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The central nucleus of the amygdala (CeA) is a key hub integrating sensory inputs and modulating behavioural outputs. The CeA is a complex structure with discrete subdivisions, high peptidergic heterogeneity and broad CNS afferent and efferent projections. While several neuropeptide systems within the CeA have been examined in detail, less is known about CeA preproenkephalin (ppENK) cells. Here, we used a recently developed transgenic Penk-Cre mouse line to advance our understanding of the efferent and afferent connectivity of ppENK in the CeA. First, to determine the fidelity of Cre expression in Penk-Cre transgenic mice, we conducted RNAscope in the CeA of Penk-Cre mice. Our analysis revealed that 96.6 % of CeA Cre+ neurons co-expressed pENK mRNA, and 99.7 % of CeA pENK+ neurons co-expressed Cre mRNA, indicating faithful recapitulation of Cre expression in CeA ppENK-expressing cells, supporting the fidelity of the Penk-Cre reporter mouse. Anterograde tracing of CeAsupPenk/supcells showed strong efferent projections to the extended amygdala, midbrain and hindbrain PBN and NTS. Retrograde tracing of Penk afferents to the CeA were more restricted, with primary innervation originating within the amygdala complex and bed nucleus of the stria terminalis, and minor innervation from the parabrachial nucleus and nucleus of the solitary tract. Together, our data provide a comprehensive map of ENKergic efferent and afferent connectivity of the CeA in Penk-Cre mice. Further, we highlight both the utility and limitations of the Penk-Cre mice to study the function of CeA, PBN and NTS ppENK cells.

An emerging novel therapeutic agent for major depressive disorder, minocycline, has the potential to influence both gut microbiome and inflammatory status. The present study showed that chronic high fat diet feeding led to changes in both behaviour and the gut microbiome in male mice, without an overt inflammatory response. The diet-induced behavioural changes were characterised as increased immobility in the forced swim test and changes in locomotor activities in the open field test. Minocycline significantly altered the gut microbiome, rendering a community distinctly different to both untreated healthy and diet-affected states. In contrast, minocycline did not reverse high fat diet-induced changes in behaviour.

Anxiety disorders are among the most prevalent neuropsychiatric conditions, but their precise aetiology and underlying pathophysiological processes remain poorly understood. In light of putative anatomical and functional interactions of the relaxin-3/RXFP3 system with anxiety-related neural circuits, we assessed the ability of central administration of the RXFP3 agonist, RXFP3-A2, to alter anxiety-like behaviours in adult C57BL/6J mice. We assessed how RXFP3-A2 altered performance in tests measuring rodent anxiety-like behaviour (large open field (LOF), elevated plus maze (EPM), light/dark (L/D) box, social interaction). We examined effects of RXFP3-A2 on low 'basal' anxiety, and on elevated anxiety induced by the anxiogenic benzodiazepine, FG-7142; and explored endogenous relaxin-3/RXFP3 signalling modulation by testing effects of an RXFP3 antagonist, R3(B1-22)R, on these behaviours. Intracerebroventricular (icv) injection of RXFP3-A2 (1 nmol, 15 min pre-test) did not alter anxiety-like behaviour under 'basal' conditions in the LOF, EPM or L/D box, but reduced elevated indices of FG-7142-induced (30 mg/kg, ip) anxiety-like behaviour in the L/D box and a single-chamber social interaction test. Furthermore, R3(B1-22)R (4 nmol, icv, 15 min pre-test) increased anxiety-like behaviour in the EPM (reflected by reduced entries into the open arms), but not consistently in the LOF, L/D box or social interaction tests, suggesting endogenous signaling only weakly participates in regulating 'basal' anxiety-like behaviour, in line with previous studies of relaxin-3 and RXFP3 gene knockout mice. Overall, these data suggest exogenous RXFP3 agonists can reduce elevated (FG-7142-induced) levels of anxiety in mice; data important for gauging how conserved such effects are, with a view to modelling human pathophysiology and the likely therapeutic potential of RXFP3-targeted drugs.

We describe our 10-year experience developing the Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program at Northwestern University Feinberg School of Medicine. The neurocritical care team includes intensivists, neurologists, and an advanced practice nurse who have expertise in critical care neurology and who continue care in long-term follow-up of intensive care unit patients in a dedicated neurocritical care outpatient clinic. Brain-directed critical care requires collaboration between intensivists and neurologists with specific expertise in neurocritical care, using protocol-directed consistent care, and physiological measures to protect brain function. The heterogeneity of neurologic disorders in the pediatric intensive care unit requires a background in the relevant basic science and pathophysiology that is beyond the scope of standard neurology or critical care fellowships. To address this need, we also created a fellowship in neurocritical care for intensivists, neurologists, and advanced practice nurses. Last, we discuss the implications for pediatric neurocritical care from the experience of management of pediatric stroke and the development of stroke centers.

