PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons.

While PTEN-induced kinase 1 (PINK1) is well characterized for its role in mitochondrial homeostasis, much less is known concerning its ability to prevent synaptodendritic degeneration. Using unbiased proteomic methods, we identified valosin-containing protein (VCP) as a major PINK1-interacting protein. RNAi studies demonstrate that both VCP and its cofactor NSFL1C/p47 are necessary for the ability of PINK1 to increase dendritic complexity.

Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases.

Over the past 20 years, the concept of mammalian autophagy as a nonselective degradation system has been repudiated, due in part to important discoveries in neurodegenerative diseases, which opened the field of selective autophagy. Protein aggregates and damaged mitochondria represent key pathological hallmarks shared by most neurodegenerative diseases. The landmark discovery in 2007 of p62/SQSTM1 as the first mammalian selective autophagy receptor defined a new family of autophagy-related proteins that serve to target protein aggregates, mitochondria, intracellular pathogens and other cargoes to the core autophagy machinery via an LC3-interacting region (LIR)-motif.

A Materials Roadmap to Functional Neural Interface Design.

Advancement in neurotechnologies for electrophysiology, neurochemical sensing, neuromodulation, and optogenetics are revolutionizing scientific understanding of the brain while enabling treatments, cures, and preventative measures for a variety of neurological disorders. The grand challenge in neural interface engineering is to seamlessly integrate the interface between neurobiology and engineered technology, to record from and modulate neurons over chronic timescales. However, the biological inflammatory response to implants, neural degeneration, and long-term material stability diminish the quality of interface overtime.

Optogenetic Activation of Colon Epithelium of the Mouse Produces High-Frequency Bursting in Extrinsic Colon Afferents and Engages Visceromotor Responses.

Epithelial cells of the colon provide a vital interface between the internal environment (lumen of the colon) and colon parenchyma. To examine epithelial-neuronal signaling at this interface, we analyzed mice in which channelrhodopsin (ChR2) was targeted to either TRPV1-positive afferents or to villin-expressing colon epithelial cells. Expression of a ChR2-EYFP fusion protein was directed to either primary sensory neurons or to colon epithelial cells by crossing Ai32 mice with TRPV1-Cre or villin-Cre mice, respectively.

Multiple pathways for mitophagy: A neurodegenerative conundrum for Parkinson's disease.

It has been nearly a decade since the first landmark studies implicating familial recessive Parkinson's disease genes in the regulation of selective mitochondrial autophagy. The PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin (encoded by the PARK2 gene) act together to mark depolarized mitochondria for degradation. There is now an extensive body of literature detailing key mediators and steps in this pathway, based mostly on work in transformed cell lines.

TrpM8-mediated somatosensation in mouse neocortex.

Somatosensation is a complex sense mediated by more than a dozen distinct neural subtypes in the periphery. Although pressure and touch sensation have been mapped to primary somatosensory cortex in rodents, it has been controversial whether pain and temperature inputs are also directed to this area. Here we use a well-defined somatosensory modality, cool sensation mediated by peripheral TrpM8-receptors, to investigate the neural substrate for cool perception in the mouse neocortex.

Differential Regulation of Bladder Pain and Voiding Function by Sensory Afferent Populations Revealed by Selective Optogenetic Activation.

Bladder-innervating primary sensory neurons mediate reflex-driven bladder function under normal conditions, and contribute to debilitating bladder pain and/or overactivity in pathological states. The goal of this study was to examine the respective roles of defined subtypes of afferent neurons in bladder sensation and function via direct optogenetic activation. To accomplish this goal, we generated transgenic lines that express a Channelrhodopsin-2-eYFP fusion protein (ChR2-eYFP) in two distinct populations of sensory neurons: TRPV1-lineage neurons (;Ai32, the majority of nociceptors) and Na1.

Basic Science and Public Policy: Informed Regulation for Nicotine and Tobacco Products.

