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Along the ascending auditory pathway, there is a broad shift from temporal coding, which is common in the lower auditory brainstem, to rate coding, which predominates in auditory cortex. This temporal-to-rate transition is particularly prominent in the inferior colliculus (IC), the midbrain hub of the auditory system, but the mechanisms that govern how individual IC neurons integrate information across time remain largely unknown. Here, we report the widespread expression of Glun2c and Glun2d mRNA in IC neurons. GluN2C/D-containing NMDA receptors are relatively insensitive to voltage-dependent Mg 2+ blockade, and thus can conduct current at resting membrane potential. Using in situ hybridization and pharmacology, we show that vasoactive intestinal peptide neurons in the IC express GluN2D-containing NMDA receptors that are activatable by commissural inputs from the contralateral IC. In addition, GluN2C/D-containing receptors have much slower kinetics than other NMDA receptors, and we found that GluN2D-containing receptors facilitate temporal summation of synaptic inputs in vasoactive intestinal peptide neurons. In a model neuron, we show that a GluN2C/D-like conductance interacts with the passive membrane properties of the neuron to alter temporal and rate coding of stimulus trains. Consistent with this, we show in vivo that blocking GluN2C/D-containing receptors decreases both the spontaneous firing rate and the overall firing rate elicited by amplitude-modulated sounds in many IC neurons. These results suggest that GluN2C/D-containing NMDA receptors influence rate coding for auditory stimuli in the IC by facilitating the temporal integration of synaptic inputs. KEY POINTS: NMDA receptors are critical components of most glutamatergic circuits in the brain, and the diversity of NMDA receptor subtypes yields receptors with a variety of functions. We found that many neurons in the auditory midbrain express GluN2C and/or GluN2D NMDA receptor subunits, which are less sensitive to Mg 2+ blockade than the more commonly expressed GluN2A/B subunits. We show that GluN2C/D-containing receptors conducted current at resting membrane potential and enhanced temporal summation of synaptic inputs. In a model, we show that GluN2C/D-containing receptors provide additive gain for input-output functions driven by trains of synaptic inputs. In line with this, we found that blocking GluN2C/D-containing NMDA receptors in vivo decreased both spontaneous firing rates and firing evoked by amplitude-modulated sounds., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Growing evidence suggests that neuropeptide signaling shapes auditory computations. We previously showed that neuropeptide Y (NPY) is expressed in the inferior colliculus (IC) by a population of GABAergic stellate neurons and that NPY regulates the strength of local excitatory circuits in the IC. NPY neurons were initially characterized using the NPY-hrGFP mouse, in which humanized renilla green fluorescent protein (hrGFP) expression indicates NPY expression at the time of assay, i.e., an expression-tracking approach. However, studies in other brain regions have shown that NPY expression can vary based on several factors, suggesting that the NPY-hrGFP mouse might miss NPY neurons not expressing NPY on the experiment date. Here, we hypothesized that neurons with the ability to express NPY represent a larger population of IC GABAergic neurons than previously reported. To test this hypothesis, we used a lineage-tracing approach to irreversibly tag neurons that expressed NPY at any point prior to the experiment date. We then compared the physiological and anatomical features of neurons labeled with this lineage-tracing approach to our prior data set, revealing a larger population of NPY neurons than previously found. In addition, we used optogenetics to test the local connectivity of NPY neurons and found that NPY neurons provide inhibitory synaptic input to other neurons in the ipsilateral IC. Together, our data expand the definition of NPY neurons in the IC, suggest that NPY expression might be dynamically regulated in the IC, and provide functional evidence that NPY neurons form local inhibitory circuits in the IC. NEW & NOTEWORTHY Across brain regions, neuropeptide Y (NPY) expression is dynamic and influenced by extrinsic and intrinsic factors. We previously showed that NPY is expressed by a class of inhibitory neurons in the auditory midbrain. Here, we find that this neuron class also includes neurons that previously expressed NPY, suggesting that NPY expression is dynamically regulated in the auditory midbrain. We also provide functional evidence that NPY neurons contribute to local inhibitory circuits in the auditory midbrain.

Background: Headache is among the most common symptoms following concussion, yet headache after concussion (HAC) remains poorly characterized. This study describes headache characteristics over the first four weeks following pediatric sport-related concussion., Methods: This is a retrospective case series of 87 athletes (mean: 14.9 years; range: 8.4-18.8 years; 38% female) treated in a specialty sports concussion clinic within 28 days of injury. Primary outcomes of headache consistency, frequency, duration, and associated migrainous symptoms were assessed at immediate (0 to 48 h) and weekly time points over the first 28 days post-injury. Generalized mixed linear models compared headache characteristics across time points. Secondary analyses compared each outcome by as-needed analgesic use., Results: During the immediate post-injury period, headache was more often constant ( p = 0.002) and associated with migrainous symptoms ( p < 0.001). By the third week post-injury, episodic headache was more prevalent ( p < 0.001). Most patients (54%) transitioned from constant, migrainous headache to episodic, non-migrainous headache. This finding was uninfluenced by as-needed analgesic medication use., Conclusions: These findings document the trajectory of HAC. Future studies should assess relationships between initial headache characteristics and recovery.

The inferior colliculus (IC) is a critical computational hub in the central auditory pathway. From its position in the midbrain, the IC receives nearly all the ascending output from the lower auditory brainstem and provides the main source of auditory information to the thalamocortical system. In addition to being a crossroads for auditory circuits, the IC is rich with local circuits and contains more than five times as many neurons as the nuclei of the lower auditory brainstem combined. These results hint at the enormous computational power of the IC, and indeed, systems-level studies have identified numerous important transformations in sound coding that occur in the IC. However, despite decades of effort, the cellular mechanisms underlying IC computations and how these computations change following hearing loss have remained largely impenetrable. In this review, we argue that this challenge persists due to the surprisingly difficult problem of identifying the neuron types and circuit motifs that comprise the IC. After summarizing the extensive evidence pointing to a diversity of neuron types in the IC, we highlight the successes of recent efforts to parse this complexity using molecular markers to define neuron types. We conclude by arguing that the discovery of molecularly identifiable neuron types ushers in a new era for IC research marked by molecularly targeted recordings and manipulations. We propose that the ability to reproducibly investigate IC circuits at the neuronal level will lead to rapid advances in understanding the fundamental mechanisms driving IC computations and how these mechanisms shift following hearing loss., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Basal forebrain (BF) projections to the hippocampus and cortex are anatomically positioned to influence a broad range of cognitive capacities that are known to decline in normal aging, including executive function and memory. Although a long history of research on neurocognitive aging has focused on the role of the cholinergic basal forebrain system, intermingled GABAergic cells are numerically as prominent and well positioned to regulate the activity of their cortical projection targets, including the hippocampus and prefrontal cortex. The effects of aging on noncholinergic BF neurons in primates, however, are largely unknown. In this study, we conducted quantitative morphometric analyses in brains from young adult (6 females, 2 males) and aged (11 females, 5 males) rhesus monkeys ( Macaca mulatta ) that displayed significant impairment on standard tests that require the prefrontal cortex and hippocampus. Cholinergic (ChAT + ) and GABAergic (GAD67 + ) neurons were quantified through the full rostrocaudal extent of the BF. Total BF immunopositive neuron number (ChAT + plus GAD67 + ) was significantly lower in aged monkeys compared with young, largely because of fewer GAD67 + cells. Additionally, GAD67 + neuron volume was greater selectively in aged monkeys without cognitive impairment compared with young monkeys. These findings indicate that the GABAergic component of the primate BF is disproportionally vulnerable to aging, implying a loss of inhibitory drive to cortical circuitry. Moreover, adaptive reorganization of the GABAergic circuitry may contribute to successful neurocognitive outcomes. SIGNIFICANCE STATEMENT A long history of research has confirmed the role of the basal forebrain in cognitive aging. The majority of that work has focused on BF cholinergic neurons that innervate the cortical mantle. Codistributed BF GABAergic populations are also well positioned to influence cognitive function, yet little is known about this prominent neuronal population in the aged brain. In this unprecedented quantitative comparison of both cholinergic and GABAergic BF neurons in young and aged rhesus macaques, we found that neuron number is significantly reduced in the aged BF compared with young, and that this reduction is disproportionately because of a loss of GABAergic neurons. Together, our findings encourage a new perspective on the functional organization of the primate BF in neurocognitive aging., (Copyright © 2023 Bañuelos et al.)

Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a class of GABAergic neurons that project locally and outside the IC. Most neurons in the IC have local axon collaterals; however, the organization and function of local circuits in the IC remain unknown. We previously found that excitatory neurons in the IC can express the NPY Y 1 receptor (Y 1 R + ) and application of the Y 1 R agonist, [Leu 31 , Pro 34 ]-NPY (LP-NPY), decreases the excitability of Y 1 R + neurons. As NPY signaling regulates recurrent excitation in other brain regions, we hypothesized that Y 1 R + neurons form interconnected local circuits in the IC and that NPY decreases the strength of recurrent excitation in these circuits. To test this hypothesis, we used optogenetics to activate Y 1 R + neurons in mice of both sexes while recording from other neurons in the ipsilateral IC. We found that nearly 80% of glutamatergic IC neurons express the Y 1 receptor, providing extensive opportunities for NPY signaling to regulate local circuits. Additionally, Y 1 R + neuron synapses exhibited modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreased recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Our findings show that Y 1 R + excitatory neurons form interconnected local circuits in the IC, and their influence over local circuits is regulated by NPY signaling. SIGNIFICANCE STATEMENT Local networks play fundamental roles in shaping neuronal computations in the brain. The IC, localized in the auditory midbrain, plays an essential role in sound processing, but the organization of local circuits in the IC is largely unknown. Here, we show that IC neurons that express the Neuropeptide Y 1 receptor (Y 1 R + neurons) make up most of the excitatory neurons in the IC and form interconnected local circuits. Additionally, we found that NPY, which is a powerful neuromodulator known to shape neuronal activity in other brain regions, decreases the extensive recurrent excitation mediated by Y 1 R + neurons in local IC circuits. Thus, our results suggest that local NPY signaling is a key regulator of auditory computations in the IC., (Copyright © 2023 the authors.)

Aged rhesus monkeys, like aged humans, show declines in cognitive function. We present cognitive test data from a large sample of male and female rhesus monkeys, 34 young (aged 3.5-13.6 years) and 71 aged (aged 19.9-32.5 years at the start of cognitive testing). Monkeys were tested on spatiotemporal working memory (delayed response), visual recognition memory (delayed nonmatching to sample), and stimulus-reward association learning (object discrimination), tasks with an extensive evidence base in nonhuman primate neuropsychology. On average, aged monkeys performed worse than young on all 3 tasks. Acquisition of delayed response and delayed nonmatching to sample was more variable in aged monkeys than in young. Performance scores on delayed nonmatching to sample and object discrimination were associated with each other, but neither was associated with performance on delayed response. Sex and chronological age were not reliable predictors of individual differences in cognitive outcome among the aged monkeys. These data establish population norms for multiple cognitive tests in young and aged rhesus monkeys in the largest sample reported to date. They also illustrate independence of cognitive aging in task domains dependent on the prefrontal cortex and medial temporal lobe., (Published by Elsevier Inc.)

Acetylcholine modulates responses throughout the auditory system, including at the earliest brain level, the cochlear nucleus (CN). Previous studies have shown multiple sources of cholinergic input to the CN but information about their relative contributions and the distribution of inputs from each source is lacking. Here, we used staining for cholinergic axons and boutons, retrograde tract tracing, and acetylcholine-selective anterograde tracing to characterize three sources of acetylcholine input to the CN in mice. Staining for cholinergic axons showed heavy cholinergic inputs to granule cell areas and the dorsal CN with lighter input to the ventral CN. Retrograde tract tracing revealed that cholinergic cells from the superior olivary complex, pontomesencephalic tegmentum, and lateral paragigantocellular nucleus send projections to the CN. When we selectively labeled cholinergic axons from each source to the CN, we found surprising similarities in their terminal distributions, with patterns that were overlapping rather than complementary. Each source heavily targeted granule cell areas and the dorsal CN (especially the deep dorsal CN) and sent light input into the ventral CN. Our results demonstrate convergence of cholinergic inputs from multiple sources in most regions of the CN and raise the possibility of convergence onto single CN cells. Linking sources of acetylcholine and their patterns of activity to modulation of specific cell types in the CN will be an important next step in understanding cholinergic modulation of early auditory processing., Competing Interests: Declaration of Competing Interest none, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The East North Central Census division (aka the Great Lakes region) experienced a decrease in life expectancy of 0.3 years from 2014 to 2016 - one of the largest declines across the nine Census divisions. Disadvantaged groups that typically have below-average life expectancy, including Black individuals and those without a college education, may have been disproportionately affected by this longevity shift. This investigation examines life expectancy changes among different sex, race, and education groups in the Great Lakes region, and how specific causes of death contributed to within-group longevity changes over time and across age., Methods: We used 2008 to 2017 death counts from the National Center for Health Statistics and American Community Survey population estimates to measure within-group change in life expectancy at age 25 among non-Hispanic Black and white males and females by educational attainment. We decomposed life expectancy change over time for each subgroup by 24 causes of death and measured their contribution to longevity change across 13 age groups., Results: Among persons with ≤ 12 years of education, white males and females experienced 1.3- and 1.7-year longevity declines respectively, compared to a 0.6-year decline among Black males and a 0.3-year decline among Black females. Life expectancy declined among all groups with 13-15 years of education, but especially Black females, who experienced a 2.2-year loss. With the exception of Black males, all groups with 16 + years of education experienced longevity gains. Homicide contributed 0.34 years to longevity decline among Black males with ≤ 12 years of education. Drug poisoning made large contributions to longevity losses among Black females with ≤ 12 years of education (0.31 years), white males and females with 13-15 years of education (0.35 and 0.21 years, respectively), and white males and females with ≤ 12 years of education (0.92 and 0.65 years, respectively)., Conclusions: Public health efforts to reduce the risks of homicide among Black males without a college education and drug poisoning among all groups could improve life expectancy and reduce racial and educational longevity disparities in the Great Lakes region., (© 2023. The Author(s).)

