A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction.

Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein-coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the "necklace" subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here, we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically relevant ligands, including pheromones and fatty acids, in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.

Recurrent Connections in the Primate Ventral Visual Stream Mediate a Trade-Off Between Task Performance and Network Size During Core Object Recognition.

The computational role of the abundant feedback connections in the ventral visual stream is unclear, enabling humans and nonhuman primates to effortlessly recognize objects across a multitude of viewing conditions. Prior studies have augmented feedforward convolutional neural networks (CNNs) with recurrent connections to study their role in visual processing; however, often these recurrent networks are optimized directly on neural data or the comparative metrics used are undefined for standard feedforward networks that lack these connections. In this work, we develop task-optimized convolutional recurrent (ConvRNN) network models that more correctly mimic the timing and gross neuroanatomy of the ventral pathway. Properly chosen intermediate-depth ConvRNN circuit architectures, which incorporate mechanisms of feedforward bypassing and recurrent gating, can achieve high performance on a core recognition task, comparable to that of much deeper feedforward networks. We then develop methods that allow us to compare both CNNs and ConvRNNs to finely grained measurements of primate categorization behavior and neural response trajectories across thousands of stimuli. We find that high-performing ConvRNNs provide a better match to these data than feedforward networks of any depth, predicting the precise timings at which each stimulus is behaviorally decoded from neural activation patterns. Moreover, these ConvRNN circuits consistently produce quantitatively accurate predictions of neural dynamics from V4 and IT across the entire stimulus presentation. In fact, we find that the highest-performing ConvRNNs, which best match neural and behavioral data, also achieve a strong Pareto trade-off between task performance and overall network size. Taken together, our results suggest the functional purpose of recurrence in the ventral pathway is to fit a high-performing network in cortex, attaining computational power through temporal rather than spatial complexity.

Widespread transcription at neuronal activity-regulated enhancers.

We used genome-wide sequencing methods to study stimulus-dependent enhancer function in mouse cortical neurons. We identified approximately 12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis.

Harm reduction isn't enough: Introducing the concept of Mindful Consumption and Benefit Maximization (MCBM).

The concept of harm reduction was a radical departure from a century of stigmatizing demand reduction initiatives targeted at people who use drugs. In fact, since the early 1980's Harm Reduction has been used with great success to protect the lives and wellbeing of these individuals. When employed with people who use opioids, the relevancy and importance of harm reduction are easy to grasp because the potential dangers are both quite visible and profound. However, promoting harm reduction practices to people consuming cannabis is a more difficult challenge. Cannabis cannot cause death due to overconsumption, is not associated with the spread of communicable diseases, and is overall a relatively harmless drug both to the individual and society when compared with other legal substances such as tobacco and alcohol. Harm reduction campaigns targeted at cannabis consumers run the risk of sounding overly fearful and stigmatizing, ultimately being ignored like many of the old demand reduction initiatives. Cannabis does have potential harms, and teaching people to mitigate those harms is an important public health goal. This commentary argues that cannabis education targeted at young people should employ mindful consumption and benefit maximization (MCBM) language that promotes harm reduction practices but does not focus on harm as the primary issue related to cannabis use. We define what we mean by mindful consumption and benefit maximization, identify their convergence with harm reduction principles, and argue for their use to both promote knowledge and normalize cannabis consumption that incorporates harm reduction practices.

CD20/MS4A1 is a mammalian olfactory receptor expressed in a subset of olfactory sensory neurons that mediates innate avoidance of predators.

The mammalian olfactory system detects and discriminates between millions of odorants to elicit appropriate behavioral responses. While much has been learned about how olfactory sensory neurons detect odorants and signal their presence, how specific innate, unlearned behaviors are initiated in response to ethologically relevant odors remains poorly understood. Here, we show that the 4-transmembrane protein CD20, also known as MS4A1, is expressed in a previously uncharacterized subpopulation of olfactory sensory neurons in the main olfactory epithelium of the murine nasal cavity and functions as a mammalian olfactory receptor that recognizes compounds produced by mouse predators. While wildtype mice avoid these predator odorants, mice genetically deleted of CD20 do not appropriately respond. Together, this work reveals a CD20-mediated odor-sensing mechanism in the mammalian olfactory system that triggers innate behaviors critical for organismal survival.

Global patterns in small-scale cannabis growers' distribution practices: Exploring the grower-distributor nexus.

BACKGROUND: While the supply of cannabis is commonly assumed to be dominated by criminal gangs, a sizable share of the domestic cannabis supply is provided by small-scale growers. This article examines the nature and scope of small-scale growers' distribution practices, with a particular focus on cross-country differences and variations between different types of grower-distributors, i.e., "non-suppliers", "exclusive social suppliers", "sharers and sellers" and "exclusive sellers". METHODS: Based on a large convenience web survey sample of predominantly small-scale cannabis growers from 18 countries, this article draws on data from two subsamples. The first subsample includes past-year growers in all 18 countries who answered questions regarding their market participation (n = 8,812). The second subsample includes past-year growers in 13 countries, who answered additional questions about their supply practices (n = 2,296). RESULTS: The majority of the cannabis growers engaged in distribution of surplus products, making them in effect "grower-distributors". Importantly, many did so as a secondary consequence of growing, and social supply (e.g., sharing and gifting) is much more common than selling. While growers who both shared and sold ("sharers and sellers"), and especially those who only sold ("exclusive sellers"), grew a higher number of plants and were most likely to grow due to a wish to sell for profits, the majority of these are best described as small-scale sellers. That is, the profit motive for growing was often secondary to non-financial motives and most sold to a limited number of persons in their close social network. CONCLUSION: We discuss the implications of the findings on the structural process of import-substitution in low-end cannabis markets, including a growing normalization of cannabis supply.

