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“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Rationale: Timeliness is one of six important dimensions of health care quality recognized by the Institute of Medicine.Objectives: To evaluate timeliness of lung cancer care and identify institutional characteristics associated with timely care within the Veterans Affairs (VA) health care system.Methods: We used data from a VA nation-wide retrospective chart review and an independent audit of VA cancer programs to examine the association between time to first treatment and potentially explanatory institutional characteristics (e.g., volume of lung cancer patients) for 2,372 veterans diagnosed with lung cancer between 1 January 2002 and 1 September 2005 at 127 VA medical centers. We developed linear mixed effects models to control for clustering of patients within hospitals and we stratified analyses by stage.Measurements and Main Results: Median time to treatment varied widely between (23 to 182 d) and within facilities. Median time to treatment was 90 days in patients with stage I or II cancer and 52 days in those with more advanced disease (P < 0.0001). Factors associated with shorter times to treatment included a nonacademic setting and the existence of a specialized diagnostic clinic (in patients with limited-stage disease), performing a patient flow analysis (in patients with advanced disease), and leadership beliefs about providing timely care (in both groups). However, institutional characteristics explained less than 1% of the observed variation in treatment times.Conclusions: Time to lung cancer treatment in U.S. veterans is highly variable. The numerous institutional characteristics we examined explained relatively little of this variability, suggesting that patient, clinician, and/or unmeasured institutional characteristics may be more important determinants of timely care. [ABSTRACT FROM AUTHOR]

Spinal projection neurons (PNs) are defined by long axons that travel from their origin in the spinal cord to the brain where they relay sensory information from the body. The existence and function of a substantial axon collateral network, also arising from PNs and remaining within the spinal cord, is less well appreciated. Here we use a retrograde viral transduction strategy to characterise a novel subpopulation of deep dorsal horn spinoparabrachial neurons. Brainbow assisted analysis confirmed that virally labelled PN cell bodies formed a discrete cell column in the lateral part of Lamina V (LV lat ) and the adjoining white matter. These PNs exhibited large dendritic territories biased to regions lateral and ventral to the cell body column and extending considerable rostrocaudal distances. Optogenetic activation of LV Lat PNs confirmed this population mediates widespread signalling within spinal cord circuits, including activation in the superficial dorsal horn. This signalling was also demonstrated with patch clamp recordings during LV Lat PN photostimulation, with a range of direct and indirect connections identified and evidence of a postsynaptic population of inhibitory interneurons. Together, these findings confirm a substantial role for PNs in local spinal sensory processing, as well as relay of sensory signals to the brain., (© 2024. The Author(s).)