Cholinergic signaling shapes sound processing and plasticity in the inferior colliculus (IC), the midbrain hub of the central auditory system, but how cholinergic terminals contact and influence individual neuron types in the IC remains largely unknown. Using pharmacology and electrophysiology, we recently found that acetylcholine strongly excites VIP neurons, a class of glutamatergic principal neurons in the IC, by activating α 3 β 4 * nicotinic acetylcholine receptors (nAChRs). Here, we confirm and extend these results using tissue from mice of both sexes. First, we show that mRNA encoding α 3 and β 4 nAChR subunits is expressed in many neurons throughout the IC, including most VIP neurons, suggesting that these subunits, which are rare in the brain, are important mediators of cholinergic signaling in the IC. Next, by combining fluorescent labeling of VIP neurons and immunofluorescence against the vesicular acetylcholine transporter (VAChT), we show that individual VIP neurons in the central nucleus of the IC (ICc) are contacted by a large number of cholinergic boutons. Cholinergic boutons were distributed adjacent to the somata and along the full length of the dendritic arbors of VIP neurons, positioning cholinergic signaling to affect synaptic computations arising throughout the somatodendritic compartments of VIP neurons. In addition, cholinergic boutons were occasionally observed in close apposition to dendritic spines on VIP neurons, raising the possibility that cholinergic signaling also modulates presynaptic release onto VIP neurons. Together, these results strengthen the evidence that cholinergic signaling exerts widespread influence on auditory computations performed by VIP neurons and other neurons in the IC., (© 2023. The Author(s) under exclusive licence to Association for Research in Otolaryngology.)

Neurons in the inferior colliculus (IC), the midbrain hub of the central auditory pathway, send ascending and descending projections to other auditory brain regions, as well as projections to other sensory and non-sensory brain regions. However, the axonal projection patterns of individual classes of IC neurons remain largely unknown. Vasoactive intestinal polypeptide (VIP) is a neuropeptide expressed by subsets of neurons in many brain regions. We recently identified a class of IC stellate neurons that we called VIP neurons because they are labeled by tdTomato (tdT) expression in VIP-IRES-Cre x Ai14 mice. Here, using fluorescence in situ hybridization, we found that tdT+ neurons in VIP-IRES-Cre x Ai14 mice express Vglut2, a marker of glutamatergic neurons, and VIP, suggesting that VIP neurons use both glutamatergic and VIPergic signaling to influence their postsynaptic targets. Next, using viral transfections with a Cre-dependent eGFP construct, we labeled the axonal projections of VIP neurons. As a group, VIP neurons project intrinsically, within the ipsilateral and contralateral IC, and extrinsically to all the major targets of the IC. Within the auditory system, VIP neurons sent axons and formed axonal boutons in higher centers, including the medial geniculate nucleus and the nucleus of the brachium of the IC. Less dense projections terminated in lower centers, including the nuclei of the lateral lemniscus, superior olivary complex, and dorsal cochlear nucleus. VIP neurons also project to several non-auditory brain regions, including the superior colliculus, periaqueductal gray, and cuneiform nucleus. The diversity of VIP projections compared to the homogeneity of VIP neuron intrinsic properties suggests that VIP neurons play a conserved role at the microcircuit level, likely involving neuromodulation through glutamatergic and VIPergic signaling, but support diverse functions at the systems level through their participation in different projection pathways., Competing Interests: Declaration of interests None, (Copyright © 2022 Elsevier B.V. All rights reserved.)

Located in the midbrain, the inferior colliculus (IC) plays an essential role in many auditory computations, including speech processing and sound localization. The right and left sides of the IC are interconnected by a dense fiber tract, the commissure of the IC (CoIC), that provides each IC with one of its largest sources of input (i.e., the contralateral IC). Despite its prominence, the CoIC remains poorly understood. Previous studies using anterograde and retrograde tract-tracing showed that IC commissural projections are predominately homotopic and tonotopic, targeting mirror-image locations in the same frequency region in the contralateral IC. However, it is unknown whether specific classes of neurons, particularly inhibitory neurons which constitute ~10%-40% of the commissural projection, follow this pattern. We, therefore, examined the commissural projections of Neuropeptide Y (NPY) neurons, the first molecularly identifiable class of GABAergic neurons in the IC. Using retrograde tracing with Retrobeads (RB) in NPY-hrGFP mice of both sexes, we found that NPY neurons comprise ~11% of the commissural projection. Moreover, focal injections of Retrobeads showed that NPY neurons in the central nucleus of the IC exhibit a more divergent and heterotopic commissural projection pattern than non-NPY neurons. Thus, commissural NPY neurons are positioned to provide lateral inhibition to the contralateral IC. Through this circuit, sounds that drive activity in limited regions on one side of the IC likely suppress activity across a broader region in the contralateral IC., 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 Anair, Silveira, Mirjalili, Beebe, Schofield and Roberts.)

Hidden hearing loss (HHL) is a deficit in auditory perception and speech intelligibility that occurs despite normal audiometric thresholds and results from noise exposure, aging, or myelin defects. While mechanisms causing perceptual deficits in HHL patients are still unknown, results from animal models indicate a role for peripheral auditory neuropathies in HHL. In humans, sound localization is particularly important for comprehending speech, especially in noisy environments, and its disruption may contribute to HHL. In this study, we hypothesized that neuropathies of cochlear spiral ganglion neurons (SGNs) that are observed in animal models of HHL disrupt the activity of neurons in the medial superior olive (MSO), a nucleus in the brainstem responsible for locating low-frequency sound in the horizontal plane using binaural temporal cues, leading to sound localization deficits. To test our hypothesis, we constructed a network model of the auditory processing system that simulates peripheral responses to sound stimuli and propagation of responses via SGNs to cochlear nuclei and MSO populations. To simulate peripheral auditory neuropathies, we used a previously developed biophysical SGN model with myelin defects at SGN heminodes (myelinopathy) and with loss of inner hair cell-SGN synapses (synaptopathy). Model results indicate that myelinopathy and synaptopathy in SGNs give rise to decreased interaural time difference (ITD) sensitivity of MSO cells, suggesting a possible mechanism for perceptual deficits in HHL patients. This model may be useful to understand downstream impacts of SGN-mediated disruptions on auditory processing and to eventually discover possible treatments for various mechanisms of HHL., 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 Budak, Roberts, Grosh, Corfas, Booth and Zochowski.)

Objectives: Assess longitudinal associations between diary-measured sleep duration and clinically assessed body mass index (BMI)., Design: Multilevel growth curve analyses examined how within-person changes and between-person differences in habitual sleep duration were associated with BMI trajectories., Setting: Sleep diaries across 2-6 consecutive weekday and weekend nights at each data collection point, repeatedly collected at approximate 4-year intervals, for an average of 9.2 (standard deviation [SD] = 3.6) years between 1989 and 2011., Participants: About 784 participants (47% women) enrolled in the Wisconsin Sleep Cohort Study (mean [SD] age = 51.1 [8.0] years at baseline)., Measurements: The outcome variable was BMI (kg/m 2 ). Key predictors were habitual sleep duration (defined as average weekday nighttime sleep duration) and sleep duration differential (defined as the difference between average weekday and average weekend nighttime sleep duration) at each data collection wave., Results: Men with shorter habitual sleep duration on weekdays had higher BMI than men with longer habitual sleep duration on weekdays (β = -0.90 kg/m 2 /hour, se = 0.34, p = .008). Participants with larger differentials between weekday and weekend sleep duration experienced more rapid BMI gain over time for both men (β = 0.033 kg/m 2 /year per hour differential, se = 0.017, p = .044) and women (β = 0.057 kg/m 2 /year per hour differential, se = 0.027, p = .036)., Conclusion: This study suggests that habitual short sleep is associated with higher BMI levels in men and that a larger weekday-weekend sleep differential is associated with increasing BMI trajectories among both men and women in mid-to-late life., (Copyright © 2021 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