CD20 is a mammalian odorant receptor expressed in a subset of olfactory sensory neurons that mediates innate avoidance of predators.

The mammalian olfactory system detects and discriminates between millions of odorants to elicit appropriate behavioral responses. While much has been learned about how olfactory sensory neurons detect odorants and signal their presence, how specific innate, unlearned behaviors are initiated in response to ethologically relevant odors remains poorly understood. Here, we show that the 4-transmembrane protein CD20, also known as MS4A1, is expressed in a previously uncharacterized subpopulation of olfactory sensory neurons in the main olfactory epithelium of the murine nasal cavity and functions as a mammalian odorant receptor that recognizes compounds produced by mouse predators. While wild-type mice avoid these predator odorants, mice genetically deleted of CD20 do not appropriately respond. Together, this work reveals a novel CD20-mediated odor-sensing mechanism in the mammalian olfactory system that triggers innate behaviors critical for organismal survival.

CD20 is a mammalian odorant receptor expressed in a subset of olfactory sensory neurons that mediates innate avoidance of predators.

The mammalian olfactory system detects and discriminates between millions of odorants to elicit appropriate behavioral responses. While much has been learned about how olfactory sensory neurons detect odorants and signal their presence, how specific innate, unlearned behaviors are initiated in response to ethologically relevant odors remains poorly understood. Here, we show that the 4-transmembrane protein CD20, also known as MS4A1, is expressed in a previously uncharacterized subpopulation of olfactory sensory neurons in the main olfactory epithelium of the murine nasal cavity and functions as a mammalian odorant receptor that recognizes compounds produced by mouse predators. While wild-type mice avoid these predator odorants, mice genetically deleted of CD20 do not appropriately respond. Together, this work reveals a novel CD20-mediated odor-sensing mechanism in the mammalian olfactory system that triggers innate behaviors critical for organismal survival.

Are cannabis use problems comparable across individuals using for recreational and medical purposes? An international cross-sectional study of individuals who use self-grown cannabis.

BACKGROUND: Little is known about cannabis use problems among individuals who use cannabis for medical purposes and whether rates and determinants of cannabis use problems in medical users differ to those observed among individuals using for recreational reasons. This study examines whether Severity of Dependence Scale (SDS) scores differ across individuals who use self-grown cannabis for the following reasons: "recreational only", "medical and recreational" and "medical only". Furthermore, the study tests whether cannabis use frequency, cannabis strain, and type of cannabis influences the strength of the association between purpose of use and cannabis use problems. METHODS: Data (n = 5,347) were collected from a subsample of the Global Cannabis Cultivation Research Consortium project, focusing on small-scale cannabis growers in 18 countries. Robust regressions analyzed differences in SDS scores across the three use motivation groups. RESULTS: Compared with respondents reporting only recreational motivations of cannabis use, those with medical (with and without recreational) motivations were associated with lower SDS scores (B: -0.190 and B: -0.459, p < 0.001 respectively). Daily use was associated with significantly higher SDS scores across all cannabis motivation groups, albeit the magnitude of the association was significantly smaller among individuals with medical motivations of use. CONCLUSION: The extent to which people experience cannabis use problems, and the determinants of these problems may differ depending on whether cannabis use is motivated by recreational or medical purposes. As such, the findings of the current study suggest that public education efforts, harm reduction approaches and policy responses should be tailored depending on whether cannabis is used for recreational or medical purposes.

Spatial transcriptomic reconstruction of the mouse olfactory glomerular map suggests principles of odor processing.

The olfactory system's ability to detect and discriminate between the vast array of chemicals present in the environment is critical for an animal's survival. In mammals, the first step of this odor processing is executed by olfactory sensory neurons, which project their axons to a stereotyped location in the olfactory bulb (OB) to form glomeruli. The stereotyped positioning of glomeruli in the OB suggests an importance for this organization in odor perception. However, because the location of only a limited subset of glomeruli has been determined, it has been challenging to determine the relationship between glomerular location and odor discrimination. Using a combination of single-cell RNA sequencing, spatial transcriptomics and machine learning, we have generated a map of most glomerular positions in the mouse OB. These observations significantly extend earlier studies and suggest an overall organizational principle in the OB that may be used by the brain to assist in odor decoding.

The zebra fish cassiopeia mutant reveals that SIL is required for mitotic spindle organization.