The main objective of the current study was to ascertain the efficacy of a newly developed online, video-based dementia training and certification program for hospital staff, the CARES® Dementia 5-Step Method for Hospitals™ Online Training and Certification Program. A parallel randomized waitlist control design was utilized. Participants (N = 272) completed online pre-evaluation measures. Forty-five days after completion of CARES® (treatment) or pre-evaluation measures (control), participants completed a post-evaluation online assessment. Analyses of variance found that participants in the treatment condition indicated greater and statistically significant (p < .001) increases in sense of competence, approaches to dementia, and patient care. The results implied that the CARES® Dementia 5-Step Method for Hospitals™ program could serve as a dynamic resource for hospitals nationwide to update training and share experiences, perspectives, and resources. The inherent scalability of the program regarding its acceptability, feasibility, and potential to incorporate seamlessly into routine workflows and staff training suggests high implementation potential., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: John V. Hobday reports a relationship with HealthCare Interactive, Inc. that includes: board membership, employment, and equity or stocks. HealthCare Interactive, Inc. is the owner of the CARES Dementia 5-Step Method Online Training and Certification Program, and John V.Hobday is the owner of HealthCare Interactive, Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Joseph E. Gaugler reports financial support was provided by Healthcare Interactive, Inc. Joseph E. Gaugler reports a relationship with Healthcare Interactive, Inc. that includes: consulting or advisory. Joseph E. Gaugler, PhD is a scientific consultant of Healthcare Interactive, Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Lisa K. Joly reports a relationship with HealthCare Interactive, Inc. that includes: employment. HealthCare Interactive, Inc. owns the CARES Dementia 5-Step Method Online Training and Certification Program, and Lisa K. Joly is an employee of HealthCare Interactive, Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Damage-control resuscitation has come full circle, with the use of whole blood and balanced components. Lack of platelet availability may limit effective damage-control resuscitation. Platelets are typically stored and transfused at room temperature and have a short shelf-life, while cold-stored platelets (CSPs) have the advantage of a longer shelf-life. The US military introduced CSPs into the battlefield surgical environment in 2016. This study is a safety analysis for the use of CSPs in battlefield trauma., Methods: The Department of Defense Trauma Registry and Armed Services Blood Program databases were queried to identify casualties who received room-temperature-stored platelets (RSPs) or both RSPs and CSPs between January 1, 2016, and February 29, 2020. Characteristics of recipients of RSPs and RSPs-CSPs were compared and analyzed., Results: A total of 274 patients were identified; 131 (47.8%) received RSPs and 143 (52.2%) received RSPs-CSPs. The casualties were mostly male (97.1%), similar in age (31.7 years), with a median Injury Severity Score of 22. There was no difference in survival for recipients of RSPs (88.5%) versus RSPs-CSPs (86.7%; p = 0.645). Adverse events were similar between the two cohorts. Blood products received were higher in the RSPs-CSPs cohort compared with the RSPs cohort. The RSPs-CSPs cohort had more massive transfusion (53.5% vs. 33.5%, p = 0.001). A logistic regression model demonstrated that use of RSPs-CSPs was not associated with mortality, with an adjusted odds ratio of 0.96 (p > 0.9; 95% confidence interval, 0.41-2.25)., Conclusion: In this safety analysis of RSPs-CSPs compared with RSPs in a combat setting, survival was similar between the two groups. Given the safety and logistical feasibility, the results support continued use of CSPs in military environments and further research into how to optimize resuscitation strategies., Level of Evidence: Therapeutic/Care Management; Level IV., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Animals are strongly connected to the environments they live in and may become adapted to local environments. Examining genetic-environment associations of key indicator species, like seabirds, provides greater insights into the forces that drive evolution in marine systems. Here we examined a RADseq dataset of 19,213 SNPs for 99 rhinoceros auklets ( Cerorhinca monocerata ) from five western Pacific and 10 eastern Pacific breeding colonies. We used partial redundancy analyses to identify candidate adaptive loci and to quantify the effects of environmental variation on population genetic structure. We identified 262 candidate adaptive loci, which accounted for 3.0% of the observed genetic variation among western Pacific and eastern Pacific breeding colonies. Genetic variation was more strongly associated with pH and maximum current velocity, than maximum sea surface temperature. Genetic-environment associations explain genetic differences between western and eastern Pacific populations; however, genetic variation within the western and eastern Pacific Ocean populations appears to follow a pattern of isolation-by-distance. This study represents a first to quantify the relationship between environmental and genetic variation for this widely distributed marine species and provides greater insights into the evolutionary forces that act on marine species., Competing Interests: The authors report no conflict of interests with this manuscript., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Childhood adversity stains the past of millions of working adults worldwide. The impact on health and well-being is substantial-a now-acknowledged public health crisis. Yet, research in the organizational sciences has failed to recognize the burden that individuals with this difficult history carry with them into the workforce. By synthesizing an interdisciplinary body of scholarship into a cohesive theoretical framework, we provide a foundation for emerging work in occupational health psychology. Empirically, across two single-level multiwave studies, we demonstrate the importance of adversity in one's childhood and its impact on the workplace specifically showing that child adversity, directly and indirectly, impacts worker attitudes and discretionary behaviors. Further, providing one of the few examinations of stress proliferation theory in the workplace, we demonstrate adulthood adversity as an essential mediating mechanism that leads to these work outcomes. From an applied perspective, our results highlight a need to focus on the healing and recovery of adult survivors as they work toward breaking the chains of the past in their lives and at work. In presenting this life course perspective on organizational attitudes and behaviors, our work offers a unique and vital contribution to occupational health theory, practice, and research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Despite financial concerns representing of the most substantial sources of stress, the intersection between individual differences and financial stress has received sparce attention. Emphasizing the cognitive-appraisal process, our study reveals financial stress perceptions partly reflect a dispositional tendency to interpret financial information either more positively or negatively. Across two studies ( N = 441; N = 348), we found that positive and negative affect predict subjective financial perceptions of income adequacy. Further, using Relative Weights Analysis, we demonstrate that in predicting financial stress perceptions, dispositional affect is as important as, or more important than, objective measures of financial stress (i.e., household income and debt). Lastly, using moderated mediation, we found that both current and future perceived income adequacy mediate the relationship between one's income and their experience of affective financial strain, and dispositional affect moderates this relationship. Our work informs current research and interventions seeking to understand individual differences in financial stress perceptions., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract: Effective communication in health care education is essential for creating an inclusive learning environment. This manuscript examines the crucial role of communication in physician assistant/associate (PA) education, particularly in the context of neurodiverse individuals, who constitute approximately 20% of the global population. A groundbreaking study by Nouri et al reveals a 3.1% overall disability prevalence among US practicing physicians, emphasizing the necessity for a comprehensive understanding of diversity in the health care profession. Considering the intersectionality of marginalized identities, this research sheds light on potential challenges health care providers face, underscoring the importance of promoting inclusivity and support for neurodiverse individuals in the PA profession. The increasing presence of neurodivergent students in postsecondary institutions, despite academic strengths, holds relevance for PA education. Recognizing the barriers and stigmas associated with neurodiversity is crucial for fostering inclusive environments within PA programs and sponsoring institutions. This manuscript explores the challenges faced by neurodiverse individuals in PA education and proposes strategies for cultivating a neuroinclusive culture through effective communication. With a focus on celebrating and using the strengths of all learners, regardless of neurodiversity, the overarching goal is to contribute to a paradigm shift in PA education, enriching the educational experience for students, educators, and support staff., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 PA Education Association.)

