Neurogenesis Drives Stimulus Decorrelation in a Model of the Olfactory Bulb

The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb -- the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells -- are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Perceptual learning.

<p>Correlation (<b>B</b>) of the test stimuli -limonene and -limonene (shown in <b>A</b>) as a function of time. Enrichment, beginning at , changes the connectivity. Enrichment with the related odors -limonene and -limonene (<b>Cii</b>, only -limonene is shown) strongly reduces the correlation, whereas enrichment with the unrelated odors -carvone and -carvone (<b>Ci</b>, only -carvone shown) does not. Enrichment with a related odor but without neurogenesis does not enhance the decorrelation. Parameters: , , , , , , , . Background stimuli: 1-butanol, 1-hexanol, 1-heptanol, and acetic acid.</p

Young granule cells show enhanced response to novel odors.

<p><b>A</b>) <b>i</b>) Granule cells are marked at . The total number of marked cells (black thick line) and the number of marked cells responding to one of the eight stimuli decreases with time. The stimulus ensemble consists of , . Stimulus 8 (acetic acid) is novel (cf. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002398#pcbi-1002398-g002" target="_blank">Fig. 2</a>). <b>ii</b>) The fraction of marked granule cells that respond to the novel stimulus decreases with time. For the familiar stimuli it mostly increases. Parameters: , , , , , , , , . <b>B</b>) The IEG-activation threshold has to be close to the resilience threshold . Bottom panel: for well above (dotted line) very few marked cells reach an activity above and are considered as responding to the stimuli. Top panel: For the response fraction decreases with time for the novel stimulus (ratio of response fractions , cf. panel Aii), while it tends to increase for the familiar stimuli (, error bars denote standard deviation across the stimuli , ). Parameters as in <b>A</b> except for the steepness of the survival curve (cf. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002398#pcbi-1002398-g001" target="_blank">Fig. 1Bi</a>), (green, small symbols), (red, large symbols). The results represent an average across 32 runs.</p

Effective decorrelation does not require complete reciprocity of the synapses.

<p><b>A</b>) A fraction of the inhibitory connections are rewired to a randomly chosen mitral cell. Dashed lines denote input correlations. <b>B</b>) The inhibitory synaptic strengths are picked with equal probability from the two values . <b>C</b>) Reducing self-inhibition in favor of lateral inhibition, , enhances the decorrelation. Parameters: , , , , , , , .</p

Resilience threshold reduces interference and enhances decorrelation of highly correlated stimuli.

<p><b>A</b>) For the networks achieve the same level of overall decorrelation as networks with suitable , but they decorrelate the representations of highly similar stimuli very poorly. Parameters: , , , , , , , . For parameters as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002398#pcbi-1002398-g002" target="_blank">Fig. 2</a>. <b>B</b>) Effective connectivity matrix for mitral cells with diagonal elements divided by 10. For the interfering connections between mitral cells that are active for -limonene <i>or</i> for -carvone (red ellipse) are as strong as those between co-active cells (black ellipses); cf. panel bottom right on <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002398#pcbi-1002398-g003" target="_blank">Fig. 3</a>. Parameters: , , , , , , , .</p

Decorrelation and connectivity.

<p>Evolution of the pattern correlation and rate of granule cell removal (scaled by their influx) (<b>A</b>), and the effective connectivity matrix between pairs of mitral cells (cf. Eq.(7)) (<b>B</b>). Initially () almost all granule cells survive, generating a random connectivity that does not decorrelate the stimuli (<b>Bi</b>). By the selective removal of weakly active granule cells leads to a structured connectivity (<b>Bii</b>) that reduces the mean correlation . The highly similar stimuli -limonene and -carvone are only decorrelated by strong inhibition between highly co-active mitral cells (marked by black circles), which emerges in the final steady state (<b>Biii</b>). Parameters for the simulation in <b>A</b> as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002398#pcbi-1002398-g002" target="_blank">Fig. 2</a>. The correlations have been averaged over 16 runs. The symbols at 0 denote output correlations for different slopes of the survival curve, 2.5,1 (cf. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002398#pcbi-1002398-g001" target="_blank">Fig. 1Bi</a>). For visual clarity the connectivities are shown in <b>B</b> for a reduced network of 50 instead of 424 mitral cells (for parameters see Fig.S1B in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002398#pcbi.1002398.s001" target="_blank">Text S1</a>). In the connectivity matrices the diagonal elements have been divided by 10.</p

Effect of enrichment protocol on the decorrelation of similar mixtures.

<p><b>A</b>) Sample test stimuli: mixtures of –limonene and –carvone with mixture fractions 35∶65 and 65∶35. <b>B</b>) Enrichment stimuli. i) -limonene, -limonene, -carvone, and -carvone alternating (only -carvone and -limonene shown), ii) 50∶50 mixture of -limonene and -carvone. <b>C</b>) Output patterns for the test stimuli shown in A. Parameters as in Di. <b>D</b>) Correlations of mitral cell activities for the test stimuli as a function of the mixture fraction. i) Eight connections per granule cell. The mixture protocol achieves substantially better decorrelation than the alternating protocol. Parameters: , , , , , , , . ii) One connection per granule cell. No significant difference between the protocols. Parameters: , , , , , , .</p

Decorrelation by inhibition of strongly co-active mitral cells.

<p>Since mitral cells 1 and 2 are strongly driven in both stimuli the population of granule cells (GC) connected to these mitral cells (red) is much larger than the other two populations (blue, green). The associated inhibition strongly suppresses the activities of mitral cells 1 and 2, but not of mitral cell 3, which reduces the correlation of the patterns from to . The mitral cells have a spontaneous activity .</p