We engineered light-gated channelrhodopsins (ChRs) whose current strength and light sensitivity enable minimally invasive neuronal circuit interrogation. Current ChR tools applied to the mammalian ...brain require intracranial surgery for transgene delivery and implantation of fiber-optic cables to produce light-dependent activation of a small volume of tissue. To facilitate expansive optogenetics without the need for invasive implants, our engineering approach leverages the substantial literature of ChR variants to train statistical models for the design of high-performance ChRs. With Gaussian process models trained on a limited experimental set of 102 functionally characterized ChRs, we designed high-photocurrent ChRs with high light sensitivity. Three of these, ChRger1-3, enable optogenetic activation of the nervous system via systemic transgene delivery. ChRger2 enables light-induced neuronal excitation without fiber-optic implantation; that is, this opsin enables transcranial optogenetics.
Ventral midbrain dopamine (DA) is unambiguously involved in motivation and behavioral arousal, yet the contributions of other DA populations to these processes are poorly understood. Here, we ...demonstrate that the dorsal raphe nucleus DA neurons are critical modulators of behavioral arousal and sleep-wake patterning. Using simultaneous fiber photometry and polysomnography, we observed time-delineated dorsal raphe nucleus dopaminergic (DRNDA) activity upon exposure to arousal-evoking salient cues, irrespective of their hedonic valence. We also observed broader fluctuations of DRNDA activity across sleep-wake cycles with highest activity during wakefulness. Both endogenous DRNDA activity and optogenetically driven DRNDA activity were associated with waking from sleep, with DA signal strength predictive of wake duration. Conversely, chemogenetic inhibition opposed wakefulness and promoted NREM sleep, even in the face of salient stimuli. Therefore, the DRNDA population is a critical contributor to wake-promoting pathways and is capable of modulating sleep-wake states according to the outside environment, wherein the perception of salient stimuli prompts vigilance and arousal.
•DRNDA neurons are activated by salient stimuli irrespective of hedonic valence•DRNDA activity fluctuates across sleep-wake states and is highest at wakefulness•Optogenetic activation promotes wakefulness•Chemogenetic inhibition opposes wakefulness, even in the presence of salient stimuli
Cho et al. demonstrate that dorsal raphe nucleus dopaminergic (DRNDA) activity escalates in response to salient stimuli irrespective of valence, correlates with sleep-wake states, and can bi-directionally modulate arousal.
DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using ...the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.
•Structure-guided approach for κ-opioid receptor (KOR)-DREADD (KORD) design•KORD is selectively activated by salvinorin B, and not by endogenous opioids•KORD robustly silenced multiple neuronal subtypes•Inhibitory KORD combined with excitatory hM3Dq for multiplexed behavioral control
The κ-opioid receptor (KOR) was used as a template to generate a novel inhibitory DREADD (KORD), which is activated by salvinorin B and insensitive to endogenous opioid peptides. Sequential activation of the inhibitory KOR-DREADD and an excitatory M3-DREADD facilitated the bidirectional, multiplexed modulation of behavior.
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•Dopaminergic dysfunction is common in many neurodevelopmental disorders.•New circuit mapping tools have refined our knowledge of these circuits at baseline.•When used in animal ...models, these tools will likely elucidate NDD pathophysiology.
Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits.
The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons ...innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations.
Objectives
To develop a reliable and valid dementia knowledge scale to address limitations of existing measures, support knowledge evaluation in diverse populations, and inform educational ...intervention development.
Design
A five‐stage, systematic scale development process was employed to construct and assess the psychometric properties of the Dementia Knowledge Assessment Scale (DKAS).
Setting
Data for the study were generated in an online environment and during clinical dementia care placements from Australian (n = 1,321) and international respondents (n = 446).
Participants
Volunteers from a dementia‐related massive open online course (n = 1,651), medical students on clinical placement in a residential aged care facility (n = 40), and members of the Australian health workforce (n = 76).
Measurements
Psychometric properties of the DKAS were established using a literature review to assess the veracity of scale items, respondent feedback during pilot testing, a Delphi study with dementia experts, construction and review by an expert panel, evaluation of item difficulty, item‐total and interitem correlations. Principal components analysis (PCA) was also performed along with measures of test–retest reliability, internal consistency, construct validity, and concurrent validity.