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVN CRH ), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another mostly unexplored hypothesis is that the direct activity of PVN CRH neurons and their input to other stress- and reward-related brain regions drives these behaviors. To further understand the direct involvement of PVN CRH neurons in motivation, we used optogenetic stimulation to activate these neurons 1 h/day for 5 consecutive days and showed increased acute stress-related behaviors and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVN CRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVN CRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioral changes may, in part, be driven by PVN CRH synaptic projections to the LH., (© 2024. The Author(s).)

Examining the frequency and distribution of hybrids across contact zones provide insights into the factors mediating hybridization. In this study, we examined the effect of habitat and climate on hybridization patterns for three phenotypically, genetically, and ecologically distinct groups of the Canada jay (Perisoreus canadensis) in a secondary contact zone in western North America. Additionally, we tested whether the frequency of hybridization involving the three groups (referred to as Boreal, Pacific and Rocky Mountain morphotypes) is similar across the hybrid zones or whether some pairs have hybridized more frequently than others. We reanalyzed microsatellite, mtDNA and plumage data, and new microsatellite and plumage data for 526 individuals to identify putative genetic and phenotypic hybrids. The genetically and phenotypically distinct groups are associated with different habitats and occupy distinct climate niches across the contact zone. Most putative genetic hybrids (86%) had Rocky Mountain ancestry. Hybrids were observed most commonly in intermediate climate niches and in habitats where Engelmann spruce (Picea engelmannii) overlaps broadly with boreal and subalpine tree species. Our finding that hybrids occupy intermediate climate niches relative to parental morphotypes matches patterns for other plant and animal species found in this region. This study demonstrates how habitat and climate influence hybridization patterns in areas of secondary contact and adds to the growing body of research on tri-species hybrid zones., (© 2023. The Author(s), under exclusive licence to The Genetics Society.)

