Comparative physiology and morphology of BLA-projecting NBM/SI cholinergic neurons in mouse and macaque.

Cholinergic projection neurons of the nucleus basalis and substantia innominata (NBM/SI) densely innervate the basolateral amygdala (BLA) and have been shown to contribute to the encoding of fundamental and life-threatening experiences. Given the vital importance of these circuits in the acquisition and retention of memories that are essential for survival in a changing environment, it is not surprising that the basic anatomical organization of the NBM/SI is well conserved across animal classes as diverse as teleost and mammal. What is not known is the extent to which the physiology and morphology of NBM/SI neurons have also been conserved. To address this issue, we made patch-clamp recordings from NBM/SI neurons in ex vivo slices of two widely divergent mammalian species, mouse and rhesus macaque, focusing our efforts on cholinergic neurons that project to the BLA. We then reconstructed most of these recorded neurons post hoc to characterize neuronal morphology. We found that rhesus macaque BLA-projecting cholinergic neurons were both more intrinsically excitable and less morphologically compact than their mouse homologs. Combining measurements of 18 physiological features and 13 morphological features, we illustrate the extent of the separation. Although macaque and mouse neurons both exhibited considerable within-group diversity and overlapped with each other on multiple individual metrics, a combined morpho-electric analysis demonstrates that they form two distinct neuronal classes. Given the shared purpose of the circuits in which these neurons participate, this finding raises questions about (and offers constraints on) how these distinct classes result in similar behavior.

Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development.

Opioid receptors within the CNS regulate pain sensation and mood and are key targets for drugs of abuse. Within the adult rodent hippocampus (HPC), µ-opioid receptor agonists suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting the circuit. However, it is uncertain if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in HPC but not neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when immature PV-INs and opioids already influence primordial network rhythmogenesis. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity during circuit maturation as well as learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic neurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto- or chemo-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

Direct Discharge from the Critical Care Resuscitation Unit: Results from a Longitudinal Assessment.

Background: The critical care resuscitation unit (CCRU) facilitates interhospital transfer (IHT) of critically ill patients for immediate interventions. Due to these patients' acuity, it is uncommon for patients to be directly discharged home from this unit, but it does happen on occasion. Since there is no literature regarding outcomes of patients being discharged from a resuscitation unit, our study investigated these patients' outcome at greater than 12 months after being discharged directly from the CCRU. Methods: We performed a retrospective cohort study of all adult patients directly discharged from the CCRU between January 01, 2017, and December 31, 2020. The primary outcome was number of ED visits or hospitalizations within 6 months. Secondary outcomes were number of ED visits or hospitalizations within 6, 12, and >12 months from CCRU discharge. Results: We analyzed 145 patients' records. Mean age was 56 (standard deviation [SD] ± 19), with a majority being male (72%) and Caucasian (58%). The most common discharge destination was home (139 patients, 96% of total subjects) versus hospice (2%) or nursing facilities (2%). Most patients (55%) did not have any hospital revisits within the first 6 months of discharge, while 31% had 1-2 revisits, and 14% had ≥3 revisits. The most common discharge diagnoses were soft tissue infection (16.5%), aortic dissection (14%), and stroke (11%). Factors which were associated with a greater likelihood of any return hospital visit within 6 months receiving mechanical ventilation during CCRU stay (coefficient -2.23, 95% CI 0.01-0.87, P=0.036), while high hemoglobin on CCRU discharge was associated with no ED revisit (coeff. 0.42, 95% CI 1.15-2.06, P=0.004). Conclusions: Most patients who were discharged from the CCRU did not require any hospital revisits in the first 6 months. Requiring mechanical ventilation and having soft tissue infection were associated with high unplanned hospital revisits following discharge. Further research is needed to validate these findings.