SUMMARY Persistent mechanical hypersensitivity that occurs in the setting of injury or disease remains a major clinical problem largely because the underlying neural circuitry is still not known. Here we report the functional identification of key components of the elusive dorsal horn circuit for mechanical allodynia. We show that the transient expression of VGLUT3 by a discrete population of neurons in the deep dorsal horn is required for mechanical pain and that activation of the cells in the adult conveys mechanical hypersensitivity. The cells, which receive direct low threshold input, point to a novel location for circuit initiation. Subsequent analysis of c-Fos reveals the circuit extends dorsally to nociceptive lamina I projection neurons, and includes lamina II calretinin neurons, which we show also convey mechanical allodynia. Lastly, using inflammatory and neuropathic pain models, we show that multiple microcircuits in the dorsal horn encode this form of pain.

Maternal iron deficiency anemia, obesity, and diabetes are prevalent during pregnancy. All are associated with neonatal brain iron deficiency (ID) and neurodevelopmental impairment. Exosomes are extracellular vesicles involved in cell–cell communication. Contactin-2 (CNTN2), a neural-specific glycoprotein, and brain-derived neurotrophic factor (BDNF) are important in neurodevelopment and found in exosomes. We hypothesized that exosomal CNTN2 and BDNF identify infants at risk for brain ID. Umbilical cord blood samples were measured for iron status. Maternal anemia, diabetes, and body mass index (BMI) were recorded. Cord blood exosomes were isolated and validated for the exosomal marker CD81 and the neural-specific exosomal marker CNTN2. Exosomal CNTN2 and BDNF levels were quantified by ELISA. Analysis of CNTN2 and BDNF levels as predictors of cord blood iron indices showed a direct correlation between CNTN2 and ferritin in all neonates (n = 79, β = 1.75, p = 0.02). In contrast, BDNF levels inversely correlated with ferritin (β = −1.20, p = 0.03), with stronger association in female neonates (n = 37, β = −1.35, p = 0.06), although there is no evidence of a sex-specific effect. Analysis of maternal risk factors for neonatal brain ID as predictors of exosomal CNTN2 and BDNF levels showed sex-specific relationships between infants of diabetic mothers (IDMs) and CNTN2 levels (Interaction p = 0.0005). While male IDMs exhibited a negative correlation (n = 42, β = −0.69, p = 0.02), female IDMs showed a positive correlation (n = 37, β = 0.92, p = 0.01) with CNTN2. A negative correlation between BNDF and maternal BMI was found with stronger association in female neonates (per 10 units BMI, β = −0.60, p = 0.04). These findings suggest CNTN2 and BNDF are respective molecular markers for male and female neonates at risk for brain ID. This study supports the potential of exosomal markers to assess neonatal brain status in at-risk infants.

Pavlovian conditioned approach behavior can be directed as much toward discrete cues as it is toward the environmental contexts in which those cues are encountered. The current experiments characterized a tendency of rats to approach object cues whose prior exposure had been paired with reward (conditioned object preference, COP). To demonstrate the phenomenon, rats were conditioned to associate cocaine or saline with two different objects. Rats acquired a preference, assessed using investigation times directed toward each object, for the cocaine-paired object following conditioning. Furthermore, high levels of object investigation during cocaine conditioning predicted stronger preferences for the cocaine-paired object in the test phase. Conditioned approach diminished across extinction but was reinstated through a priming injection of cocaine. To determine whether preferences are affected by reward value, rats were conditioned using three objects paired with 0, 5, or 20 mg/kg of cocaine. This produced object preferences in the post-test that scaled with cocaine dose used for conditioning. Finally, we explored whether contextual cues modulate expression of COP by testing rats for renewal of cocaine seeking. When conditioning was conducted in one context and extinction training in a second context, COP was renewed when the rats were retested in the original context. Thus, conditioned object preferences are readily acquired, easily measured, and amenable to a number of standard Pavlovian conditioning manipulations. This task promises to become a valuable addition to the panoply of behavioral tools available to test mechanisms underlying adaptive and maladaptive reward processing.