Introduction: Falls are a leading mechanism of injury. Hospitalization and outpatient clinic visits due to fall injury are frequently reported among both deployed and non-deployed U.S. Military personnel. Falls have been previously identified as a leading injury second only to sports and exercise as a cause for non-battle air evacuations., Materials and Methods: This retrospective study analyzed the Department of Defense Trauma Registry fall injury data from September 11, 2001 to December 31, 2018. Deployed U.S. Military personnel with fall listed as one of their mechanisms of injury were included for analysis., Results: Of 31,791 injured U.S. Military personnel captured by the Department of Defense Trauma Registry within the study time frame, a total of 3,101 (9.8%) incurred injuries from falls. Those who had fall injuries were primarily 21 to 30 years old (55.4%), male (93.1%), Army (75.6%), and enlisted personnel (56.9%). The proportion of casualties sustaining injuries from falls generally increased through the years of the study. Most fall injuries were classified as non-battle injury (91.9%). Falls accounted for 24.2% of non-battle injury hospital admissions with a median hospital stay of 2 days. More non-battle-related falls were reported in Iraq-centric military operations (62.7%); whereas more battle-related falls were reported in Afghanistan-centric military operations (58.3%)., Conclusions: This study is the largest analysis of deployed U.S. Military personnel injured by falls to date. Highlighted are preventive strategies to mitigate fall injury, reduce workforce attrition, and preserve combat mission capability., Level of Evidence: Level III Epidemiologic., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch., (© 2023. The Author(s).)

Introduction: Erectile dysfunction (ED) is defined as the inability to attain and/or maintain a penile erection. The first introduction of intracavernosal injection (ICI) for the treatment of erectile failure was in 1982 by Virag who reported the positive effects of papaverine on erectile tissue, followed by Brindley concurrently conducting research on ICI therapy with alpha-blockade. ICI remains a viable option for the treatment of ED, even after FDA approval of phosphodiesterase type 5 inhibitors in 1998. The American Urological Association (AUA) and the European Association of Urology (EAU) both recommend ICI as a second-line therapy for the treatment of ED. We herein provide an overview of the current state of ICI therapy for the treatment of ED., Areas Covered: We performed a literature review from 1977-2022, using PubMed and the current AUA and EAU guidelines to discuss the current state of ICI for the treatment of ED., Expert Opinion: Although other oral agents are considered first line for the treatment of ED, the current guidelines and literature demonstrate that ICI is a safe and effective option for patients; however, careful patient selection and counseling should be performed to maximize the effectiveness and safety of this ED treatment.

Introduction: Priapism is a compartment syndrome, defined as an unwanted penile erection lasting longer than 4 h, unrelated to sexual stimulation, and persistent even after ejaculation/orgasm. Ischemic priapism is considered a urologic emergency requiring time-sensitive management. Studies have documented that untreated priapism is associated with progressive ischemic histological changes in the corpora cavernosa, such as widespread smooth muscle necrosis, blood vessel and nerve attrition, and trabecular fibrosis. Treatment options include conservative management, corporal irrigation, pharmacologic therapy, and surgery. We herein provide an overview of the emergency pharmacology for priapism., Areas Covered: The American Urological Association (AUA) and the European Association of Urology (EAU) both recommend penile aspiration in conjunction with intracavernosal injection of sympathomimetics as the initial management of ischemic priapism. We have performed a retrospective review of the literature from 1914 to 2022 by using PubMed and a review of the treatment guidelines from the AUA and the EAU to discuss the various therapies for ischemic priapism in the emergent setting., Expert Opinion: After a thorough overview of the literature regarding the treatment of ischemic priapism in the emergent setting, we conclude that intracavernosal phenylephrine is superior to other agents due to its demonstrated efficacy and limited systemic side effects.