To assess trends in life expectancy and the contribution of specific causes of death to Native American-White longevity gaps in the Four Corners states, we used death records from the National Center for Health Statistics and population estimates from the U.S. Census Bureau from 1999-2017 to generate period life tables and decompose racial gaps in life expectancy. Native American-White life expectancy gaps narrowed between 2001 and 2012 but widened thereafter, reaching 4.92 years among males and 2.06 years among females in 2015. The life expectancy disadvantage among Native American males was primarily attributable to motor vehicle accidents (0.96 years), liver disease (1.22 years), and diabetes (0.78 years). These causes of deaths were also primary contributors to the gap among females, forming three successive waves of mortality that occurred in young adulthood, midlife, and late adulthood, respectively, among Native American males and females. Interventions to reduce motor vehicle accidents in early adulthood, alcohol-related mortality in midlife, and diabetes complications at older ages could reduce Native American-White longevity disparities in the Four Corners states., Competing Interests: The authors have declared that no competing interests exist.

The inferior colliculus (IC), the midbrain hub of the central auditory system, receives extensive cholinergic input from the pontomesencephalic tegmentum. Activation of nicotinic acetylcholine receptors (nAChRs) in the IC can alter acoustic processing and enhance auditory task performance. However, how nAChRs affect the excitability of specific classes of IC neurons remains unknown. Recently, we identified vasoactive intestinal peptide (VIP) neurons as a distinct class of glutamatergic principal neurons in the IC. Here, in experiments using male and female mice, we show that cholinergic terminals are routinely located adjacent to the somas and dendrites of VIP neurons. Using whole-cell electrophysiology in brain slices, we found that acetylcholine drives surprisingly strong and long-lasting excitation and inward currents in VIP neurons. This excitation was unaffected by the muscarinic receptor antagonist atropine. Application of nAChR antagonists revealed that acetylcholine excites VIP neurons mainly via activation of α 3 β 4 ∗ nAChRs, a nAChR subtype that is rare in the brain. Furthermore, we show that acetylcholine excites VIP neurons directly and does not require intermediate activation of presynaptic inputs that might express nAChRs. Lastly, we found that low frequency trains of acetylcholine puffs elicited temporal summation in VIP neurons, suggesting that in vivo -like patterns of cholinergic input can reshape activity for prolonged periods. These results reveal the first cellular mechanisms of nAChR regulation in the IC, identify a functional role for α 3 β 4 ∗ nAChRs in the auditory system, and suggest that cholinergic input can potently influence auditory processing by increasing excitability in VIP neurons and their postsynaptic targets., 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 © 2021 Rivera-Perez, Kwapiszewski and Roberts.)

Background: Currently, there is no accepted system for the classification of psychotherapies for application within systematic reviews. The creation of anuncomplicated, understandable and practical classification system is neccessary for conducting reliable systematic reviews., Objective: To devise a system for classification of psychotherapy interventions-for use, initially, in systematic reviews., Methods: Cochrane Schizophrenia's Register used as the source of randomised controlled trial. After being piloted and refined at least twice, finally we applied it to all relevant trials within the register. Basic statistical data already held within the register were extracted and used to calculate the distribution of schizophrenia research by form of psychotherapy., Findings: The final classification system consisted of six definable broad 'boughs' two of which were further subdivided into 'branches'. The taxonomy accommodated all psychotherapy interventions described in the register. Of the initial 1645 intervention categories within the register, after careful recoding, 539 (33%) were psychotherapies (234 coded as 'Thought/Action' (cognitive & behavioural)-1495 studies; 135 'Cognitive Functioning'-652 studies; 113 'Social'-684 studies; 55 'Humanistic'-272 studies; 23 'Psychoanalytic/dynamic'-40 studies; and 63 'Other'-387 studies). For people with schizophrenia, across categories, the average size of psychotherapy trial is small (107) but there are notable and important exceptions., Conclusion: We reported a practical method for categorising psychotherapy interventions in evaluative studies with applications beyond schizophrenia. A move towards consensus on the classification and reporting of psychotherapies is needed., Clinical Implications: This classification can aid clinicians, clinical practice guideline developers, and evidence synthesis experts to recognise and compare the interventions from same or different classes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Commercial video games are a vastly popular form of recreational activity. Whilst concerns persist regarding possible negative effects of video games, they have been suggested to provide cognitive benefits to users. They are also frequently employed as control interventions in comparisons of more complex cognitive or psychological interventions. If independently effective, video games - being both engaging and relatively inexpensive - could provide a much more cost-effective add-on intervention to standard treatment when compared to costly, cognitive interventions., Objectives: To review the effects of video games (alone or as an additional intervention) compared to standard care alone or other interventions including, but not limited to, cognitive remediation or cognitive behavioural therapy for people with schizophrenia or schizophrenia-like illnesses., Search Methods: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (March 2017, August 2018, August 2019)., Selection Criteria: Randomised controlled trials focusing on video games for people with schizophrenia or schizophrenia-like illnesses., Data Collection and Analysis: Review authors extracted data independently. For binary outcomes we calculated risk ratio (RR) with its 95% confidence interval (CI) on an intention-to-treat basis. For continuous data we calculated the mean difference (MD) between groups and its CI. We employed a fixed-effect model for analyses. We assessed risk of bias for the included studies and created a 'Summary of findings' table using GRADE., Main Results: This review includes seven trials conducted between 2009 and 2018 (total = 468 participants, range 32 to 121). Study duration varied from six weeks to twelve weeks. All interventions in the included trials were given in addition to standard care, including prescribed medication. In trials video games tend to be the control for testing efficacy of complex, cognitive therapies; only two small trials evaluated commercial video games as the intervention. We categorised video game interventions into 'non-exergame' (played statically) and 'exergame' (the players use bodily movements to control the game). Our main outcomes of interest were clinically important changes in: general functioning, cognitive functioning, social functioning, mental state, quality of life, and physical fitness as well as clinically important adverse effects. We found no clear difference between non-exergames and cognitive remediation in general functioning scores (Strauss Carpenter Outcome Scale) (MD 0.42, 95% CI -0.62 to 1.46; participants = 86; studies = 1, very low-quality evidence) or social functioning scores (Specific Levels of Functioning Scale) (MD -3.13, 95% CI -40.17 to 33.91; participants = 53; studies = 1, very low-quality evidence). There was a clear difference favouring cognitive remediation for cognitive functioning (improved on at least one domain of MATRICS Consensus Cognitive Battery Test) (RR 0.58, 95% CI 0.34 to 0.99; participants = 42; studies = 1, low-quality evidence). For mental state, Positive and Negative Syndrome Scale (PANSS) overall scores showed no clear difference between treatment groups (MD 0.20, 95% CI -3.89 to 4.28; participants = 269; studies = 4, low-quality evidence). Quality of life ratings (Quality of Life Scale) similarly showed no clear intergroup difference (MD 0.01, 95% CI -0.40 to 0.42; participants = 87; studies = 1, very low-quality evidence). Adverse effects were not reported; we chose leaving the study early as a proxy measure. The attrition rate by end of treatment was similar between treatment groups (RR 0.96, 95% CI 0.87 to 1.06; participants = 395; studies = 5, low-quality evidence). One small trial compared exergames with standard care, but few outcomes were reported. No clear difference between interventions was seen for cognitive functioning (measured by MATRICS Consensus Cognitive Battery Test) (MD 2.90, 95% CI -1.27 to 7.07; participants = 33; studies = 1, low-quality evidence), however a benefit in favour of exergames was found for average change in physical fitness (aerobic fitness) (MD 3.82, 95% CI 1.75 to 5.89; participants = 33; studies = 1, low-quality evidence). Adverse effects were not reported; we chose leaving the study early as a proxy measure. The attrition rate by end of treatment was similar between treatment groups (RR 1.06, 95% CI 0.75 to 1.51; participants = 33; studies = 1). Another small trial compared exergames with non-exergames. Only one of our main outcomes was reported - physical fitness, which was measured by average time taken to walk 3 metres. No clear intergroup difference was identified at six-week follow-up (MD -0.50, 95% CI -1.17 to 0.17; participants = 28; studies = 1, very low-quality evidence). No trials reported adverse effects. We chose leaving the study early as a proxy outcome., Authors' Conclusions: Our results suggest that non-exergames may have a less beneficial effect on cognitive functioning than cognitive remediation, but have comparable effects for all other outcomes. These data are from a small number of trials, and the evidence is graded as of low or very low quality and is very likely to change with more data. It is difficult to currently establish if the more sophisticated cognitive approaches do any more good - or harm - than 'static' video games for people with schizophrenia. Where players use bodily movements to control the game (exergames), there is very limited evidence suggesting a possible benefit of exergames compared to standard care in terms of cognitive functioning and aerobic fitness. However, this finding must be replicated in trials with a larger sample size and that are conducted over a longer time frame. We cannot draw any firm conclusions regarding the effects of video games until more high-quality evidence is available. There are ongoing studies that may provide helpful data in the near future., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Located in the midbrain, the inferior colliculus (IC) integrates information from numerous auditory nuclei and is an important hub for sound processing. Despite its importance, little is known about the molecular identity and functional roles of defined neuron types in the IC. Using a multifaceted approach in mice of both sexes, we found that neuropeptide Y (NPY) expression identifies a major class of inhibitory neurons, accounting for approximately one-third of GABAergic neurons in the IC. Retrograde tracing showed that NPY neurons are principal neurons that can project to the medial geniculate nucleus. In brain slice recordings, many NPY neurons fired spontaneously, suggesting that NPY neurons may drive tonic inhibition onto postsynaptic targets. Morphologic reconstructions showed that NPY neurons are stellate cells, and the dendrites of NPY neurons in the tonotopically organized central nucleus of the IC cross isofrequency laminae. Immunostaining confirmed that NPY neurons express NPY, and we therefore hypothesized that NPY signaling regulates activity in the IC. In crosses between Npy1r cre and Ai14 Cre-reporter mice, we found that NPY Y 1 receptor (Y 1 R)-expressing neurons are glutamatergic and were broadly distributed throughout the rostrocaudal extent of the IC. In whole-cell recordings, application of a high-affinity Y 1 R agonist led to hyperpolarization in most Y 1 R-expressing IC neurons. Thus, NPY neurons represent a novel class of inhibitory principal neurons that are well poised to use GABAergic and NPY signaling to regulate the excitability of circuits in the IC and auditory thalamus. SIGNIFICANCE STATEMENT The identification of neuron types is a fundamental question in neuroscience. In the inferior colliculus (IC), the hub of the central auditory pathway, molecular markers for distinct classes of inhibitory neurons have remained unknown. We found that neuropeptide Y (NPY) expression identifies a class of GABAergic principal neurons that constitute one-third of the inhibitory neurons in the IC. NPY neurons fire spontaneously, have a stellate morphology, and project to the auditory thalamus. Additionally, we found that NPY signaling hyperpolarized the membrane potential of a subset of excitatory IC neurons that express the NPY Y 1 receptor. Thus, NPY neurons are a novel class of inhibitory neurons that use GABA and NPY signaling to regulate activity in the IC and auditory thalamus., (Copyright © 2020 the authors.)

