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Many of us had refresher courses in virology, immunology, and epidemiology in 2020, and we were reminded of the fact that Homo sapiens , the wiliest predator on the planet, has been hunting everything that moves for millennia. These repeated interspecies contacts inherently lead to recurrent zoonosis (nonhuman to human) and anthroponosis (human to nonhuman). Given the accelerating changes in our ecosystems since the neolithic revolution, it was not surprising to see a virus that spreads via aerosolization and liquid droplets cause a pandemic in a few months. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic begs the question—which viruses could cause a global threat? In this Opinion, the characteristics that make adenoviruses a risk, which include efficient intra- and interspecies transmission, thermostable particles, persistent/latent infections in diverse hosts, and the ability to readily recombine and escape herd immunity, are discussed.

To better understand the relationship between input and output connectivity for neurons of interest in specific brain regions, a viral-genetic tracing approach is used to identify input based on a combination of neurons’ projection and cell type, as illustrated in a study of locus coeruleus noradrenaline neurons. Noradrenaline circuit architecture New circuit tracing techniques have steadily increased our knowledge of the connectivity between brain regions and how such links may contribute to function and information processing. Here, Liqun Luo and colleagues expand this toolbox to include TRIO, a new strategy designed to characterize the input–output relationships between genetically specified populations of neurons. As a proof of concept, input–output tracing relationships and projection patterns were completed for the noradrenaline neurons of the locus coeruleus. Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input–output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The ‘tracing the relationship between input and output’ method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input–output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.

A small population of brainstem noradrenaline neurons powerfully modulates global brain function, but how they regulate diverse—and at times opposing—functions is not clear. The authors report that a modular organization in this neuromodulatory system, coupled with context-dependent activation modes, controls the balance between opposing emotional and flexible learning states. Noradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility.

The locus coeruleus (LC) projects throughout the brain and spinal cord and is the major source of central noradrenaline. It remains unclear whether the LC acts functionally as a single global effector or as discrete modules. Specifically, while spinal-projections from LC neurons can exert analgesic actions, it is not known whether they can act independently of ascending LC projections. Using viral vectors taken up at axon terminals, we expressed chemogenetic actuators selectively in LC neurons with spinal (LC:SC) or prefrontal cortex (LC:PFC) projections. Activation of the LC:SC module produced robust, lateralised anti-nociception while activation of LC:PFC produced aversion. In a neuropathic pain model, LC:SC activation reduced hind-limb sensitisation and induced conditioned place preference. By contrast, activation of LC:PFC exacerbated spontaneous pain, produced aversion and increased anxiety-like behaviour. This independent, contrasting modulation of pain-related behaviours mediated by distinct noradrenergic neuronal populations provides evidence for a modular functional organisation of the LC.

The TrkB receptor is critical for the control of energy balance, as mutations in its gene ( NTRK2 ) lead to hyperphagia and severe obesity. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVH TrkB ) neurons suppresses or increases food intake, respectively. PVH TrkB neurons project to multiple brain regions, including ventromedial hypothalamus (VMH) and lateral parabrachial nucleus (LPBN). We find that PVH TrkB neurons projecting to LPBN are distinct from those to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Additionally, TrkB activation with BDNF increases firing of these PVH neurons. Therefore, TrkB signaling is a key regulator of a previously uncharacterized neuronal population within the PVH that impinges upon multiple circuits to govern appetite. The TrkB receptor is known to regulate obesity via appetite control, but the underlying neural circuits are not known. Here, the authors show that selective modulation of TrkB+ neurons in the paraventricular hypothalamus regulates food intake via circuits to ventromedial hypothalamus and lateral parabrachial nucleus.

The aim of this review is to highlight how, in a syngeneic system, human mononuclear phagocytes respond to environments containing human adenovirus (HAdV) and soluble extracellular proteins that influence their innate immune response. Soluble extracellular proteins, including immunoglobulins, blood clotting factors, proteins of the complement system, and/or antimicrobial peptides (AMPs) can exert direct effects by binding to a virus capsid that modifies interactions with pattern recognition receptors and downstream signaling. In addition, the presence, generation, or secretion of extracellular proteins can indirectly influence the response to HAdVs via the activation and recruitment of cells at the site of infection.