Introduction: Scientific discoveries over the past few decades have provided significant insight into the abuse liability and negative health consequences associated with tobacco and nicotine-containing products. While many of these advances have led to the development of policies and laws that regulate access to and formulations of these products, further research is critical to guide future regulatory efforts, especially as novel nicotine-containing products are introduced and selectively marketed to vulnerable populations.

Discussion: In this narrative review, we provide an overview of the scientific findings that have impacted regulatory policy and discuss considerations for further translation of science into policy decisions.

Prenatal and Early Postnatal Odorant Exposure Heightens Odor-Evoked Mitral Cell Responses in the Mouse Olfactory Bulb.

Early sensory experience shapes the anatomy and function of sensory circuits. In the mouse olfactory bulb (OB), prenatal and early postnatal odorant exposure through odorized food (food/odorant pairing) not only increases the volume of activated glomeruli but also increases the number of mitral and tufted cells (M/TCs) connected to activated glomeruli. Given the importance of M/TCs in OB output and in mediating lateral inhibitory networks, increasing the number of M/TCs connected to a single glomerulus may significantly change odorant representation by increasing the total output of that glomerulus and/or by increasing the strength of lateral inhibition mediated by cells connected to the affected glomerulus.

Animal Research on Nicotine Reduction: Current Evidence and Research Gaps.

Unlabelled: A mandated reduction in the nicotine content of cigarettes may improve public health by reducing the prevalence of smoking. Animal self-administration research is an important complement to clinical research on nicotine reduction. It can fill research gaps that may be difficult to address with clinical research, guide clinical researchers about variables that are likely to be important in their own research, and provide policy makers with converging evidence between clinical and preclinical studies about the potential impact of a nicotine reduction policy.

Self-administered nicotine differentially impacts body weight gain in obesity-prone and obesity-resistant rats.

Obesity and tobacco smoking represent the largest challenges to public health, but the causal relationship between nicotine and obesity is poorly understood. Nicotine suppresses body weight gain, a factor impacting smoking initiation and the failure to quit, particularly among obese smokers. The impact of nicotine on body weight regulation in obesity-prone and obesity-resistant populations consuming densely caloric diets is unknown.

Differences in Glomerular-Layer-Mediated Feedforward Inhibition onto Mitral and Tufted Cells Lead to Distinct Modes of Intensity Coding.

Understanding how each of the many interneuron subtypes affects brain network activity is critical. In the mouse olfactory system, mitral cells (MCs) and tufted cells (TCs) comprise parallel pathways of olfactory bulb output that are thought to play distinct functional roles in odor coding. Here, in acute mouse olfactory bulb slices, we test how the two major classes of olfactory bulb interneurons differentially contribute to differences in MC versus TC response properties.

Reducing nicotine exposure results in weight gain in smokers randomised to very low nicotine content cigarettes.

Background: The Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain.

Methods: Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.

Early Odorant Exposure Increases the Number of Mitral and Tufted Cells Associated with a Single Glomerulus.

Unlabelled: The highly specific organization of the olfactory bulb (OB) is well known, but the impact of early odorant experience on its circuit structure is unclear. Olfactory sensory neurons (OSNs) project axons from the olfactory epithelium to the OB, where they form spherical neuropil structures called glomeruli. These glomeruli and the postsynaptic targets of OSNs, including mitral and tufted cells (M/TCs) and juxtaglomerular cells, form glomerular modules, which represent the basic odor-coding units of the OB.

Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators.

Inflammatory pain is thought to arise from increased transmission from nociceptors and recruitment of 'silent' afferents. To evaluate inflammation-induced changes, mice expressing GCaMP3 in cutaneous sensory neurons were generated and neuronal responses to mechanical stimulation in vivo before and after subcutaneous infusion of an 'inflammatory soup' (IS) were imaged in an unanesthetized preparation. Infusion of IS rapidly altered mechanical responsiveness in the majority of neurons.