The incidence of pain symptoms such as allodynia are known to increase with age. Parvalbumin expressing interneurons (PVINs) within the dorsal horn (DH) of the spinal cord play an important role in allodynia whereby their inhibitory connections prevent innocuous touch information from exciting nociceptive pathways. Here we ask whether the functional properties of PVINs are altered by aging, comparing their functional properties in adult (3-7 month) and aged mice (23-28 month). Patch clamp recordings were made from PVINs in laminae IIi-III of parasagittal spinal cord slices. The intrinsic excitability of PVINs changed with age. Specifically, AP discharge shifted from initial bursting to tonic firing, and firing duration during current injection increased. The nature of excitatory synaptic input to PVINs also changed with age with larger but less frequent spontaneous excitatory currents occurring in aged mice, however, the net effect of these differences produced a similar level of overall excitatory drive. Inhibitory drive was also remarkably similar in adult and aged PVINs. Photostimulation of ChR2 expressing PVINs was used to study inhibitory connections between PVINs and unidentified DH neurons and other PVINs. Based on latency and jitter, monosynaptic PVIN to unidentified-cell and PVIN-PVIN connections were compared in adult and aged mice, showing that PVIN to unidentified-cell connection strength increased with age. Fitting single or double exponentials to the decay phase of IPSCs showed there was also a shift from mixed (glycinergic and GABAergic) to GABAergic inhibitory transmission in aged animals. Overall, our data suggest the properties of PVIN neurons in aged animals enhance their output in spinal circuits in a manner that would blunt allodynia and help maintain normal sensory experience during aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gradwell, Smith, Dayas, Smith, Hughes, Callister and Graham.)

Following postglacial expansion, secondary contact can occur between genetically distinct lineages. These genetic lineages may be associated with specific habitat or environmental variables and therefore, their distributions in secondary contact could reflect such conditions within these areas. Here we used mtDNA, microsatellite, and morphological data to study three genetically distinct groups of warbling vireo (Vireo gilvus) and investigate the role that elevation and habitat play in their distributions. We studied two main contact zones and within each contact zone, we examined two separate transects. Across the Great Plains contact zone, we found that hybridization between eastern and western groups occurs along a habitat and elevational gradient, whereas hybridization across the Rocky Mountain contact zone was not as closely associated with habitat or elevation. Hybrids in the Great Plains contact zone were more common in transitional areas between deciduous and mixed-wood forests, and at lower elevations (<1000 m). Hybridization patterns were similar along both Great Plains transects indicating that habitat and elevation play a role in hybridization between distinct eastern and western genetic groups. The observed patterns suggest adaptation to different habitats, perhaps originating during isolation in multiple Pleistocene refugia, is facilitating hybridization in areas where habitat types overlap., (© 2022. The Author(s), under exclusive licence to The Genetics Society.)

Abstract: Parvalbumin-expressing interneurons (PVINs) in the spinal dorsal horn are found primarily in laminae II inner and III. Inhibitory PVINs play an important role in segregating innocuous tactile input from pain-processing circuits through presynaptic inhibition of myelinated low-threshold mechanoreceptors and postsynaptic inhibition of distinct spinal circuits. By comparison, relatively little is known of the role of excitatory PVINs (ePVINs) in sensory processing. Here, we use neuroanatomical and optogenetic approaches to show that ePVINs comprise a larger proportion of the PVIN population than previously reported and that both ePVIN and inhibitory PVIN populations form synaptic connections among (and between) themselves. We find that these cells contribute to neuronal networks that influence activity within several functionally distinct circuits and that aberrant activity of ePVINs under pathological conditions is well placed to contribute to the development of mechanical hypersensitivity., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

The roles and connectivity of specific types of neurons within the spinal cord dorsal horn (DH) are being delineated at a rapid rate to provide an increasingly detailed view of the circuits underpinning spinal pain processing. However, the effects of these connections for broader network activity in the DH remain less well understood because most studies focus on the activity of single neurons and small microcircuits. Alternatively, the use of microelectrode arrays (MEAs), which can monitor electrical activity across many cells, provides high spatial and temporal resolution of neural activity. Here, the use of MEAs with mouse spinal cord slices to study DH activity induced by chemically stimulating DH circuits with 4-aminopyridine (4-AP) is described. The resulting rhythmic activity is restricted to the superficial DH, stable over time, blocked by tetrodotoxin, and can be investigated in different slice orientations. Together, this preparation provides a platform to investigate DH circuit activity in tissue from naïve animals, animal models of chronic pain, and mice with genetically altered nociceptive function. Furthermore, MEA recordings in 4-AP-stimulated spinal cord slices can be used as a rapid screening tool to assess the capacity of novel antinociceptive compounds to disrupt activity in the spinal cord DH.