Acute kidney injury is a common morbidity of pediatric sepsis and carries an increased risk of mortality. The pathophysiology of sepsis associated acute kidney injury was previously believed to be secondary to decreased global renal perfusion causing hypoxia-induced injury; however, newer research suggests this paradigm is overly simplistic, and injury is now considered multifactorial in origin. Mechanisms that contribute to kidney injury include alterations in microvascular renal blood flow, inflammation and changes in bioenergetics. Clinically, defining acute kidney injury has undergone recent examination and revision, with new interest in evaluating novel biomarkers which measure kidney function more accurately with greater predictive power for patient outcomes. Specific interventions to prevent sepsis associated kidney injury by emergency care practitioners and other frontline providers are currently lacking, and no significant evidence for such practices exist. With a growing understanding of the mechanisms of injury, novel therapeutic targets have been proposed, but current human studies have yet to be performed to help guide the practitioner.

The relaxin-3 gene was identified in 2001 by searching the human genome database for homologues of the relaxin hormone, and was subsequently discovered to encode a highly conserved neuropeptide in mammals and lower species. In the decade since its discovery there have been significant advances in our knowledge of the peptide, including the identification of its cognate receptor (a type 1 G-protein coupled receptor, GPCR135 or RXFP3), an understanding of its structure–activity and associated cellular signalling, and the elucidation of key neuroanatomical aspects of relaxin-3/RXFP3 networks in mammalian brain. The latter studies revealed that relaxin-3 is expressed within GABA neurons of the brainstem including an area known as the nucleus incertus , and that ascending relaxin-3 projections innervate a broad range of RXFP3-rich forebrain areas. These maps provided a foundation for pharmacological and physiological studies to elucidate the neurobiological nature of relaxin-3/RXFP3 signalling in vivo . Recent findings from our laboratory and others suggest the relaxin-3 neural network represents a newly identified ascending arousal system, able to modulate a range of interrelated functions including responses to stress, spatial and emotional memory, feeding and metabolism, motivation and reward, and circadian rhythm and sleep/wake states. More research is now required to discover further important facts about relaxin-3 neurons, such as their various regulatory inputs, and to characterise populations of RXFP3-positive neurons and determine their influence on particular neural circuits, physiology and complex behaviour.

The primary objective of this study was to characterize changes in cerebral blood flow measured using transcranial Doppler in children with central nervous system infections. We hypothesized that children with central nervous system infections have abnormal cerebral blood flow, associated with a greater frequency of complications and poor neurological outcome.We conducted a single-center, retrospective study of children admitted to the neonatal or pediatric intensive care unit with central nervous system infection and undergoing transcranial Doppler as part of routine care between March 2011 and July 2015.A total of 20 children with central nervous system infection underwent 35 transcranial Dopplers. The mean age was 8.2 ± 6.3 years, including 12 boys and eight girls. The most common infection was meningitis (n = 11, 55%), with the remainder comprising encephalitis (15%), meningoencephalitis (20%), and abscess or empyema (10%). Bacterial (n = 10, 50%) and viral (n = 6) sources were common with only one (5%) fungal infection and three (15%) unknown but presumed viral etiology. The patients underwent transcranial Doppler 4 ± 9 days after intensive care unit admission. Mean cerebral blood flow velocities were overall increased compared with reference values for age (healthy children and critically ill children) mostly because of hyperemia (n = 21, 60%) and vasospasm (6%). Hypoperfusion (cerebral blood flow velocity1 S.D. of normal value) in at least one vessel was associated with morbidity (intubation, vasoactive medications, neurosurgery, cardiac arrest) (P = 0.04) and mortality (P = 0.03). Two patients had increased intracranial pressure and hyperventilation was safely achieved with transcranial Doppler monitoring to avoid ischemia. Serial transcranial Dopplers were used to guide blood pressure management.Transcranial Doppler can be used in children with central nervous system infection as a tool to assess cerebral blood flow. In this retrospective study, cerebral hypoperfusion was associated with increased morbidity and mortality. If transcranial Doppler is to guide medical therapy and management of cerebral blood flow in children with central nervous system infections, these results will need to be validated in prospective studies with a more homogenous population of children with encephalitis or meningitis.

To examine the effects of bronchiolitis on feeding efficiency and respiratory integration.We studied 21 infants with bronchiolitis and 21 bottle-fed healthy infants who formed a comparison group. Repeat evaluations of half the bronchiolitis group were performed during recovery. During each feeding study we measured the duration and frequency of sucking, the frequency of single and multiple swallows, the respiratory rate, the postswallow respiratory direction, and the suck and swallow volumes.The infants with bronchiolitis devoted significantly less time to sucking than their healthy peers (P.05), and the mean suck volume was reduced. Although the frequency of swallowing was slightly higher, the volume of milk consumed per swallow was almost half the amount consumed by the comparison group (P.01). Coordination of breathing with swallowing was also less effective (P.01).Although most aspects of feeding are less efficient during periods of respiratory illness, others are preserved or recover rapidly. Coordination of breathing during feeding is also significantly impaired.