Sex-, stress-, and sympathetic post-ganglionic-dependent changes in identity and proportions of immune cells in the dura.

Aim of investigation Due to compelling evidence in support of links between sex, stress, sympathetic post-ganglionic innervation, dural immune cells, and migraine, our aim was to characterize the impacts of these factors on the type and proportion of immune cells in the dura. Methods Dural immune cells were obtained from naïve or stressed adult male and female Sprague Dawley rats for flow cytometry. Rats with surgical denervation of sympathetic post-ganglionic neurons of the dura were also studied.

Trafficking of Na+/Ca2+ exchanger to the site of persistent inflammation in nociceptive afferents.

Persistent inflammation results in an increase in the amplitude and duration of depolarization-evoked Ca(2+) transients in putative nociceptive afferents. Previous data indicated that these changes were the result of neither increased neuronal excitability nor an increase in the amplitude of depolarization. Subsequent data also ruled out an increase in voltage-gated Ca(2+) currents and recruitment of Ca(2+)-induced Ca(2+) release.

Experience-dependent regulation of presynaptic NMDARs enhances neurotransmitter release at neocortical synapses.

Sensory experience can selectively alter excitatory synaptic strength at neocortical synapses. The rapid increase in synaptic strength induced by selective whisker stimulation (single-row experience/SRE, where all but one row of whiskers has been removed from the mouse face) is due, at least in part, to the trafficking of AMPA receptors (AMPARs) to the post-synaptic membrane, and is developmentally regulated. How enhanced sensory experience can alter presynaptic release properties in the developing neocortex has not been investigated.

Evidence for Cerebellar Contributions to Adaptive Plasticity in Speech Perception.

Human speech perception rapidly adapts to maintain comprehension under adverse listening conditions. For example, with exposure listeners can adapt to heavily accented speech produced by a non-native speaker. Outside the domain of speech perception, adaptive changes in sensory and motor processing have been attributed to cerebellar functions.

Speech perception under adverse conditions: insights from behavioral, computational, and neuroscience research.

Adult speech perception reflects the long-term regularities of the native language, but it is also flexible such that it accommodates and adapts to adverse listening conditions and short-term deviations from native-language norms. The purpose of this article is to examine how the broader neuroscience literature can inform and advance research efforts in understanding the neural basis of flexibility and adaptive plasticity in speech perception. Specifically, we highlight the potential role of learning algorithms that rely on prediction error signals and discuss specific neural structures that are likely to contribute to such learning.

Neuronal correlates of visual time perception at brief timescales.

Successful interaction with the world depends on accurate perception of the timing of external events. Neurons at early stages of the primate visual system represent time-varying stimuli with high precision. However, it is unknown whether this temporal fidelity is maintained in the prefrontal cortex, where changes in neuronal activity generally correlate with changes in perception.

Division of labor in frontal eye field neurons during presaccadic remapping of visual receptive fields.

Our percept of visual stability across saccadic eye movements may be mediated by presaccadic remapping. Just before a saccade, neurons that remap become visually responsive at a future field (FF), which anticipates the saccade vector. Hence, the neurons use corollary discharge of saccades.

Preparatory attention relies on dynamic interactions between prelimbic cortex and anterior cingulate cortex.

An emerging view of prefrontal cortex (PFC) function is that multiple PFC areas process information in parallel, rather than as distinct modules. Two key functions assigned to the PFC are the regulation of top-down attention and stimulus-guided action. Electrophysiology and lesion studies indicate the involvement of both the anterior cingulate cortex (ACC) and prelimbic cortex (PL) in these functions.

Sex differences in the inflammatory mediator-induced sensitization of dural afferents.

Approximately 20% of the adult population suffers from migraine. This debilitating pain disorder is three times more prevalent in women than in men. To begin to evaluate the underlying mechanisms that may contribute to this sex difference, we tested the hypothesis that there is a sex difference in the inflammatory mediator (IM)-induced sensitization of dural afferents.