The glycoprotein reelin has been implicated in both memory-related synaptic plasticity and Alzheimer's disease pathogenesis. Aged rats with memory impairment display decreased reelin expression in layer II of the entorhinal cortex (EC) relative to memory-intact subjects, and here we tested whether this effect extends to the primate brain. Seven young adult (8-10 years) and 14 aged (27-38 years) rhesus monkeys (Macaca mulatta) were examined, including 7 old animals classified as impaired based on their scores from a delayed nonmatching-to-sample recognition memory test. Histological sections spanning the rostrocaudal extent of the intermediate and caudal divisions of EC were processed by immunohistochemistry and the total number of reelin-positive neurons in layer II was estimated using design-based stereological techniques. The main finding was that the number of reelin-expressing neurons in EC layer II is decreased selectively in aged monkeys with memory deficits relative to young adult and aged subjects with intact memory. The results add to evidence implicating EC-hippocampal integrity in neurocognitive aging, and they suggest that disrupted reelin signaling may be among the mechanisms that mediate the associated vulnerability of this circuitry in Alzheimer's disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

When investigating neural circuits, a standard limitation of the in vitro patch clamp approach is that axons from multiple sources are often intermixed, making it difficult to isolate inputs from individual sources with electrical stimulation. However, by using channelrhodopsin assisted circuit mapping (CRACM), this limitation can now be overcome. Here, we report a method to use CRACM to map ascending inputs from lower auditory brainstem nuclei and commissural inputs to an identified class of neurons in the inferior colliculus (IC), the midbrain nucleus of the auditory system. In the IC, local, commissural, ascending, and descending axons are heavily intertwined and therefore indistinguishable with electrical stimulation. By injecting a viral construct to drive expression of a channelrhodopsin in a presynaptic nucleus, followed by patch clamp recording to characterize the presence and physiology of channelrhodopsin-expressing synaptic inputs, projections from a specific source to a specific population of IC neurons can be mapped with cell type-specific accuracy. We show that this approach works with both Chronos, a blue light-activated channelrhodopsin, and ChrimsonR, a red-shifted channelrhodopsin. In contrast to previous reports from the forebrain, we find that ChrimsonR is robustly trafficked down the axons of dorsal cochlear nucleus principal neurons, indicating that ChrimsonR may be a useful tool for CRACM experiments in the brainstem. The protocol presented here includes detailed descriptions of the intracranial virus injection surgery, including stereotaxic coordinates for targeting injections to the dorsal cochlear nucleus and IC of mice, and how to combine whole cell patch clamp recording with channelrhodopsin activation to investigate long-range projections to IC neurons. Although this protocol is tailored to characterizing auditory inputs to the IC, it can be easily adapted to investigate other long-range projections in the auditory brainstem and beyond.