Results
The pilot DKAS was reduced from 40 to 27 items during analysis. PCA identified four distinct and interpretable factors. The revised DKAS displays high levels of test–retest reliability; internal consistency; and preliminary construct, concurrent, and factorial validity.
Conclusion
The 27‐item DKAS is reliable and shows preliminary validity for the assessment of knowledge deficiencies and change in those who provide care and treatment for people with dementia.
Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and coordinate social interactions. However, the neural circuit mechanisms for these processes ...remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors, comprises molecularly diverse neurons with widespread projections. Here we identify a steroid-responsive subset of neurotensin (Nts)-expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially engaged reward circuit. Using in vivo two-photon imaging in female mice, we show that mPOA
neurons preferentially encode attractive male cues compared to nonsocial appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue-encoding properties of these cells. Furthermore, optogenetic stimulation of mPOA
-VTA circuitry promotes rewarding phenotypes, social approach and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically relevant stimuli and co-opt midbrain reward circuits to promote prosocial behaviors critical for species survival.
The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders FASD). In 1996, the Institute of Medicine established diagnostic categories ...delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol.
To determine the prevalence and characteristics of fetal alcohol spectrum disorders (FASD) among first grade students (6- to 7-year-olds) in a representative Midwestern US community.
From a consented ...sample of 70.5% of all first graders enrolled in public and private schools, an oversample of small children (≤ 25th percentile on height, weight, and head circumference) and randomly selected control candidates were examined for physical growth, development, dysmorphology, cognition, and behavior. The children's mothers were interviewed for maternal risk.
Total dysmorphology scores differentiate significantly fetal alcohol syndrome (FAS) and partial FAS (PFAS) from one another and from unexposed controls. Alcohol-related neurodevelopmental disorder (ARND) is not as clearly differentiated from controls. Children who had FASD performed, on average, significantly worse on 7 cognitive and behavioral tests and measures. The most predictive maternal risk variables in this community are late recognition of pregnancy, quantity of alcoholic drinks consumed 3 months before pregnancy, and quantity of drinking reported for the index child's father. From the final multidisciplinary case findings, 3 techniques were used to estimate prevalence. FAS in this community likely ranges from 6 to 9 per 1000 children (midpoint, 7.5), PFAS from 11 to 17 per 1000 children (midpoint, 14), and the total rate of FASD is estimated at 24 to 48 per 1000 children, or 2.4% to 4.8% (midpoint, 3.6%).
Children who have FASD are more prevalent among first graders in this Midwestern city than predicted by previous, popular estimates.
Dementia is a life-limiting condition that is increasing in global prevalence in line with population ageing. In this context, it is necessary to accurately measure dementia knowledge across a ...spectrum of health professional and lay populations with the aim of informing targeted educational interventions and improving literacy, care, and support. Building on prior exploratory analysis, which informed the development of the preliminarily valid and reliable version of the Dementia Knowledge Assessment Scale (DKAS), a Confirmatory Factor Analysis (CFA) was performed to affirm construct validity and proposed subscales to further increase the measure's utility for academics and educators.
A large, de novo sample of 3649 volunteer respondents to a dementia-related online course was recruited to evaluate the performance of the DKAS and its proposed subscales. Respondents represented diverse cohorts, including health professionals, students, and members of the general public. Analyses included CFA (using structural equation modelling), measures of internal consistency (α), and non-parametric tests of subscale correlation (Spearman Correlation) and score differences between cohorts (Kruskal-Wallis one-way analysis of variance).
Findings of the CFA supported a 25-item, four-factor model for the DKAS with two items removed due to poor performance and one item moved between factors. The resultant model exhibited good reliability (α = .85; ω
= .87; overall scale), with acceptable subscale internal consistency (α ≥ .65; subscales). Subscales showed acceptable correlation without any indication of redundancy. Finally, total and DKAS subscale scores showed good discrimination between cohorts of respondents who would be anticipated to hold different levels of knowledge on the basis of education or experience related to dementia.
The DKAS has been confirmed as a reliable and valid measure of dementia knowledge for diverse populations that is capable of elucidating knowledge characteristics across four coherent domains: 1) Causes and Characteristics, 2) Communication and Behaviour, 3) Care Considerations, and 4) Risks and Health Promotion. Importantly, the four confirmed subscales clearly distinguish between groups who might be expected to hold differing levels of knowledge about dementia, allowing for a fine-grained level of detail to be established when evaluating baseline understanding or knowledge change associated with educational intervention.
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