Nicotinic Receptor Subtype-Selective Circuit Patterns in the Subthalamic Nucleus

The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in the STN effectively alleviate motor symptoms in movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about the mechanisms of cholinergic modulation in the STN, we studied cellular and circuit aspects of nicotinic acetylcholine receptors (nAChRs) in mouse STN. We discovered two largely divergent microcircuits in the STN; these are regulated in part by either α4β2 or α7 nAChRs. STN neurons containing α4β2 nAChRs (α4β2 neurons) received more glutamatergic inputs, and preferentially innervated GABAergic neurons in the substantia nigra pars reticulata. In contrast, STN neurons containing α7 nAChRs (α7 neurons) received more GABAergic inputs, and preferentially innervated dopaminergic neurons in the substantia nigra pars compacta. Interestingly, local electrical stimuli excited a majority (79%) of α4β2 neurons but exerted strong inhibition in 58% of α7 neurons, indicating an additional diversity of STN neurons: responses to electrical stimulation. Chronic exposure to nicotine selectively affects α4β2 nAChRs in STN: this treatment increased the number of α4β2 neurons, upregulated α4-containing nAChR number and sensitivity, and enhanced the basal firing rate of α4β2 neurons both ex vivo and in vivo. Thus, chronic nicotine enhances the function of the microcircuit involving α4β2 nAChRs. This indicates chronic exposure to nicotinic agonist as a potential pharmacological intervention to alter selectively the balance between these two microcircuits, and may provide a means to inhibit substantia nigra dopaminergic neurons

Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways

The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms, we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons; however, although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders

Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization

The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with α4 nicotinic subunits containing a single point mutation, Leu^(9′) → Ala^(9′) in the pore-forming M2 domain, rendering α4* receptors hypersensitive to nicotine. Selective activation of α4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of α4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization

An Inquiry into Gradable Zero-Waste Apparel Design

The implementation of standardized grading production practices within the mass market has been challenging for scholars experimenting with zero-waste apparel design. The purpose of this research was to test the efficacy of the Carrico Zero-waste Banded Grading (CZWBG) technique, which utilizes bands inserted in strategic locations as a method of grading zero-waste patterns across various consumer categories. An additional purpose was to evaluate the ways in which this grading approach affected the aesthetic outcomes of garments across a size run, and to determine whether this method affected the overall design process of the designers involved. Through experimental research design, six design scholars successfully tested and incorporated the CZWBG technique in zero-waste one or two-piece apparel item(s), subsequently developing three sizes in an industry-specified size range for their product category. Each design was cut from zero-waste patterns in a mid-range size and graded up and down one–two sizes using an industry-standardized grading scale. The grading was achieved by varying the widths and lengths of strategically inserted bands of fabric or trim. The designers utilized various grading methods, textiles, pattern development methods, and size runs, showing that the CZWBG technique can successfully be applied across multiple consumer categories in the apparel industry.This article is published as Carrico, M.; Dragoo, S.L.; McKinney, E.; Stannard, C.; Moretz, C.; Rougeaux-Burnes, A. An Inquiry into Gradable Zero-Waste Apparel Design. Sustainability 2022, 14, 452. https://doi.org/10.3390/su14010452. Posted with permission.This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cite

Effects of Menthol on α3β4∗ Nicotinic Receptors

Manufacturers add menthol to roughly 30% of tobacco cigarettes sold in the US, and to an unknown fraction of other tobacco products and electronic cigarettes. Smokers of menthol cigarettes find it harder to quit smoking, raising questions about the mechanism of this apparently harmful menthol effect. Menthol modestly affects the pharmacokinetics of nicotine and acts as a chemical chaperone for nicotinic acetylcholine receptors (nAChRs) [1]. In this study, we have investigated the effects of menthol on α3β4∗ nAChRs, which are mostly expressed in medial habenula (MHb) - interpeduncular nucleus (IPN) circuit: a key mediator of nicotine's aversive properties and withdrawal [2]. Fluorescently labeled α3 and β4 subunits are transiently expressed in Neuro-2a cells to form monomers, and oligomers. Using a Förster Resonance Energy Transfer (FRET) micro-spectroscopy method [3], we have found that menthol up-regulates α3 subunit while having no effects on β4 subunit and α3β4 pentamer numbers. Our results also show that menthol favors (α3)3(β4)2 stoichiometry over (α3)2(β4)3 stoichiometry. However, the study using Total Internal Reflection Fluorescence Microscopy (TIRFM) reveals that though menthol up-regulates α3 subunit numbers in peripheral Endoplasmic Reticulum, it decreases the α3β4 receptor numbers at the plasma membrane

Effects of Menthol on α3β4∗ Nicotinic Receptors

Manufacturers add menthol to roughly 30% of tobacco cigarettes sold in the US, and to an unknown fraction of other tobacco products and electronic cigarettes. Smokers of menthol cigarettes find it harder to quit smoking, raising questions about the mechanism of this apparently harmful menthol effect. Menthol modestly affects the pharmacokinetics of nicotine and acts as a chemical chaperone for nicotinic acetylcholine receptors (nAChRs) [1]. In this study, we have investigated the effects of menthol on α3β4∗ nAChRs, which are mostly expressed in medial habenula (MHb) - interpeduncular nucleus (IPN) circuit: a key mediator of nicotine's aversive properties and withdrawal [2]. Fluorescently labeled α3 and β4 subunits are transiently expressed in Neuro-2a cells to form monomers, and oligomers. Using a Förster Resonance Energy Transfer (FRET) micro-spectroscopy method [3], we have found that menthol up-regulates α3 subunit while having no effects on β4 subunit and α3β4 pentamer numbers. Our results also show that menthol favors (α3)3(β4)2 stoichiometry over (α3)2(β4)3 stoichiometry. However, the study using Total Internal Reflection Fluorescence Microscopy (TIRFM) reveals that though menthol up-regulates α3 subunit numbers in peripheral Endoplasmic Reticulum, it decreases the α3β4 receptor numbers at the plasma membrane