Introduction: In a competency-based approach to resident education, a component of training should focus on skills needed for the transition from residency to independent practice. The ability to run an outpatient clinic represents one such skill. Resident-run clinics (RRC) have been implemented in family medicine programs to allow residents to practice this skill, and have enhanced learning while providing excellent patient satisfaction. To date, there has been little experience with RRCs in surgical residency programs. We describe a urology RRC and report assessments of both resident performance and patient satisfaction., Methods: The RRC was run independently by a senior urology resident. All cases were reviewed with faculty at the end of the day, and an evaluation form assessing resident performance was completed. Residents also completed a brief self-assessment. All patients completed an anonymous survey to assess aspects of patient satisfaction., Results: Overall, resident performance was excellent, with changes to the management plan in 6% (3/47) of cases after faculty review. All clinics finished within 30 minutes of planned end time. Residents reported confidence in their ability to manage the clinic (8.25/10). Forty-three patient surveys were completed. On a five-point scale, patient ratings of wait time, clinic environment, and appointment duration were 3.91, 4.23, and 4.12, respectively. Patient ratings of resident skills (communication, sensitivity, treatment options, and answering questions) were 4.30, 4.35, 4.40, and 4.42, respectively. Overall, confidence in residents was 9.07/10 and 100% of patients would recommend the RRC., Conclusions: Based on our ongoing experience, RRCs provide well-received, safe patient care and serve as a learning tool for residents as they prepare for independent practice. Given these results, residency programs could consider inclusion of a RRC as a component of the transition- to-practice training within a competency-based curriculum.

Background: Although the black-white gap in life expectancy has narrowed in the U.S., there is considerable variability across states. In Wisconsin, the black-white gap exceeds 6 years, well above the national average. Reducing this disparity is an urgent public health priority, but there is limited understanding of what contributes to Wisconsin's racial gap in longevity. Our investigation identifies causes of death that contribute most to Wisconsin's black-white gap in life expectancy among males and females, and highlights specific ages where each cause of death contributes most to the gap., Methods: Our study employs 1999-2016 restricted-use mortality data provided by the National Center for Health Statistics. After generating race- and sex-specific life tables for each 3-year period of observation (e.g., 1999-2001), we trace recent trends in the black-white life expectancy gap in Wisconsin. We subsequently conduct a series of analyses to decompose the black-white gap in three time periods into 13 separate causes and 19 different age groups., Results: In 2014-16, Wisconsin's black-white gap in life expectancy was 7.34 years for males (67% larger than the national gap), and 5.61 years for females (115% larger than the national gap). Among males, homicide was the single largest contributor, accounting for 1.56 years of the total gap. Heart disease and cancer followed, contributing 1.43 and 1.42 years, respectively. Among females, heart disease and cancer were the two leading contributors to the gap, accounting for 1.12 and 1.00 years, respectively. Whereas homicide contributed most to the racial gap in male longevity during late adolescence and early adulthood, heart disease and cancer exerted most of their influence between ages 50-70 for both males and females. Other notable contributors were unintentional injuries (males), diabetes and cerebrovascular disease (females), and perinatal conditions (males and females)., Conclusions: Our study identifies targets for future policy interventions that could substantially reduce Wisconsin's racial gap in life expectancy. Concerted efforts to eliminate racial disparities in perinatal mortality and homicide early in the life course, and chronic conditions such as cancer and heart disease in later life, promise to help Wisconsin achieve the public health objective of racial parity in longevity.

Purpose: The purpose of this study was to assess the sensitivity and responsiveness of the Segmental Assessment of Trunk Control (SATCo) for evaluating trunk control in children with spinal cord injury (SCI) receiving activity-based locomotor training (AB-LT)., Methods: Prospective study of nine outcomes for consecutively enrolled children in outpatient AB-LT. To evaluate sensitivity to change, linear-mixed models were constructed and adjusted for covariates: age at and time since SCI. To evaluate responsiveness, standardized response means and 95% confidence intervals were estimated per outcome., Results: SATCo scores increased significantly (p < 0.05) regardless of chronicity, initial score, and injury level. The SATCo was the most responsive measure and the only outcome demonstrating a large effect size after 3 months of therapy., Conclusions: Children with SCI receiving AB-LT improved trunk control regardless of chronicity, initial impairment, or prior experience. SATCo sensitivity and responsiveness support its usefulness in measuring trunk control in children with SCI.

Located in the midbrain, the inferior colliculus (IC) is the hub of the central auditory system. Although the IC plays important roles in speech processing, sound localization, and other auditory computations, the organization of the IC microcircuitry remains largely unknown. Using a multifaceted approach in mice, we have identified vasoactive intestinal peptide (VIP) neurons as a novel class of IC principal neurons. VIP neurons are glutamatergic stellate cells with sustained firing patterns. Their extensive axons project to long-range targets including the auditory thalamus, auditory brainstem, superior colliculus, and periaqueductal gray. Using optogenetic circuit mapping, we found that VIP neurons integrate input from the contralateral IC and the dorsal cochlear nucleus. The dorsal cochlear nucleus also drove feedforward inhibition to VIP neurons, indicating that inhibitory circuits within the IC shape the temporal integration of ascending inputs. Thus, VIP neurons are well-positioned to influence auditory computations in a number of brain regions., Competing Interests: DG, MS, AG, NB, RE, PM, BS, MR No competing interests declared, (© 2019, Goyer et al.)

Background: In synergy with the mounting scientific evidence for the capacity of recovery after spinal cord injury (SCI) and training, new evidence-based therapies advancing neuromuscular recovery are emerging. There is a parallel need for outcome instruments that specifically address recovery. The Pediatric Neuromuscular Recovery Scale (Pediatric NRS) is one example with established content validity to assess neuromuscular capacity within task performance. Objective: The objective of this study was to determine interrater reliability of the Pediatric NRS to classify motor capacity in children after SCI. Methods: Pediatric physicians (3), occupational therapists (5), and physical therapists (6) received standardized training in scoring the scale, then rated video assessments of 32 children post SCI, 2-12 years of age, 78% non-ambulatory. Interrater reliability was analyzed using Kendall coefficient of concordance for individual Pediatric NRS items and overall score. Results: The interrater reliability coefficient was determined to be near 1 for the overall Pediatric NRS score (ICC = 0.966; 95% CI, 0.89-0.98). Twelve of 16 individual items exhibited high concordance coefficients (Kendall's W ≥ 0.8) and four items demonstrated concordance coefficients, < 0.8 and > 0.69. Interrater reliability was equivalent among groups defined by age and neurological level, but lower among non-ambulatory individuals. Conclusion: Strong interrater reliability was demonstrated by pediatric clinicians who scored children with SCI using the Pediatric NRS., Competing Interests: Conflicts of Interest Dr. Ardolino reports grants from the Craig H. Neilsen Foundation during the conduct of the study and non-financial support from NeuroRecovery Training Institute outside the submitted work. Dr. Behrman reports grants from the Craig H. Neilsen Foundation and from Kosair Charities during the conduct of the study and personal fees from NeuroRecovery Training Institute, other from NeuroRecovery Learning, Inc., and personal fees from Shriners Research Foundation outside the submitted work. Dr. Mulcahey reports grants from Jefferson University (Philadelphia University + Thomas Jefferson University) during the conduct of the study and personal fees from Topics in Spinal Cord Injury Rehabilitation, grants from Craig H. Neilsen Foundation, and personal fees from Craig H. Neilsen Foundation outside the submitted work. Dr. Roberts reports grants from NeuroRecovery Network during the conduct of the study. Ms. Clayton, Ms. Gregg, and Dr. Lorenz have nothing to disclose.