ObjectivesClassically, hot flash studies included a baseline period of 1 week or longer. The objective of this study was to compare the accuracy of a 1-day baseline diary to a traditional 1-week diary.MethodsRaw data from 5 pilot studies and 15 phase III randomised controlled trials (RCTs), all of which used a 1-week baseline period, were obtained. Descriptive statistics were used to describe day-by-day variations in hot flash frequencies and scores, during the baseline week. Additional analyses evaluated whether the conclusions from any of the individual pilot studies would have been changed if only a 1-day baseline period had been used. For the RCTs, p values were recalculated using mixed models, adjusting for the baseline value by including it as a covariate.ResultsA total of 2573 participants were included. On average, participants had 8.5 hot flashes per day on day 1. Mean hot flash frequencies and scores on subsequent days (days 2–7) were within 6% of day 1 values. When comparing a 1-day to a 1-week baseline period, there was an absolute difference of only 0.29 hot flashes per day (SD 2.25). Reanalysis for each pilot study revealed that no individual study conclusions would have been altered by a shorter baseline. For the RCTs, a shorter baseline period changed the results of only 1 of 24 comparisons from statistically significant to not significant, or vice versa.ConclusionsA 1-day hot flash diary appears to accurately reflect the true frequency and severity of baseline symptoms in appropriately sized cohorts.

Background: Schizophrenia, schizoaffective disorder, and psychotic bipolar disorder may have distinct and shared neurophysiological indicators of disease risk, although a psychosis continuum model accounts best for neurobiological data when groups are defined by DSM diagnoses. Previous B-SNIP data, however, document 3 distinct psychosis Biotypes with unique neurobiological features not accounted for by a continuum of severity model. Disrupted sensory processing is a core feature of psychotic disorders and is likely a major contributor to associated cognitive impairments. This study investigated plasticity of sensory-attentional processing. Deviations in these neurobiological features are better captured by biotype designations than a psychosis continuum. Methods: EEG was collected while healthy individuals (N = 221) and psychosis probands (N = 455) were administered auditory oddball (OB) and paired stimuli (PS) tasks. Complex responses evoked by these tasks exhibit amplitude changes with tone repetition in healthy individuals, indexing sensorineural plasticity mechanisms. Adaptation to repetition was assessed by comparing neural responses to early, middle, and late trials (eg, the 150 OB trials were analyzed as 3 sets of 50 trials). Analyses were calculated using 2 psychosis subgrouping systems: (1) Biotypes and (2) Schizo-Bipolar Scale (SBS), a psychosis continuum scale. Results: Clinical-based subgroupings revealed lower amplitude neural responses than healthy individuals for both tasks. A minority of ERP components discriminated SBS subgroups, though not in a consistent pattern. Likewise, neural adaptation effects were largely similar across SBS groups. Biotype-based subgroups however show a number of differences. Biotypes differed drastically in overall neural response amplitudes, with Biotype 1 being the most impaired, Biotype 2 showing the greatest amplitude and often not differing from healthy, and Biotype 3 showing slightly lesser amplitude than Biotype 2. Trial repetition analyses revealed differences in the extent of neural adaptation, with Biotype 1 showing little change over time. Further, biotypes differed on adaption functions. Biotype 3, like the healthy group, showed a much larger decrease between early and middle trials than between middle and late trials. In contrast, Biotype 2 often showed a steady amplitude decrease over time. Conclusion: Our findings using clinical symptom-based subgrouping suggest that while auditory disruptions may differ slightly according to psychosis severity, these differences are inconsistent and do not extent to neural adaptation mechanisms. Biotypes, however, revealed subgroup differences in overall neural response levels, the extent of neural adaptation, and the rate at which adaptation occurs. These findings provide support for neurobiological heterogeneity in brain plasticity not accounted for by clinical symptomatology. Background: Oxidative stress and neuroinflammation may contribute to decreased neuronal activity in schizophrenia by affecting the high metaboli...