Opioids depress breathing through two small brainstem sites.

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose- opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem's breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

Opioids such as morphine or fentanyl are powerful substances used to relieve pain in medical settings. However, taken in too high a dose they can depress breathing ­ in other words, they can lead to slow, shallow breaths that cannot sustain life. In the United States, where the misuse of these drugs has been soaring in the past decades, about 130 people die each day from opioid overdose. Pinpointing the exact brain areas and neurons that opioids act on to depress breathing could help to create safer painkillers that do not have this deadly effect. While previous studies have proposed several brain regions that could be involved, they have not been able to confirm these results, or determine which area plays the biggest role. Opioids influence the brain of animals (including humans) by attaching to proteins known as opioid receptors that are present at the surface of neurons. Here, Bachmutsky et al. genetically engineered mice that lack these receptors in specific brain regions that control breathing. The animals were then exposed to opioids, and their breathing was closely monitored. The experiments showed that two small brain areas were responsible for breathing becoming depressed under the influence of opioids. The region with the most critical impact also happens to be where the breathing rhythms originate. There, a small group of 50 to 140 neurons were used by opioids to depress breathing. Crucially, these cells were not necessary for the drugs' ability to relieve pain. Overall, the work by Bachmutsky et al. highlights a group of neurons whose role in creating breathing rhythms deserves further attention. It also opens the possibility that targeting these neurons would help to create safer painkillers.

Systematic variation of acquisition rate in delay eyelid conditioning.

Averaging artifacts inherent in group acquisition curves can mask behavioral phenomena that are potentially revealing in terms of underlying neural mechanisms. To address this, we implemented a behavioral analysis of 106 rabbits trained over 4 sessions using delay eyelid conditioning. Group results showed the typical monotonic increase in conditioned responses (CRs). For most subjects CRs first appeared (as indexed by the criterion of 8 CRs in 9 trials) during the first 18 trials of the second training session. Subdividing subjects according to the training block at which they met criterion revealed systematic differences in the subsequent rate that CR amplitudes increased, but not in asymptotic CR amplitudes. Subjects meeting criterion early in sessions showed more rapid increases in CR amplitude than those meeting criterion later in sessions. This effect was solely dependent on how early within a session criterion was met, as subjects meeting criterion at the beginning of the third and fourth sessions showed more rapid increases in CR amplitude than those meeting criterion after the first 18 trials of the second session. The exceptions were the 7% of the subjects that met criterion late in the first session. Their CR amplitudes increased at a rate similar to subjects meeting criterion early in sessions. These results suggest an interplay between consolidation processes and a previously reported short-term plasticity process that makes CR acquisition a nonmonotonic and complex function of the point during training sessions at which CRs first appear. (PsycINFO Database Record

Lognormal distribution of firing time and rate from a single neuron?

Even a single neuron may be able to produce significant lognormal features in its firing statistics due to noise in the charging ion current. A mathematical scheme introduced in advanced nanotechnology is relevant for the analysis of this mechanism in the simplest case, the integrate-and-fire model with white noise in the charging ion current.