Abstract: Projection neurons in the spinal dorsal horn relay sensory information to higher brain centres. The activation of these populations is shaped by afferent input from the periphery, descending input from the brain, and input from local interneuron circuits. Much of our recent understanding of dorsal horn circuitry comes from studies in transgenic mice; however, information on projection neurons is still based largely on studies in monkey, cat, and rat. We used viral labelling to identify and record from mouse parabrachial nucleus (PBN) projecting neurons located in the dorsal horn of spinal cord slices. Overall, mouse lamina I spinoparabrachial projection neurons (SPBNs) exhibit many electrophysiological and morphological features that overlap with rat. Unbiased cluster analysis distinguished 4 distinct subpopulations of lamina I SPBNs, based on their electrophysiological properties that may underlie different sensory signalling features in each group. We also provide novel information on SPBNs in the deeper lamina (III-V), which have not been previously studied by patch clamp analysis. These neurons exhibited higher action potential discharge frequencies and received weaker excitatory synaptic input than lamina I SPBNs, suggesting this deeper population produces different sensory codes destined for the PBN. Mouse SPBNs from both regions (laminae I and III-V) were often seen to give off local axon collaterals, and we provide neuroanatomical evidence they contribute to excitatory input to dorsal horn circuits. These data provide novel information to implicate excitatory input from parabrachial projection neuron in dorsal horn circuit activity during processing of nociceptive information, as well as defining deep dorsal horn projection neurons that provide an alternative route by which sensory information can reach the PBN., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

The pain experience depends on the relay of nociceptive signals from the spinal cord dorsal horn to higher brain centers. This function is ultimately achieved by the output of a small population of highly specialized neurons called projection neurons (PNs). Like output neurons in other central nervous system (CNS) regions, PNs are invested with a substantial axon collateral system that ramifies extensively within local circuits. These axon collaterals are widely distributed within and between spinal cord segments. Anatomical data on PN axon collaterals have existed since the time of Cajal, however, their function in spinal pain signaling remains unclear and is absent from current models of spinal pain processing. Despite these omissions, some insight on the potential role of PN axon collaterals can be drawn from axon collateral systems of principal or output neurons in other CNS regions, such as the hippocampus, amygdala, olfactory cortex, and ventral horn of the spinal cord. The connectivity and actions of axon collaterals in these systems have been well-defined and used to confirm crucial roles in memory, fear, olfaction, and movement control, respectively. We review this information here and propose a framework for characterizing PN axon collateral function in the dorsal horn. We highlight that experimental approaches traditionally used to delineate axon collateral function in other CNS regions are not easily applied to PNs because of their scarcity relative to spinal interneurons (INs), and the lack of cellular organization in the dorsal horn. Finally, we emphasize how the rapid development of techniques such as viral expression of optogenetic or chemogenetic probes can overcome these challenges and allow characterization of PN axon collateral function. Obtaining detailed information of this type is a necessary first step for incorporation of PN collateral system function into models of spinal sensory processing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Browne, Hughes, Dayas, Callister and Graham.)

