Mol Neurobiol. 2020 Oct 24. doi: 10.1007/s12035-020-02169-w. Online ahead of print.
Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic functions and cognition in the nervous system. Two enzymes, farnesyltransferase (FT) and geranylgeranyltransferase type I (GGT), are essential for the prenylation process. Genetic reduction of FT or GGT ameliorates neuropathology but only FT haplodeficiency rescues cognitive function in transgenic mice of Alzheimer's disease. A follow-up study showed that systemic or forebrain neuron-specific deficiency of GGT leads to synaptic and cognitive deficits under physiological conditions. Whether FT plays different roles in shaping neuronal functions and cognition remains elusive. This study shows that in contrast to the detrimental effects of GGT reduction, systemic haplodeficiency of FT has little to no impact on hippocampal synaptic plasticity and cognition. However, forebrain neuron-specific FT deletion also leads to reduced synaptic plasticity, memory retention, and hippocampal dendritic spine density. Furthermore, a novel prenylomic analysis identifies distinct pools of prenylated proteins that are affected in the brain of forebrain neuron-specific FT and GGT knockout mice, respectively. Taken together, this study uncovers that physiological levels of FT and GGT in neurons are essential for normal synaptic/cognitive functions and that the prenylation status of specific signaling molecules regulates neuronal functions.
Stem Cell Reports. 2020 Oct 13;15(4):804-810. doi: 10.1016/j.stemcr.2020.08.018. Epub 2020 Oct 1.
We report findings from a new survey of US public attitudes toward human-animal chimeric embryo (HACE) research, designed to compare with recently reported Japanese survey data. We find that 59% of the US public can personally accept the process of injecting human induced pluripotent stem cells into genetically modified swine embryos and having human tissues produced in a pig's body transplanted into a human. This is greater acceptance than in Japan, and there is even strong acceptance among those with strong religious affiliations and who self-identify as conservatives. We argue that strong public support for HACE research, as well as the emerging literature suggesting that humanization of research animals is very unlikely, should compel the NIH to lift its current moratorium on HACE research.
Biol Lett. 2020 Sep;16(9):20200573. doi: 10.1098/rsbl.2020.0573. Epub 2020 Sep 23.
For many animals, navigating their environment requires an ability to organize continuous streams of sensory input into discrete 'perceptual objects' that correspond to physical entities in visual and auditory scenes. The human visual and auditory systems follow several Gestalt laws of perceptual organization to bind constituent features into coherent perceptual objects. A largely unexplored question is whether nonhuman animals follow similar Gestalt laws in perceiving behaviourally relevant stimuli, such as communication signals. We used females of Cope's grey treefrog (Hyla chrysoscelis) to test the hypothesis that temporal coherence-a powerful Gestalt principle in human auditory scene analysis-promotes perceptual binding in forming auditory objects of species-typical vocalizations. According to the principle of temporal coherence, sound elements that start and stop at the same time or that modulate coherently over time are likely to become bound together into the same auditory object. We found that the natural temporal coherence between two spectral components of advertisement calls promotes their perceptual binding into auditory objects of advertisement calls. Our findings confirm the broad ecological validity of temporal coherence as a Gestalt law of auditory perceptual organization guiding the formation of biologically relevant perceptual objects in animal behaviour.
Lung-to-ear sound transmission does not improve directional hearing in green treefrogs (<em>Hyla cinerea</em>)
J Exp Biol. 2020 Sep 6:jeb.232421. doi: 10.1242/jeb.232421. Online ahead of print.
Amphibians are unique among extant vertebrates in having middle ear cavities that are internally coupled to each other and to the lungs. In frogs, the lung-to-ear sound transmission pathway can influence the tympanum's inherent directionality, but what role such effects might play in directional hearing remain unclear. In this study of the American green treefrog (Hyla cinerea), we tested the hypothesis that the lung-to-ear sound transmission pathway functions to improve directional hearing, particularly in the context of intraspecific sexual communication. Using laser vibrometry, we measured the tympanum's vibration amplitude in females in response to a frequency modulated sweep presented from 12 sound incidence angles in azimuth. Tympanum directionality was determined across three states of lung inflation (inflated, deflated, reinflated) both for a single tympanum in the form of the vibration amplitude difference (VAD) and for binaural comparisons in the form of the interaural vibration amplitude difference (IVAD). The state of lung inflation had negligible effects (typically less than 0.5 dB) on both VADs and IVADs at frequencies emphasized in the advertisement calls produced by conspecific males (834 Hz and 2730 Hz). Directionality at the peak resonance frequency of the lungs (1558 Hz) was improved by≅3 dB for a single tympanum when the lungs were inflated versus deflated, but IVADs were not impacted by the state of lung inflation. Based on these results, we reject the hypothesis that the lung-to-ear sound transmission pathway functions to improve directional hearing in frogs.
Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment
Mol Ther Nucleic Acids. 2020 Sep 4;21:1006-1016. doi: 10.1016/j.omtn.2020.07.030. Epub 2020 Jul 25.
Spinocerebellar ataxia type 1 (SCA1) is a lethal, autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in the ATAXIN-1 (ATXN1) protein. Preclinical studies demonstrate the therapeutic efficacy of approaches that target and reduce Atxn1 expression in a non-allele-specific manner. However, studies using Atxn1-/- mice raise cautionary notes that therapeutic reductions of ATXN1 might lead to undesirable effects such as reduction in the activity of the tumor suppressor Capicua (CIC), activation of the protease β-secretase 1 (BACE1) and subsequent increased amyloidogenic cleavage of the amyloid precursor protein (APP), or a reduction in hippocampal neuronal precursor cells that would impact hippocampal function. Here, we tested whether an antisense oligonucleotide (ASO)-mediated reduction of Atxn1 produced unwanted effects involving BACE1, CIC activity, or reduction in hippocampal neuronal precursor cells. Notably, no effects on BACE1, CIC tumor suppressor function, or number of hippocampal neuronal precursor cells were found in mice subjected to a chronic in vivo ASO-mediated reduction of Atxn1. These data provide further support for targeted reductions of ATXN1 as a therapeutic approach for SCA1.
Hippocampus. 2020 Aug 18. doi: 10.1002/hipo.23250. Online ahead of print.
Deliberation is thought to involve the internal simulation of the outcomes of candidate actions, the valuation of those outcomes, and the selection of the actions with the highest expected value. While it is known that deliberation involves prefrontal cortical areas, specifically the dorsomedial prefrontal cortex (dmPFC), as well as the hippocampus (HPC) and other brain regions, how these areas process prospective information and select actions is not well understood. We recorded simultaneously from ensembles in dmPFC and CA1 of dorsal HPC in rats during performance of a spatial contingency switching task, and examined the relationships between spatial and reward encoding in these two areas during deliberation at the choice point. We found that CA1 and dmPFC represented either goal locations or the current position simultaneously, but that when goal locations were encoded, HPC and dmPFC did not always represent the same goal location. Ensemble activity in dmPFC predicted when HPC would represent goal locations, but on a broad timescale on the order of seconds. Also, reward encoding in dmPFC increased during hippocampal theta cycles where CA1 ensembles represented the goal location. These results suggest that dmPFC and HPC share prospective information during deliberation, that dmPFC may influence whether HPC represents prospective information, and that information recalled about goal locations by HPC may be integrated into dmPFC reward representations on fast timescales.
Bidirectional sex-dependent regulation of α6 and β3 nicotinic acetylcholine receptors by protein kinase Cε
Addict Biol. 2020 Aug 10:e12954. doi: 10.1111/adb.12954. Online ahead of print.
Nicotine and alcohol are the most commonly abused substances worldwide and are frequently coabused. Nicotinic acetylcholine receptors (nAChRs) containing the α6 and β3 subunits are expressed in neural reward circuits and are critical for nicotine and alcohol reward. nAChRs are dynamically regulated by signaling molecules such as protein kinase C epsilon (PKCε), which impact transcription of α6 and β3 subunit mRNA (Chrna6 and Chrnb3, respectively). Previous work found decreased expression of Chrna6 and Chrnb3 transcripts in the ventral midbrain of male PKCε-/- mice, who also consume less nicotine and alcohol compared with wild-type (WT) littermates. Using RT-qPCR, we show that female PKCε-/- mice have higher expression of Chrna6 and Chrnb3 transcripts in the ventral midbrain, which functionally impacts nAChR-dependent behavior as female but not male PKCε-/- mice exhibit locomotor hypersensitivity to low-dose (0.25 mg/kg i.p.) nicotine. Female PKCε-/- mice show no differences in alcohol-induced sedation in the loss-of-righting reflex assay (4.0 g/kg i.p.) compared with WT littermates, whereas male PKCε-/- mice have enhanced sedation compared with WT mice. Female PKCε-/- mice also show reduced immobility time in response to varenicline (1.0 mg/kg i.p.) compared with WT littermates in the tail suspension test, and this effect was absent in male mice. Additionally, we found that female PKCε-/- mice show altered alcohol and nicotine consumption patterns in chronic voluntary two-bottle choice assays. Our data reveal a bidirectional effect of sex in the transcriptional regulation of nicotinic receptors by PKCε, highlighting the importance of studying both sexes in preclinical animal models.