A critical step in cell division is formation of the mitotic spindle, which is a bipolar array of microtubules that mediates chromosome separation. Here, we report that the SCL-interrupting locus (SIL), a vertebrate-specific cytosolic protein, is necessary for proper mitotic spindle organization in zebrafish and human cells. A homozygous lethal zebrafish mutant, cassiopeia (csp), was identified by a genetic screen for mitotic mutant. csp mutant embryos have an increased mitotic index, have highly disorganized mitotic spindles, and often lack one or both centrosomes. These phenotypes are caused by a loss-of-function mutation in zebrafish sil. To determine if the requirement for SIL in mitotic spindle organization is conserved in mammals, we generated an antibody against human SIL, which revealed that SIL localizes to the poles of the mitotic spindle during metaphase. Furthermore, short hairpin RNA knockdown of SIL in human cells recapitulates the zebrafish csp mitotic spindle defects. These data, taken together, identify SIL as a novel, vertebrate-specific regulator of mitotic spindle assembly.

From Toques to Tokes: Two challenges facing nationwide legalization of cannabis in Canada.

BACKGROUND: In 2015, a new Liberal Government came to power in Canada, elected on a platform that included legalization and regulation of cannabis for recreational purposes. Their legislation, based on recommendations from a Federal Task Force on Marijuana Legalization and Regulation, is due in early April 2017. METHODS: This commentary utilizes Canadian Federal policy papers, previous literature, and internal and international agreements to examine two key areas critical to the development of a nationwide regulated market for cannabis in Canada; the need to overcome restrictions to legalizing cannabis in United Nations' drug control treaties, and the unique challenges that non-medical cannabis creates for navigating interprovincial trade policies in Canada. RESULTS: Irrespective of UN conventions that appear to prohibit legalization of cannabis the Government is preparing to bring forward legislation as this article goes to print. At the same time significant squabbles impede the selling of even beer and wine inter-provincially in Canada. This paper identifies the challenges facing Canadian legalization efforts, but also shows how the legalization legislation may provide opportunities to engender significant change beyond the simple legalization of a specific drug. CONCLUSION: This commentary does not argue for any specific course of action for Canada, but rather explores the nuance of legalization absent from the declaration in the Liberal party platform. The paper argues that Canada's efforts may hasten the dismantling of the UN drug control structure, and provide renewed opportunities for intern-provincial trade in Canada.

The Evolving Neural and Genetic Architecture of Vertebrate Olfaction.

Evolution sculpts the olfactory nervous system in response to the unique sensory challenges facing each species. In vertebrates, dramatic and diverse adaptations to the chemical environment are possible because of the hierarchical structure of the olfactory receptor (OR) gene superfamily: expansion or contraction of OR subfamilies accompanies major changes in habitat and lifestyle; independent selection on OR subfamilies can permit local adaptation or conserved chemical communication; and genetic variation in single OR genes can alter odor percepts and behaviors driven by precise chemical cues. However, this genetic flexibility contrasts with the relatively fixed neural architecture of the vertebrate olfactory system, which requires that new olfactory receptors integrate into segregated and functionally distinct neural pathways. This organization allows evolution to couple critical chemical signals with selectively advantageous responses, but also constrains relationships between olfactory receptors and behavior. The coevolution of the OR repertoire and the olfactory system therefore reveals general principles of how the brain solves specific sensory problems and how it adapts to new ones.

Digital ethnography and the social dimension of introspection: an empirical study in two Colombian schools.

We developed a teaching-led research project to empirically ground methodological reflection about digital ethnography. Drawing on Cordelois' collective ethnographic observation approach, fifteen emerging professionals (from a private general education university and a Police Academy in Bogota) collaborated in a method seminar on digital ethnography. They worked in cross-institutional research teams, each carrying SenseCams for 3 days. Students had a dual role as both participants and observers during self-confrontation interviews. The research design enabled emerging professionals to introspect about what it is to be a member of their institution. The SenseCam provided an additional opportunity for observation as it elicited different reactions in the two institutions. The fact that SenseCams produce sequential accounts of activity as well as its situated nature made apparent the autonomy to study and solve daily issues (e.g. transport, security, commitments) by students from the university, while students in the police academy are more focused on responding to unforeseen activities (e.g. police services, unexpected requests). Finally, our research highlights the relevance of the social dimension of introspection for digital ethnography. How digital data that captures an individual perspective is negotiated in a group becomes a key methodological question.

Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection.

Although many transcription factors are known to control important aspects of neural development, the genome-wide programs that are directly regulated by these factors are not known. We have characterized the genetic program that is activated by MEF2, a key regulator of activity-dependent synapse development. These MEF2 target genes have diverse functions at synapses, revealing a broad role for MEF2 in synapse development. Several of the MEF2 targets are mutated in human neurological disorders including epilepsy and autism spectrum disorders, suggesting that these disorders may be caused by disruption of an activity-dependent gene program that controls synapse development. Our analyses also reveal that neuronal activity promotes alternative polyadenylation site usage at many of the MEF2 target genes, leading to the production of truncated mRNAs that may have different functions than their full-length counterparts. Taken together, these analyses suggest that the ubiquitously expressed transcription factor MEF2 regulates an intricate transcriptional program in neurons that controls synapse development.