ve Treg. We propose that PI16 has utility as a biomarker of functional human Treg subsets and may be useful for tracking loss of immune function in vivo. The ability to stratify at risk patients so that tailored interventions can be applied would open the door to personalised medicine for Type 1 diabetes.

An Unusual Presentation of Parvimonas micra Infective Endocarditis.

Parvimonas micra has been identified as a prominent oral pathogen. This organism has been implicated in periodontal, soft tissue and bone infections. It causes a subacute presentation with high morbidity. We present a case of severe infective endocarditis caused by Parvimonas micra requiring valvular surgery despite appropriate antibiotics. To our knowledge, this is the second case report of Parvimonas micra infective endocarditis since its reclassification in 2006.

Long-term Outcome of Second Ahmed Valves in Adult Glaucoma.

PURPOSE: To evaluate the long-term outcomes of second Ahmed glaucoma valve (AGV) implants in eyes with glaucoma. DESIGN: Retrospective interventional case series. METHODS: Patients with sequential second Ahmed valves implanted in the same eye from 1994 to 2016 were included. Success was defined with 3 criteria: (1) intraocular pressure (IOP) ≤ 21 mm Hg and IOP reduction of 20%; (2) IOP ≤ 18 mm Hg and IOP reduction of 25%; and (3) IOP ≤15 mm Hg and IOP reduction of 30%. The primary analysis was the 5-year Kaplan-Meier survival rate for each criterion. Failure was established when the success criterion was not met at 2 consecutive visits at least 3 months after the surgery. Loss of light perception, requirement for additional glaucoma surgery, hypotony maculopathy, and serious complications were also considered failures. RESULTS: One hundred ten eyes from 104 patients were included with a mean follow-up of 5.0 years (interquartile range [IQR] 1.6-7.33 years). The median (IQR) age at the second AGV was 68.0 (53.5-77.9) years. The median (IQR) time between surgeries was 2.1 (0.7-4.0) years. The 5-year Kaplan-Meier survival rates were 57%, 51%, and 30% for criteria 1, 2, and 3, respectively. CONCLUSION: A second AGV is effective in reducing IOP in patients who require additional IOP lowering after a first AGV. The success rates are comparable to primary AGV implantation, and to trabeculectomy in eyes with a previously implanted glaucoma drainage device. A second AGV is a viable option in eyes with inadequate IOP levels after a primary AGV.