J Neurosci. 2020 Sep 2;40(36):6910-6926. doi: 10.1523/JNEUROSCI.0763-20.2020. Epub 2020 Aug 7.
Here we examine what effects acute manipulation of the cerebellum, a canonically motor structure, can have on the hippocampus, a canonically cognitive structure. In male and female mice, acute perturbation of the cerebellar vermis (lobule 4/5) or simplex produced reliable and specific effects in hippocampal function at cellular, population, and behavioral levels, including evoked local field potentials, increased hippocampal cFos expression, and altered CA1 calcium event rate, amplitudes, and correlated activity. We additionally noted a selective deficit on an object location memory task, which requires objection-location pairing. We therefore combined cerebellar optogenetic stimulation and CA1 calcium imaging with an object-exploration task, and found that cerebellar stimulation reduced the representation of place fields near objects, and prevented a shift in representation to the novel location when an object was moved. Together, these results clearly demonstrate that acute modulation of the cerebellum alters hippocampal function, and further illustrates that the cerebellum can influence cognitive domains.SIGNIFICANCE STATEMENT The cerebellum, a canonically motor-related structure, is being increasingly recognized for its influence on nonmotor functions and structures. The hippocampus is a brain region critical for cognitive functions, such as episodic memory and spatial navigation. To investigate how modulation of the cerebellum may impact the hippocampus, we stimulated two sites of the cerebellar cortex and examined hippocampal function at multiple levels. We found that cerebellar stimulation strongly modulates hippocampal activity, disrupts spatial memory, and alters object-location processing. Therefore, a canonically cognitive brain area, the hippocampus, is sensitive to cerebellar modulation.
Focused Ultrasound Neuromodulation and the Confounds of Intracellular Electrophysiological Investigation
eNeuro. 2020 Aug 24;7(4):ENEURO.0213-20.2020. doi: 10.1523/ENEURO.0213-20.2020. Print 2020 Jul/Aug.
Focused ultrasound (US) can modulate neuronal activity noninvasively with high spatial specificity. In intact nervous systems, however, efforts to determine its enigmatic mode of efficacy have been confounded by the indirect effects of US on mechanosensitive sensory cells and the inability to target equivalent populations of cells with precision across preparations. Single-cell approaches, either via cultured mammalian neurons or tractable invertebrate neural systems, hold great promise for elucidating the cellular mechanisms underlying the actions of US. Here, we present evidence from the medicinal leech, Hirudo verbana, that researchers should apply caution when using US in conjunction with single-cell electrophysiological recording techniques, including sharp-electrode intracellular recording. Although we found that US could elicit depolarization of the resting membrane potential of single neurons, a finding with precedent, we determined that this effect and others could be reliably mimicked via subtle manual displacement of the recording electrode. Because focused US is known to induce resonance of recording electrodes, we aimed to determine how similarly US-induced depolarizations matched those produced by micro movements of a sharp glass electrode, a phenomenon we believe can account for purported depolarizations measured in this manner. Furthermore, we show that when clonally related homologous neurons, which are essentially isopotential, are impaled before the application of focused US, they show a statistically significant change in their membrane potential as compared with the homologous cells that received US with no initial impalement. Future investigations into US's cellular effects should attempt to control for potential electrode resonance or use alternative recording strategies.
Eye alignment changes caused by sustained GDNF treatment of an extraocular muscle in infant non-human primates
Sci Rep. 2020 Jul 17;10(1):11927. doi: 10.1038/s41598-020-68743-3.
The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested. Six infant non-human primates received a pellet containing GDNF, releasing 2 µg/day for 90 days, on one medial rectus muscle. Eye alignment was assessed up to 6 months. Five of the six animals showed a slow decrease in eye misalignment from the significant exotropia present at birth, ending with approximately 10° of exotropia. Controls became orthotropic. Misalignment averaged 8° three months after treatment ended. After sustained GDNF treatment, few changes were seen in mean myofiber cross-sectional areas compared to age-matched naïve controls. Neuromuscular junction number was unaltered in the medial rectus muscles, but were significantly reduced in the untreated lateral recti. Neuromuscular junctions on slow fibers became multiply innervated after this sustained GDNF treatment. Pitx2-positive cells significantly decreased in treated and contralateral medial rectus muscles. Our study suggests that balanced GDNF signaling plays a role in normal development and maintenance of orthotropia. Sustained GDNF treatment of one medial rectus muscle resulted in a measurable misalignment largely maintained 3 months after treatment ended. Structural changes suggest mechanisms for producing an imbalance in muscle function.