Background: Activity-based therapies aim to improve neuromuscular capacity after spinal cord injury (SCI). Objective: The purpose of this prospective study was to report the impact of Activity-based Locomotor Training (AB-LT) on neuromuscular capacity in pediatric patients with SCI. Methods: Participants were enrolled for their first episode of AB-LT for a minimum of 60 daily, 1.5-hour sessions. The Segmental Assessment of Trunk Control (SATCo) and the Pediatric Neuromuscular Recovery Scale (Pediatric NRS) were assessed initially, every 20 sessions, and post 60 sessions. Results: Twenty-six consecutive patients, mean age 5 years ( SD = 3), completed a mean 55 sessions ( SD = 4) within 63 weekdays ( SD = 9). The Pediatric NRS total score improved significantly, adjusted mean 11.4, from initial to post-60 sessions ( p < .05) with an average adjusted evaluation-to-evaluation 3.7 change. SATCo scores improved significantly across 60 sessions, mean change 5.2, an estimated 1.7 change between evaluations ( p < .05). Age at enrollment and chronicity had no effect; however, initial neuromuscular capacity scores were negatively correlated with change scores ( p < .05). Conclusion: Sixty AB-LT sessions significantly improved trunk and neuromuscular capacity in children with SCI, regardless of age or chronicity at enrollment. Patients with lower initial scores made greater improvements than patients with higher initial neuromuscular capacity. Anecdotal parent reports of their child's functional change in the home and community highlight the synergy between quantitative change in neuromuscular capacity and meaningful, improved quality of life and the need for formal investigation of this relationship., Competing Interests: Conflicts of Interest Dr. Behrman reports grants from the Craig H. Neilsen Foundation, Helmsley Charitable Trust, and Kosair Charities during the conduct of the study and personal fees from NeuroRecovery Training Institute, other from NeuroRecovery Learning, Inc., and personal fees from Shriners Research Foundation outside the submitted work. Dr. Thompson, Dr. Ugiliweneza, Dr. Argetsinger, Dr. Roberts, and Ms. Stout have nothing to disclose.

The diet of the domestic dog has changed significantly from that of its wolf ancestor, with to date only two studies having examined macronutrient self-selection in dogs. Whilst the first focused solely on protein intake, determining an intake of 30% metabolisable energy (ME), the second investigated dietary protein, fat and carbohydrate (PFC), indicating an intake ratio of 30:63:7% by energy. This study's aim was to further elucidate macronutrient intake by providing greater macronutrient range, energy content, and to investigate over a longer duration than previous studies. Fifteen adult dogs were given access to three wet diets providing 500% of daily ME, twice daily over 10 days. The diets were nutritionally complete and formulated using the same four ingredients in different proportions to supply high levels of protein (58% ME), fat (86% ME) or carbohydrate (54% ME). Overall fat and carbohydrate consumption significantly declined from 6,382 to 917 kcals per day (p < 0.001) and 553 to 214 kcals day -1 (p < .01) respectively. Protein intake, however, remained constant over the study and ranged from 4,786 to 4,156 kcals day -1 . Such results impacted on percentage total energy intake, with fat decreasing from 68% to 52% (p < .001) and protein increasing from 29% to 44% (p < .01). Our findings suggest that dogs still possess a "feast or famine" mentality, wherein energy dense fat is prioritised over protein initially. With continued feeding over 10 days, a transition to a more balanced energy contribution from both macronutrients is evident. The study also shows that given the option, dogs do not select carbohydrate to be a significant portion of the diet. The health implications of such dietary selection are of interest., (© 2017 The Authors. Journal of Animal Physiology and Animal Nutrition Published by Blackwell Verlag GmbH.)

Myelin allows for the rapid and precise timing of action potential propagation along neuronal circuits and is essential for healthy auditory system function. In this article, we discuss what is currently known about myelin in the auditory system with a focus on the timing of myelination during auditory system development, the role of myelin in supporting peripheral and central auditory circuit function, and how various myelin pathologies compromise auditory information processing. Additionally, in keeping with the increasing recognition that myelin is dynamic and is influenced by experience throughout life, we review the growing evidence that auditory sensory deprivation alters myelin along specific segments of the brain's auditory circuit. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 80-92, 2018., (© 2017 Wiley Periodicals, Inc.)

Facing a tension between the increasing use of genetically engineered or modified food and consumer concerns over the risks associated with GMOs, China has established a GM food labeling regime through regulations-known as Agro-GMO regulations-to protect consumers' right to know. However, the design and enforcement of this GM food labeling regime is problematic. As a result, the labeling regime is ineffective and inconsistent, leaving consumers' rights unprotected. As the recently amended Food Safety Law in China requires GM food labeling for the first time, this article argues that China should replace the current Agro-GMO food labeling scheme with a special regulatory scheme. A comparative analysis of the GM food labeling systems in the European Union and United States, coupled with a rigorous examination of the problems and barriers of GM food labeling in China, sets a solid foundation by which to propose changes to incorporate into a special regulatory scheme. To this end, this article engages in such an analysis and recommends practical steps to guide the enactment of a special regulatory scheme. The recommendations comport with China's unique legal and political culture, but also could be used by other national regulatory regimes who permit use of GM food while also being committed to improving consumers' right to know.

Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay that offsets the acoustic delay and determines neural tuning. We used in vivo patch-clamp recordings of binaural neurons in the Mongolian gerbil and pharmacological manipulations to directly compare neuronal input to output and to separate excitation from inhibition. Our results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process, but is instead shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can therefore be combined in a single operation.

The medial superior olive (MSO) senses microsecond differences in the coincidence of binaural signals, a critical cue for detecting sound location along the azimuth. An important component of this circuit is provided by inhibitory neurons of the medial and lateral nuclei of the trapezoid body (MNTB and LNTB, respectively). While MNTB neurons are fairly well described, little is known about the physiology of LNTB neurons. Using whole cell recordings from gerbil brainstem slices, we found that LNTB and MNTB neurons have similar membrane time constants and input resistances and fire brief action potentials, but only LNTB neurons fire repetitively in response to current steps. We observed that LNTB neurons receive graded excitatory and inhibitory synaptic inputs, with at least some of the latter arriving from other LNTB neurons. To address the relative timing of inhibition to the MSO from the LNTB versus the MNTB, we examined inhibitory responses to auditory nerve stimulation using a slice preparation that retains the circuitry from the auditory nerve to the MSO intact. Despite the longer physical path length of excitatory inputs driving contralateral inhibition, inhibition from both pathways arrived with similar latency and jitter. An analysis of paired whole cell recordings between MSO and MNTB neurons revealed a short and reliable delay between the action potential peak in MNTB neurons and the onset of the resulting IPSP (0.55 ± 0.01 ms, n = 4, mean ± SEM). Reconstructions of biocytin-labeled neurons showed that MNTB axons ranged from 580 to 858 μm in length (n = 4). We conclude that while both LNTB and MNTB neurons provide similarly timed inhibition to MSO neurons, the reliability of inhibition from the LNTB at higher frequencies is more constrained relative to that from the MNTB due to differences in intrinsic properties, the strength of excitatory inputs, and the presence of feedforward inhibition.

Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of 4 HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Feedforward inhibition sharpens the precision of neurons throughout ascending auditory pathways, including the binaural neurons of the medial superior olive (MSO). However, the biophysical influence of inhibition is poorly understood, particularly at higher frequencies at which the relative phase of inhibition and excitation becomes ambiguous. Here, we show in gerbil MSO principal cells in vitro that feedforward inhibition precedes direct excitation, providing a concurrent hyperpolarization and conductance shunt during EPSP summation. We show with dual-patch recordings and dynamic clamp that both the linearity and temporal fidelity of synaptic integration is improved by reducing Kv1 potassium channel conductance during inhibition, which counters membrane shunting even at high frequencies at which IPSPs sum. The reduction of peak excitation by preceding inhibition lowers spike probability, narrowing but not shifting the window for detecting binaural coincidence. The interplay between inhibition and potassium conductances thus improves the consistency and resolution of ITD coding across different frequencies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own "best ITD" to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aged rhesus monkeys exhibit deficits in hippocampus-dependent memory, similar to aging humans. Here we explored the basis of cognitive decline by first testing young adult and aged monkeys on a standard recognition memory test (delayed nonmatching-to-sample test; DNMS). Next we quantified synaptic density and morphology in the hippocampal dentate gyrus (DG) outer (OML) and inner molecular layer (IML). Consistent with previous findings, aged monkeys were slow to learn DNMS initially, and they performed significantly worse than young subjects when challenged with longer retention intervals. Although OML and IML synaptic parameters failed to differ across the young and aged groups, the density of perforated synapses in the OML was coupled with recognition memory accuracy. Independent of chronological age, monkeys classified on the basis of menses data as peri- or post-menopausal scored worse on DNMS, and displayed lower OML perforated synapse density, than premenopausal monkeys. These results suggest that naturally occurring reproductive senescence potently influences synaptic connectivity in the DG OML, contributing to individual differences in the course of normal cognitive aging., (Published by Elsevier Inc.)

We report the development of a reliable and efficient method for molecular sexing of all extant elephant taxa. We developed primers that amplify two short Y-specific fragments (SRY1 and AMELY2) and one longer X-specific fragment (PLP1), developed from elephant sequences in one multiplex PCR. All fragments were designed to be short (< 200 basepairs) for use with degraded DNA and to be 50 basepairs apart to optimize visualization on agarose gels or as electropherograms. The multiplex PCR method matched sexes for at least 97.9% of the noninvasive savannah elephant samples and produced the expected female/male banding patterns for 14 African forest and 11 Asian elephant samples. We found this method to be more robust, efficient and less prone to contamination than previously developed sexing methods for elephants., (Published 2011. This article is a US Government work and is in the public domain in the USA.)

Trust underpins the Chinese social system, and yet it is lacking from a Chinese food system that is riddled with safety disasters and disgruntled consumers. Government and industry play a major role in rehabilitating consumer trust in China. To this end, food safety and quality laws have been constructed to foster this process; however, safety scandals continue even in the face of stricter regulations and increased enforcement. A potential toll to abate food-safety problems and to build trust is the implementation of Corporate Social Responsibility ("CSR"). Mandates by the government promote CSR in enterprise activity, including Article 3 of the 2009 China Food Safety Law. Officials have also recently touted the need for "moral education" of operators in the food industry. Regardless of government activity or whether CSR is employed by food enterprises, it is imperative that the food industry recognizes how critical it is to establish trust with Chinese consumers, who increasingly expect safe, quality food. The case study with pistachios highlights this evolving consumer expectation and the principles of social responsibility in the framework of the relationship between government and industry and consumers, while demonstrating the benefits of doing the right thing for food companies doing business in China.

In the outer layers of the dorsal cochlear nucleus, a cerebellum-like structure in the auditory brain stem, multimodal sensory inputs drive parallel fibers to excite both principal (fusiform) cells and inhibitory cartwheel cells. Cartwheel cells, in turn, inhibit fusiform cells and other cartwheel cells. At the microcircuit level, it is unknown how these circuit components interact to modulate the activity of fusiform cells and thereby shape the processing of auditory information. Using a variety of approaches in mouse brain stem slices, we investigated the synaptic connectivity and synaptic strength among parallel fibers, cartwheel cells, and fusiform cells. In paired recordings of spontaneous and evoked activity, we found little overlap in parallel fiber input to neighboring neurons, and activation of multiple parallel fibers was required to evoke or alter action potential firing in cartwheel and fusiform cells. Thus neighboring neurons likely respond best to distinct subsets of sensory inputs. In contrast, there was significant overlap in inhibitory input to neighboring neurons. In recordings from synaptically coupled pairs, cartwheel cells had a high probability of synapsing onto nearby fusiform cells or other nearby cartwheel cells. Moreover, single cartwheel cells strongly inhibited spontaneous firing in single fusiform cells. These synaptic relationships suggest that the set of parallel fibers activated by a particular sensory stimulus determines whether cartwheel cells provide feedforward or lateral inhibition to their postsynaptic targets.

Complex spikes are high-frequency bursts of Na+ spikes, often riding on a slower Ca2+-dependent waveform. Although complex spikes may propagate into axons, given their unusual shape it is not clear how reliably these bursts reach nerve terminals, whether their spikes are efficiently transmitted as a cluster of postsynaptic responses, or what function is served by such a concentrated postsynaptic signal. We examined these questions by recording from synaptically coupled pairs of cartwheel cells, neurons which fire complex spikes and form an inhibitory network in the dorsal cochlear nucleus. Complex spikes in the presynaptic soma were reliably propagated to nerve terminals and elicited powerful, temporally precise postsynaptic responses. Single presynaptic neurons could prevent their postsynaptic partner from firing complex but not simple spikes, dramatically reducing dendritic Ca2+ signals in the postsynaptic neuron. We suggest that rapid transmission of complex spikes may control the susceptibility of neighboring neurons to Ca2+-dependent plasticity.

The behavior of colloidal gels under pressure-driven flow in square microchannels is quantified by microscopic particle image velocimetry (muPIV) and compared to predictions of available rheological models. The gels consist of hydrophobically modified silica microspheres (phi = 0.15-0.33) suspended in a refractive index-matched fluid along with fluorescent tracers to aid visualization. Measured velocity flow profiles show a transition from plug flow to more fluid-like behavior with increasing volumetric flow rate (Q) at all phi. This transition is not captured by theoretical predictions of the flow profile based on the Herschel-Bulkley model. Rather, a model that accounts for gel breakup into a suspension of clusters at elevated shear rates by assuming a finite viscosity at infinite shear is needed to accurately predict the flow behavior of colloidal gels at large Q.

Leishmaniasis affects 12 million people, but there are no vaccines in routine clinical use. Th1 polarizing vaccines that elicit long-term protection are required to prevent disease in susceptible populations. We recently showed that heterologous priming-boosting with tryparedoxin peroxidase (TRYP) DNA followed by TRYP-modified vaccinia virus Ankara (TRYP MVA) protected susceptible BALB/c mice from Leishmania major. Here we compared treatment with TRYP DNA with treatment with TRYP DNA/TRYP MVA. We found that equivalent levels of protection during the postvaccination effector phase correlated with equivalent levels of serum immunoglobulin G2a and gamma interferon (IFN-gamma) in draining lymph nodes. In contrast, challenge infection during the memory phase revealed that there was enhanced clinical efficacy with TRYP DNA/TRYP MVA. This correlated with higher levels of effector phase splenic IFN-gamma, sustained prechallenge levels of memory phase IFN-gamma, and a more polarized post-L. major challenge Th1 response compared to the Th2/T(reg) response. Thus, TRYP DNA/TRYP MVA, but not TRYP DNA alone, provides long-term protection against murine leishmaniasis.