Neurons located in dorsal root ganglia (DRG) are crucial for transmitting peripheral sensations such as proprioception, touch, temperature, and nociception to the spinal cord before propagating these signals to higher brain structures. To date, difficulty in identifying modality-specific DRG neurons has limited our ability to study specific populations in detail. As the calcium-binding protein parvalbumin (PV) is a neurochemical marker for proprioceptive DRG cells we used a transgenic mouse line expressing green fluorescent protein (GFP) in PV positive DRGs, to study the functional and molecular properties of putative proprioceptive neurons. Immunolabeled DRGs showed a 100% overlap between GFP positive (GFP+) and PV positive cells, confirming the PVeGFP mouse accurately labeled PV neurons. Targeted patch-clamp recording from isolated GFP+ and GFP negative (GFP-) neurons showed the passive membrane properties of the two groups were similar, however, their active properties differed markedly. All GFP+ neurons fired a single spike in response to sustained current injection and their action potentials (APs) had faster rise times, lower thresholds and shorter half widths. A hyperpolarization-activated current (I h ) was observed in all GFP+ neurons but was infrequently noted in the GFP- population (100% vs. 11%). For GFP+ neurons, I h activation rates varied markedly, suggesting differences in the underlying hyperpolarization-activated cyclic nucleotide-gated channel (HCN) subunit expression responsible for the current kinetics. Furthermore, quantitative polymerase chain reaction (qPCR) showed the HCN subunits 2, 1, and 4 mRNA (in that order) was more abundant in GFP+ neurons, while HCN 3 was more highly expressed in GFP- neurons. Likewise, immunolabeling confirmed HCN 1, 2, and 4 protein expression in GFP+ neurons. In summary, certain functional properties of GFP+ and GFP- cells differ markedly, providing evidence for modality-specific signaling between the two groups. However, the GFP+ DRG population demonstrates considerable internal heterogeneity when hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel) properties and subunit expression are considered. We propose this heterogeneity reflects the existence of different peripheral receptors such as tendon organs, muscle spindles or mechanoreceptors in the putative proprioceptive neuron population., (Copyright © 2020 Madden, Davies, Boyle, Iredale, Browne, Callister, Smith, Jobling, Hughes and Graham.)

This article reviews the contributions of the English neurophysiologist, Charles Scott Sherrington [1857-1952], and his Australian PhD trainee and collaborator, John Carew Eccles [1903-1997], to the concept of central inhibition in the spinal cord and brain. Both were awarded Nobel Prizes; Sherrington in 1932 for "discoveries regarding the function of neurons," and Eccles in 1963 for "discoveries concerning the ionic mechanisms involved in excitation and inhibition in central portions of the nerve cell membrane." Both spoke about central inhibition at their Nobel Prize Award Ceremonies. The subsequent publications of their talks were entitled "Inhibition as a coordinative factor" and "The ionic mechanism of postsynaptic inhibition", respectively. Sherrington's work on central inhibition spanned 41 years (1893-1934), and for Eccles 49 years (1928-1977). Sherrington first studied central inhibition by observing hind limb muscle responses to electrical (peripheral nerve) and mechanical (muscle) stimulation. He used muscle length and force measurements until the early 1900s and electromyography in the late 1920s. Eccles used these techniques while working with Sherrington, but later employed extracellular microelectrode recording in the spinal cord followed in 1951 by intracellular recording from spinal motoneurons. This considerably advanced our understanding of central inhibition. Sherrington's health was poor during his retirement years but he nonetheless made a small number of largely humanities contributions up to 1951, one year before his death at the age of 94. In contrast, Eccles retained his health and vigor until 3 years before his death and published prolifically on many subjects during his 22 years of official retirement. His last neuroscience article appeared in 1994 when he was 91. Despite poor health he continued thinking about his life-long interest, the mind-brain problem, and was attempting to complete his autobiography in the last years of his life., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The superficial dorsal horn (SDH, LI-II) of the spinal cord receives and processes multimodal sensory information from skin, muscle, joints, and viscera then relay it to the brain. Neurons within the SDH fall into two broad categories, projection neurons and interneurons. The later can be further subdivided into excitatory and inhibitory types. Traditionally, interneurons within the SDH have been divided into overlapping groups according to their neurochemical, morphological and electrophysiological properties. Recent clustering analyses, based on molecular transcript profiles of cells and nuclei, have predicted many more functional groups of interneurons than expected using traditional approaches. In this study, we used electrophysiological and morphological data obtained from genetically-identified excitatory (vGLUT2) and inhibitory (vGAT) interneurons in transgenic mice to cluster cells into groups sharing common characteristics and subsequently determined how many clusters can be assigned by combinations of these properties. Consistent with previous reports, we show differences exist between excitatory and inhibitory interneurons in terms of their excitability, nature of the ongoing excitatory drive, action potential (AP) properties, sub-threshold current kinetics, and morphology. The resulting clusters based on statistical and unbiased assortment of these data fell well short of the numbers of molecularly predicted clusters. There was no clear characteristic that in isolation defined a population, rather multiple variables were needed to predict cluster membership. Importantly though, our analysis highlighted the appropriateness of using transgenic lines as tools to functionally subdivide both excitatory and inhibitory interneuron populations., (Copyright © 2020 Browne, Gradwell, Iredale, Maden, Callister, Hughes, Dayas and Graham.)