Human adenoviruses (HAdVs) are nonenveloped proteinaceous particles containing a linear double-stranded DNA genome. HAdVs cause a spectrum of pathologies in all populations regardless of health standards. Following repeat exposure to multiple HAdV types, we develop robust and long-lived humoral and cellular immune responses that provide life-long protection from de novo infections and persistent HAdV. How HAdVs, anti-HAdV antibodies and antigen presenting cells (APCs) interact to influence infection is still incompletely understood. In our study, we used physical, pharmacological, biochemical, fluorescence and electron microscopy, molecular and cell biology approaches to dissect the impact of immune-complexed HAdV (IC-HAdV) on human monocyte-derived dendritic cells (MoDCs). We show that IC-HAdV generate stabilized complexes of ~200 nm that are efficiently internalized by, and aggregate in, MoDCs. By comparing IC-HAdV, IC-empty capsid, IC-Ad2ts1 (a HAdV-C2 impaired in endosomal escape due to a mutation that impacts protease encapsidation) and IC-AdL40Q (a HAdV-C5 impaired in endosomal escape due to a mutation in protein VI), we demonstrate that protein VI-dependent endosomal escape is required for the HAdV genome to engage the DNA pattern recognition receptor AIM2 (absent in melanoma 2). AIM2 engagement induces pyroptotic MoDC death via ASC (apoptosis-associated speck protein containing a caspase activation/recruitment domain) aggregation, inflammasome formation, caspase 1 activation, and IL-1β and gasdermin D (GSDMD) cleavage. Our study provides mechanistic insight into how humoral immunity initiates an innate immune response to HAdV-C5 in human professional APCs.

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is typically caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1, a 250-kDa voltage-gated sodium channel. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A open reading frame into the brain improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus and/or the thalamus of DS mice increased survival, reduced the occurrence of epileptic spikes, provided protection from thermally induced seizures, corrected background electrocorticographic activity and behavioral deficits, and restored hippocampal inhibition. Together, our results provide a proof of concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.

Highly distributed neural circuits are thought to support adaptive decision-making in volatile and complex environments. Notably, the functional interactions between prefrontal and reciprocally connected thalamic nuclei areas may be important when choices are guided by current goal value or action-outcome contingency. We examined the functional involvement of selected thalamocortical and corticothalamic pathways connecting the dorsomedial prefrontal cortex (dmPFC) and the mediodorsal thalamus (MD) in the behaving rat. Using a chemogenetic approach to inhibit projection-defined dmPFC and MD neurons during an instrumental learning task, we show that thalamocortical and corticothalamic pathways differentially support goal attributes. Both pathways participate in adaptation to the current goal value, but only thalamocortical neurons are required to integrate current causal relationships. These data indicate that antiparallel flow of information within thalamocortical circuits may convey qualitatively distinct aspects of adaptive decision-making and highlight the importance of the direction of information flow within neural circuits. Planning and decision-making rely upon a region of the brain called the prefrontal cortex. But the prefrontal cortex does not act in isolation. Instead, it works together with a number of other brain regions. These include the thalamus, an area long thought to pass information on to the cortex for further processing. But signals also travel in the opposite direction, from the cortex back to the thalamus. Does the cortex-to-thalamus pathway carry the same information as the thalamus-to-cortex pathway? To find out, Alcaraz et al. blocked each pathway in rats performing a decision-making task. The rats had learned that pressing a lever led to one type of reward, whereas moving a rod led to another. Alcaraz et al. reduced the desirability of one of the rewards by giving the rats free access to it for an hour. Afterwards, the rats opted mainly for the action associated with the reward that had remained desirable. However, blocking either the thalamus-to-cortex or cortex-to-thalamus pathway prevented this preference from emerging. This suggests that an information flow in both directions is necessary to update knowledge about the value of a reward. In a second experiment, Alcaraz et al. removed the link between one of the actions and its reward. The reward instead appeared at random, irrespective of the rat’s own behavior. Control rats responded by focusing their efforts on the action that still delivered a reliable reward, and by performing the other action less often. Blocking the thalamus-to-cortex pathway prevented this response, but blocking the cortex-to-thalamus pathway did not. This suggests that only the former pathway is necessary to re-evaluate the relationship between an action and an outcome. Two key aspects of goal-directed behavior – recognizing the value of a reward and the link between an action and an outcome – thus depend differently on the thalamus-to-cortex and cortex-to-thalamus pathways. This same principle may also be at work in other neural circuits with bidirectional connections. Understanding such principles may lead to better strategies for treating disorders of brain connectivity, such as schizophrenia.

  [...]it is still unclear how significantly the integrin repertoire involved in membrane penetration influences different AdV types. [...]when injected intravenously in mice, some AdVs can interact with specific coagulation factors [9] that alter tissue tropism by preventing binding of naturally occurring antibodies and then by acting as a bridge to attach to proteoglycans on liver cells [10]. [...]the routes and modes of AdV cell entry are variable and cell-type dependent.