A striking and debilitating property of the nervous system is that damage to this tissue can cause chronic intractable pain, which persists long after resolution of the initial insult. This neuropathic form of pain can arise from trauma to peripheral nerves, the spinal cord, or brain. It can also result from neuropathies associated with disease states such as diabetes, human immunodeficiency virus/AIDS, herpes, multiple sclerosis, cancer, and chemotherapy. Regardless of the origin, treatments for neuropathic pain remain inadequate. This continues to drive research into the underlying mechanisms. While the literature shows that dysfunction in numerous loci throughout the CNS can contribute to chronic pain, the spinal cord and in particular inhibitory signalling in this region have remained major research areas. This review focuses on local spinal inhibition provided by dorsal horn interneurons, and how such inhibition is disrupted during the development and maintenance of neuropathic pain.

Clinically, pain has an uneven incidence throughout lifespan and impacts more on the elderly. In contrast, preclinical models of pathological pain have typically used juvenile or young adult animals to highlight the involvement of glial populations, proinflammatory cytokines, and chemokines in the onset and maintenance of pathological signalling in the spinal dorsal horn. The potential impact of this mismatch is also complicated by the growing appreciation that the aged central nervous system exists in a state of chronic inflammation because of enhanced proinflammatory cytokine/chemokine signalling and glial activation. To address this issue, we investigated the impact of aging on the expression of genes that have been associated with neuropathic pain, glial signalling, neurotransmission and neuroinflammation. We used qRT-PCR to quantify gene expression and focussed on the dorsal horn of the spinal cord as this is an important perturbation site in neuropathic pain. To control for global vs region-specific age-related changes in gene expression, the ventral half of the spinal cord was examined. Our results show that expression of proinflammatory chemokines, pattern recognition receptors, and neurotransmitter system components was significantly altered in aged (24-32 months) versus young mice (2-4 months). Notably, the magnitude and direction of these changes were spinal-cord region dependent. For example, expression of the chemokine, Cxcl13, increased 119-fold in dorsal spinal cord, but only 2-fold in the ventral spinal cord of old versus young mice. Therefore, we propose the dorsal spinal cord of old animals is subject to region-specific alterations that prime circuits for the development of pathological pain, potentially in the absence of the peripheral triggers normally associated with these conditions.

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target., Competing Interests: KS, TB, OD, AC, KB, MW, SD, JI, MG, PJ, RC, CD, DH, BG No competing interests declared, (© 2019, Smith et al.)

The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug-naïve animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, including in animals with cocaine experience. First, we verified that group III mGluRs regulate orexin cell activity in behaving animals by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces c-fos expression in orexin cells following 24 h food deprivation. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. Importantly, L-AP4 had no effect on lever pressing for sucrose pellets or general motoric behavior. Finally, using whole-cell patch-clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show enhanced presynaptic drive to orexin cells following 14d withdrawal and that this plasticity can be normalized by L-AP4. Together, these data indicate that activation of group III mGluRs in LHA reduces orexin cell activity in vivo and may be an effective strategy to suppress cocaine-seeking behavior following withdrawal. These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure. This article is part of the Special Issue entitled 'Hypothalamic Control of Homeostasis'., (Copyright © 2018. Published by Elsevier Ltd.)